New trials for NRAS and Mucosal Melanoma patients - ASCO 2021

Melanoma sucks great big green hairy stinky wizard balls for everyone!  Still, it remains even more challenging for NRAS positive and mucosal melanoma patients.  Here are prior posts on Mucosal Melanoma. Now, there's this neoadjuvant trial:

A phase 2 clinical trial of neoadjuvant anti-PD-1 ab (toripalimab) plus axitinib in resectable mucosal melanoma.  Cui, Wang, Lian, et al.  ASCO 2021.

Background:  The outcome of patients (pts) with resectable mucosal melanoma (MM) is still poor. Toripalimab combined with axitinib has shown impressive results in metastatic MM with an ORR of 48.3% and a median PFS of 7.5 months in a phase 1b trial. It was hypothesized that this combination therapy might cause pathologic response in neoadjuvant setting for resectable MM, so we conducted this single arm phase 2 trial.

Methods:  Eligible pts were adults (aged 18 to 75) with histologically confirmed resectable (localized or regional lymph node metastasis) MM disease. Exclusion criteria included ocular or unknown primary melanoma, distant metastatic disease or previous use of anti PD-1 ab. Pts received toripalimab 3 mg/kg Q2W plus axitinib 5 mg BID for 8 weeks as neoadjuvant therapy, then surgery and the adjuvant toripalimab 3 mg/kg Q2W starting 2±1week after surgery for totally 52 weeks. The primary end point is pathologic response rate according to the International Neoadjuvant Melanoma Consortium (pCR+pPR, pCR is defined as the complete absence of residual viable tumor and pPR less than/= to 50% of viable tumor cells). The secondary end point is RFS in the ITT population.

Results:  From Aug 2019 to Dec 2020, 21 pts have been eligible and enrolled. Basic characteristics: median age 62 years; M: F 28.6% : 71.4%; primary sites 8 female genital(1urethra, 7vagina), 5 esophagus, 4 ano-rectal, 4 head and neck(3 nasal,1 oral), in which 47.6% localized disease (T3/4 60%), 52.4% regional lymphatic disease; Gene mutation: 4 cKit (1 amplification), 2 Nras,1 Braf (N581), 1mTOR. This therapy was tolerable with grade 3-4 treatment related AEs of 23.8% (liver dysfunction 14.3%, hyperglycemia 9.5% and hypertension 4.8%). 13 pts had received surgeries (local excision 30.8%, wide excision ± CLND72.7%)and 5 pts still in neoadjuvant treatment. One patient was inoperable for bone metastasis, and 2 pts withdrew for covid 19 epidemic. At a median follow up time of 59 weeks, the pathologic response rate was 28.6% (4/14, 2 pCR, 2pPR). Of the post-surgical specimens, 61.5% (8/13) showed significant TIL infiltration, with 38.5% Brisk and 23.1% Nonbrisk according to the definition of AJCC 8th edition. Plenty of plasma cells, histiocyte and pigment with hyaline fibrosis were also found in responders. No recurrence or metastasis was observed in responders until now, with a RFS reaching more than 58weeks. 5 pts with pNR (greater than 50% viable tumor cells) got disease progression, with 1 local recurrence, 1 regional lymphatic metastasis, and 3 distant metastases. The median RFS has not been reached.

Conclusions:  Neoadjuvant toripalimab plus axitinib in resectable MM has shown promising pathologic responses with good tolerance, which supports further investigation of neoadjuvant therapies in MM. Survival is still in follow-up. Clinical trial information: NCT04180995.

And this report on patients with unresectable disease:

Atezolizumab in combination with bevacizumab in patients with unresectable locally advanced or metastatic mucosal melanoma: Interim analysis of an open-label phase II trial.  Si, Fang, Chen, et al.  ASCO 2021.

Background:  Mucosal melanoma is a rare malignant melanoma in Caucasians but ranks the second most common subtype in the Asian population. It is more often diagnosed at an advanced stage and responds poorly to current PD-1/PD-L1 inhibitors. Here we report the interim analysis results of ML41186, an open-label, multicenter, single-arm phase II study, aiming to evaluate the efficacy and safety of atezolizumab in combination with bevacizumab in patients (pts) with advanced mucosal melanoma.

Methods:  Eligible pts aged 18 to 75 years with histologically confirmed unresectable locally advanced or metastatic mucosal melanoma had at least one measurable lesion per RECIST version 1.1 at baseline, with an ECOG PS 0 or 1 and adequate hematologic and organ function. ML41186 is a Simon two-stage design study, if 22 pts completed ORR evaluation and more than 3 pts respond in stage I, the study then continue to Stage II. Atezolizumab and bevacizumab were administered at a fixed dose of 1200 mg and 7.5 mg/kg Q3W respectively (on day 1 of each 21-day cycle) until unacceptable toxicity or loss of clinical benefit. The primary endpoint is the objective response rate (ORR). The secondary endpoints include progression-free survival (PFS), duration of objective response (DoR), disease control rate (DCR), and safety.

Results:  By the cut-off date of 9th September 2020, 35 pts has been enrolled, among whom 22 pts in the stage I analysis set has completed two efficacy evaluation, while 28 pts (full analysis set) has completed at least one efficacy evaluation. In ITT populations (n=35), mean age was 58.9 years with 10 (28%) pts had ECOG PS of 1. LDH level elevated in 9 (25.7%) pts. More than half pts (19, 54.3%) had metastatic mucosal melanoma, of whom 3 (15.8%) pts had more than 3 metastasis sites and 4 (21.1%) pts had liver metastasis. In stage I analysis set (n=22), the best confirmed ORR was 36.4% (17.0%-59.3%). Median progression-free survival was 5.32 months (1.58-not reached), and the best confirmed DCR was 59.1% (36.4%-79.3%). The median confirmed DoR was not reached ( 2.76-NR). In the full analysis set (n=28), the unconfirmed ORR was 42.9% (24.5%-62.8%). In ITT populations (n=35), 28 pts (80%) experienced at least one adverse event (AE) and 5 pts (14.3%) experienced at least one grade 3-4 AEs. Only one patient experienced AE leading to treatment discontinuation. One patient died of autoimmune lung disease.

Conclusions:  The combination of atezolizumab plus bevacizumab showed promising benefit and was tolerable in pts with advanced mucosal melanoma. At the time of this interim analysis, the primary endpoint did not cross the futility boundary, thus the study will run into Stage II. Clinical trial information: NCT04091217.

The NRAS mutation has it's own challenges.  Here are prior NRAS Reports.  Now, there are these:

A phase Ib trial of belvarafenib in combination with cobimetinib in patients with advanced solid tumors: Interim results of dose-escalation and patients with NRAS-mutant melanoma of dose-expansion. Shin, Lee, Kim, et al.  ASCO 2021.

Background:  Belvarafenib, a potent, selective RAF dimer (type II) inhibitor, exhibits clinical activity in BRAFV600E- and NRAS-mutant (NRASm) melanoma patients. The combination of belvarafenib and cobimetinib more potently and durably suppressed MAPK pathway output and tumor growth than currently approved BRAF/MEK inhibitors in RAS- or RAF-mutant tumor xenograft models. This interim results of phase 1b trial evaluated the safety, tolerability, pharmacokinetics, and anti-tumor activity of belvarafenib in combination with cobimetinib in dose-escalation and NRASm melanoma patients among the 9 indication-specific expansion cohorts.

Methods: Patients with locally advanced or metastatic solid tumors harboring RAS or RAF mutation were enrolled in the dose-escalation stage, and the recommended doses were explored in the indication-specific expansion stage. Patients in the dose-escalation stage were given belvarafenib (100–300mg BID) in combination with cobimetinib (20–40mg QD) and the dose of subsequent cohorts was decided by a traditional 3+3 design and safety profile. Primary objectives were to evaluate the safety and tolerability, to estimate the maximum tolerable dose, and to identify the RP2D of the combination.

Results:  A total of 32 patients enrolled were evaluated for safety analysis; 19 were enrolled in 4 cohorts in the dose-escalation stage and 13 NRASm melanoma patients were enrolled in the indication-specific expansion stage (cut-off date: 2020-7-24). There were 3 DLTs (G3 colitis, G3 diarrhoea, G3 nausea) in 2 patients at the starting dose of belvarafenib 200mg BID continuously and cobimetinib 40mg QD 21/7 schedule. Belvarafenib dose was escalated to 300mg BID with cobimetinib 20mg QD, which did not result in DLTs. The most common treatment-emergent adverse events that occurred in ≥30% of 32 patients were dermatitis acneiform, diarrhoea, constipation, and increase in blood creatine phosphokinase. Two combination doses were explored in the indication-specific expansion stage. Out of the 9 indication-specific expansion cohorts, NRASm melanoma patients exhibited promising efficacy signal; 5 patients reached partial responses (PRs) out of 13, giving a response rate of 38.5%. Among them, 11 had been previously treated with checkpoint inhibitors (CPIs), including 5 (45.5%) who achieved PR. The median PFS was 7.3 months and 5 patients remained on the treatment at the cut-off date.

Conclusions: Belvarafenib in combination with cobimetinib showed acceptable tolerability and encouraging efficacy in NRASm melanoma, and in those with prior CPI treatment. Further research is ongoing in other cohorts (Clinicaltrial.gov, NCT03284502) and in NRASm melanoma (reference GO42273 by clinicaltrials.gov ID number). Clinical trial information: NCT03284502.

Fingers crossed that there will soon be viable treatments for all melanoma ratties.  For what it's worth - c

ASCO 2021 - NEOadjuvant treatments - immunotherapy vs targeted and nivo plus relatlimab (anti-LAG3)

Having covered adjuvant therapy yesterday, today I turn to NEOadjuvant treatments.  In 2018 I wrote -

"Adjuvant therapy, is when a treatment is given AFTER signs of obvious disease have been removed, usually with surgery.  And we have very good data that adjuvant treatments, both with targeted and immunotherapy, work in melanoma to prevent progression in many of those patients.  After all, that is what the NED Stage IV ratties in my nivo trial proved from 2010 - 2013!!!!  NEO-adjuvant therapy, is when a treatment is given BEFORE melanoma has been removed. "

Here are a zillion Neoadjuvant reports.  Now, there are these:

Pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC).  Menzies, Amaria, Rozeman, et al.  Nat Med.  Feb 2021.

The association among pathological response, recurrence-free survival (RFS) and overall survival (OS) with neoadjuvant therapy in melanoma remains unclear. In this study, we pooled data from six clinical trials of anti-PD-1-based immunotherapy or BRAF/MEK targeted therapy. In total, 192 patients were included; 141 received immunotherapy (104, combination of ipilimumab and nivolumab; 37, anti-PD-1 monotherapy), and 51 received targeted therapy. A pathological complete response (pCR) occurred in 40% of patients: 47% with targeted therapy and 33% with immunotherapy (43% combination and 20% monotherapy). pCR correlated with improved RFS (pCR 2-year 89% versus no pCR 50%) and OS (pCR 2-year OS 95% versus no pCR 83%). In patients with pCR, near pCR or partial pathological response with immunotherapy, very few relapses were seen (2-year RFS 96%), and, at this writing, no patient has died from melanoma, whereas, even with pCR from targeted therapy, the 2-year RFS was only 79%, and OS was only 91%. Pathological response should be an early surrogate endpoint for clinical trials and a new benchmark for development and approval in melanoma.

Hmmm....  While targeted therapy is almost magical in BRAF positive melanoma peeps for melting away tumors and those responses have proven at times to be durable, that durability can be fickle.  This report (while not necessarily about neoadjuvant administration) is similarly illuminating:

First-line immunotherapy versus targeted therapy in patients with BRAF-mutant advanced melanoma: a real-world analysis.  Pavlick, Zhao, Lee, et al.  Future Oncol. Feb 2021.

Aim: To compare effectiveness of nivolumab + ipilimumab (NIVO + IPI) versus BRAF + MEK inhibitors (BRAFi + MEKi) in patients with BRAF-mutant advanced melanoma in the real-world setting. 

Materials & methods: This study used the Flatiron Health electronic medical record database. Results: After adjusting for differences in baseline characteristics, NIVO + IPI was associated with a 32% reduction in risk of death versus BRAFi + MEKi. At a mean follow-up of 15-16 months, 64% of NIVO + IPI patients and 43% of BRAFi + MEKi patients were alive; subsequent therapy was administered to 33 and 41% of patients, respectively. After first-line NIVO + IPI, 20% of patients died before subsequent therapy, whereas 32% died after first-line BRAFi + MEKi. 

Conclusion: In this real-world study, patients treated with first-line NIVO + IPI showed significant survival benefit versus those receiving first-line BRAFi + MEKi.

Then there's this, from ASCO....

Neoadjuvant and adjuvant nivolumab (nivo) with anti-LAG3 antibody relatlimab (rela) for patients (pts) with resectable clinical stage III melanoma.  Amaria, Postow, Tetzlaff, et al.  ASCO 2021

Background:  Neoadjuvant therapy (NT) for pts with clinical stage III melanoma remains an active area of research interest. Recent NT trial data demonstrates that achieving a pathologic complete response (pCR) correlates with improved relapse-free (RFS) and overall survival (OS). Checkpoint inhibitor (CPI) NT with either high or low dose ipilimumab and nivolumab regimens produces a high pCR rate of 30-45% but with grade 3-4 toxicity rate of 20-90%. In metastatic melanoma (MM), the combination of nivo with rela (anti Lymphocyte Activation Gene-3 antibody) has demonstrated a favorable toxicity profile and responses in both CPI-naïve and refractory MM. We hypothesized that NT with nivo + rela will safely achieve high pCR rates and provide insights into mechanisms of response and resistance to this regimen.

Methods:  We conducted a multi-institutional, investigator-initiated single arm study (NCT02519322) enrolling pts with clinical stage III or oligometastatic stage IV melanoma with RECIST 1.1 measurable, surgically-resectable disease. Pts were enrolled at 2 sites and received nivo 480mg IV with rela 160mg IV on wks 1 and 5. Radiographic response was assessed after completion of NT; surgery was conducted at wk 9 and specimens were assessed for pathologic response per established criteria. Pts received up to 10 additional doses of nivo and rela after surgery, with scans every 3 mo to assess for recurrence. The primary study objective was determination of pCR rate. Secondary objectives included safety, radiographic response by RECIST 1.1, event-free survival (EFS), RFS, and OS analyses. Blood and tissue were collected at baseline, at day 15, day 28, and at surgery for correlative analyses.

Results:  A total of 30 pts (19 males, median age 60) were enrolled with clinical stage IIIB/IIIC/IIID/IV (M1a) in 18/8/2/2 pts, respectively. 29 pts underwent surgery; 1 pt developed distant metastatic disease while on NT. pCR rate was 59% and near pCR ( less than10% viable tumor) was 7% for a major pathologic response (MPR, pCR + near pCR) of 66%. 7% of pts achieved a pPR (10-50% viable tumor) and 27% pNR (greater than/= to 50% viable tumor). RECIST ORR was 57%. With a median follow up of 16.2 mos, the 1-year EFS was 90%, RFS was 93%, and OS was 95%. 1-year RFS for MPR was 100% compared to 80% for non-MPR pts. There were no treatment related gr 3/4 AEs that arose during NT; 26% of pts had a gr 3/4 AE that began during adjuvant treatment.

Conclusions:  Neoadjuvant and adjuvant treatment with nivo and rela achieved high pCR and MPR rates with a favorable toxicity profile in the neoadjuvant and adjuvant settings. Pts with MPR had improved outcomes compared to non-MPR pts. Translational studies to discern mechanisms of response and resistance to this combination are underway. Clinical trial information: NCT02519322.

Perhaps neoadjuvant care will become the way of the future.  Thanks ratties.

best - c

Adjuvant therapy for melanoma - a history, the latest from ASCO 2021 and a remembering...

 I have been screaming about the need for adjuvant care since I became Stage IV with a zapped brain met and surgically removed lung met in April 2010 and could not attain a position in ongoing ipi trials because I had "no measurable disease".  After yet another met (surgically removed) to a tonsil in October of that year, I did gain placement in the adjuvant arm of a nivo trial being run by Weber (then of Moffitt in Tampa) that December.  Here's the report on how I and my 30 fellow ratties did, published in 2014:  C'est moi!!! Results from the 33 ratties in my Nivolumb/Opdivo trial...published!  

Since then, both targeted and immunotherapy have been FDA approved as adjuvant treatments for Stage III and IV melanoma patients. Here is a post with a break down of the science and FDA approvals from 2020:  ADJUVANT therapy for melanoma!!!!!!!!!!!!!! State of the science....  Here are a zillion additional posts, filled with the science, data and rants: All things Adjuvant 

Now there are these reports from earlier this year:

Novel adjuvant options for cutaneous melanoma.  Dimitriou, Long, Menzies.  Ann Oncol.  March 2021.

Background: Patients with resected stage III and IV melanoma have a high risk of recurrence. As the outcomes for patients with metastatic disease have improved dramatically over the past decade due to systemic therapy, more recently so too have the outcomes of patients with resected stage III and IV melanoma with the introduction of checkpoint inhibitor immunotherapy and targeted therapy in the adjuvant setting.

Results: Anti-programmed cell death protein 1 monotherapy and BRAF/MEK inhibitors are currently deemed standard of care for resected stage III melanoma. For patients with stage IIIB melanoma, 2-year and 3-year recurrence-free survival is approximately 72% and 65% for nivolumab, 70% and 65.7% for pembrolizumab and 68% and 60% for dabrafenib/trametinib, respectively. For stage IIIC  melanoma, 2-year and 3-year recurrence-free survival is 60% and 53.5% for nivolumab, 60% and 54.3% for pembrolizumab and 59% and 47% for dabrafenib/trametinib, respectively. Adjuvant treatment is recommended for patients with stage IIIB-IIID melanoma, and may be considered for patients with stage IIIA melanoma. For resected stage IV, nivolumab is the only approved agent; however, recent results from a phase II clinical trial show promising efficacy for combined ipilimumab and nivolumab as well. Long-term data are required to determine which therapy has the greatest impact on overall survival. Schedules, delivery and toxicity are also important factors to consider when selecting adjuvant treatment.

Conclusions: Randomized studies of patients with resected high-risk melanoma have shown that immunotherapy or targeted therapy improve recurrence-free survival compared with placebo/ipilimumab. In order to optimize these treatments, prognostic and predictive biomarkers, as well as strategies to reduce treatment-related toxicities and overcome resistance, are required. 

Adjuvant Therapy of High-Risk (Stages IIC-IV) Malignant Melanoma in the Post Interferon-Alpha Era: A Systematic Review and Meta-Analysis.  Christofyllakis, Pföhler, Bewarder, et al. Front Oncol.  Feb 2021.

Introduction: Multiple agents are approved in the adjuvant setting of completely resected high-risk (stages IIC-IV) malignant melanoma. Subgroups may benefit differently depending on the agent used. We performed a systematic review and meta-analysis to evaluate the efficiency and tolerability of available options in the post interferon era across following subgroups: patient age, stage, ulceration status, lymph node involvement, BRAF status.

Methods: The PubMed and Cochrane Library databases were searched without restriction in year of publication in June and September 2020. Data were extracted according to the PRISMA Guidelines from two authors independently and were pooled according to the random-effects model. The predefined primary outcome was recurrence-free survival (RFS). Post-data extraction it was noted that one trial (BRIM8) reported disease-free survival which was defined in the exact same way as RFS.

Results: Five prospective randomized placebo-controlled trials were included in the meta-analysis. The drug regimens included ipilimumab, pembrolizumab, nivolumab, nivolumab/ipilimumab, vemurafenib, and dabrafenib/trametinib. Adjuvant treatment was associated with a higher RFS than placebo. Nivolumab/ipilimumab in stage IV malignant melanoma was associated with the highest RFS benefit, followed by dabrafenib/trametinib in stage III BRAF-mutant melanoma. The presence of a BRAF mutation was associated with higher RFS rates compared to the wildtype group. Patient age did not influence outcomes. Immune checkpoint inhibitor monotherapy was associated with lower RFS in non-ulcerated melanoma. Patients with stage IIIA benefited equally from adjuvant treatment as those with stage IIIB/C. Nivolumab/ipilimumab and ipilimumab monotherapy were associated with higher toxicity.

Conclusion: Adjuvant therapy should not be withheld on account of advanced age or stage IIIA alone. The presence of a BRAF mutation is prognostically favorable in terms of RFS. BRAF/MEK inhibitors should be preferred in the adjuvant treatment of BRAF-mutant non-ulcerated melanoma.

Melanoma recurrence patterns and management after adjuvant targeted therapy: a multicentre analysis.  Bhave, Pallan, Long, et al.  Br J Cancer.  Feb 2021.

Background: Adjuvant targeted therapy (TT) improves relapse free survival in patients with resected BRAF mutant stage III melanoma. The outcomes and optimal management of patients who relapse after adjuvant TT is unknown.

Methods: Patients from twenty-one centres with recurrent melanoma after adjuvant TT were included. Disease characteristics, adjuvant therapy, recurrence, treatment at relapse and outcomes were examined.

Results: Eighty-five patients developed recurrent melanoma; nineteen (22%) during adjuvant TT. Median time to first recurrence was 18 months and median follow-up from first recurrence was 31 months. Fifty-eight (68%) patients received immunotherapy (IT) or TT as 1st line systemic therapy at either first or subsequent recurrence and had disease that was assessable for response. Response to anti-PD-1 (±trial agent), combination ipilimumab-nivolumab, TT rechallenge and ipilimumab monotherapy was 63%, 62% 25% and 10% respectively. Twenty-eight (33%) patients had died at census, all from melanoma. Two-year OS was 84% for anti-PD-1 therapy (±trial agent), 92% for combination ipilimumab and nivolumab, 49% for TT and 45% for ipilimumab monotherapy.

Conclusions: Patients who relapse after adjuvant TT respond well to subsequent anti-PD-1 based therapy and have outcomes similar to those seen when first line anti-PD-1 therapy is used in stage IV melanoma.

And these out of ASCO:

Management of resected stage III/IV melanoma with adjuvant immunotherapy.  Johnson, Atkinson, Bhave, et al.  ASCO 2021. 

Background:  Adjuvant anti-PD1 therapy reduces the risk of recurrence in resected stage III/IV melanoma and is now standard care. Limited data exist beyond registration trials. We sought to explore the use of adjuvant immunotherapy in routine clinical practice.

Methods:  Patients (pts) from 11 Australian centres who received adjuvant nivolumab (nivo) for resected stage III/IV melanoma were included in this study. Efficacy, toxicity, surveillance, recurrence characteristics, management and further treatment outcomes were examined.

Results: 471 pts received adjuvant nivo between 8/2018 to 3/2020. 318 (68%) were male, median age 64y (range 17-94), 28 (6%) were AJCC v8 IIIA, 194 (41%) IIIB, 175 (37%) IIIC, 11 (2%) IIID, and 63 (13%) IV. 65 (14%) pts had in-transit only disease, 152 (37%) pts were sentinel lymph node biopsy (SLNB+) and only 9 (6%) of these had CLND. 128 (27%) had BRAF mutant (BRAFmt) melanoma. Median time from resection to start of adjuvant nivo was 1.8 months (mo) (range 0.2-4.0). Median FU was 17.5 mo. 256 (54%) pts completed 12 months of nivo, 86 (18%) ceased early for toxicity, 76 (16%) for disease recurrence, 25 (5%) other reasons (COVID-19 8, co-morbidities 7, pt choice 10); 28 (6%) pts were still receiving nivo at data cut. Median duration of treatment was 10.4 mo (range 0-16.8). 117 (25%) pts recurred; 76 (65%) while ON nivo and 41 (35%) OFF nivo (greater than 1 month after last dose, including 20 pts who stopped early for toxicity). 24 mo RFS was 69%. Median time to recurrence was 6.0 mo. 56 (48%) had first recurrence with locoregional (LR) disease only and 61 (52%) had distant +/- LR recurrence. Of those who recurred with LR disease only, 46/56 (82%) underwent surgery, 15/46 (33%) then had adjuvant radiotherapy, and 15/46 (33%) had ‘second adjuvant’ therapy with BRAF/MEK inhibitors (15/21, 71% BRAFmt pts). 10/56 (37%) pts who recurred with LR disease subsequently recurred distantly. 58/80 (73%) pts received systemic therapy at either 1st or subsequent unresectable recurrence. For recurrences ON nivo, 18 pts received combination ipilimumab (ipi) and nivo (ORR 44%), 4 pts had ipi monotherapy (ORR 0%), 7 pts had anti-PD1 + investigational agent (ORR 57%), 11 pts had BRAF/MEK inhibitors (ORR 82%). 1 pt had PD with ongoing PD1 monotherapy. For recurrences OFF nivo, no patients responded to PD1 alone (n = 1) or with an investigational agent (n = 1), ipi+nivo (n = 3), ipi monotherapy (n = 4) or chemotherapy (n = 2); 6 pts received BRAF/MEK inhibitors (ORR 50%). 2-year OS was 92%.

Conclusions: Despite higher rates of discontinuation due to toxicity compared with clinical trial cohorts, the efficacy data appear similar. Most early recurrences are distant, and many with LR recurrence soon recur distantly thereafter. Second line adjuvant BRAF/MEK inhibitors are frequently used for resected LR recurrence. Both ipi+nivo and BRAF/MEK inhibitors appear to have activity after distant recurrence.

Final analysis of overall survival (OS) and relapse-free-survival (RFS) in the intergroup S1404 phase III randomized trial comparing either high-dose interferon (HDI) or ipilimumab to pembrolizumab in patients with high-risk resected melanoma. Grossmann, Othus, Patel, et al.  ASCO 2021. 

Background:   We assessed whether or not adjuvant pembrolizumab given over 1 year would improve OS and RFS in comparison to high dose ipilimumab (ipi10) or HDI - the two FDA-approved adjuvant treatments for high risk resected melanoma at the time of study design.

Methods:  Patients age 18 or greater with resected stages IIIA(N2), B, C and IV were eligible. Patients with CNS metastasis were excluded. [SO OVER THIS!!!!!!!!!!!!!!]  At entry, patients must have had complete staging and adequate surgery to render them free of melanoma including completion lymph node dissection for those with sentinel node positive disease. Prior therapy with PD-1 blockade, ipilimumab or interferon was not allowed. Two treatment arms were assigned based on stratification by stage, PD-L1 status (positive vs. negative vs. unknown), and intended control arm (HDI vs. Ipi10). Patients enrolled between 10/2015 and 8/2017 were randomized 1:1 to either the control arm [(1) interferon alfa-2b 20 MU/m2 IV days 1-5, weeks 1-4, followed by 10 MU/m2/d SC days 1, 3, and 5, weeks 5-52 (n=190), or (2) ipilimumab 10 mg/kg IV q3w for 4 doses, then q12w for up to 3 years (n=465)], or the experimental arm [pembrolizumab 200 mg IV q3w for 52 weeks (n=648)]. The study had three primary comparisons: 1) RFS among all patients, 2) OS among all patients, 3) OS among patients with PD-L1+ baseline biopsies. 

Results: 1,426 patients were screened and 1,345 patients were randomized with 11%, 49%, 34%, and 6% AJCC7 stage IIIA(N2), IIIB, IIIC and IV, respectively. This final analysis was performed per-protocol 3.5 years from the date the last patient was randomized, with 512 RFS and 199 OS events. The pembrolizumab group had a statistically significant improvement in RFS compared to the control group (pooled HDI and ipi10) with HR 0.740 (99.618% CI, 0.571 to 0.958). There was no statistically significant improvement in OS in the 1,303 eligible randomized overall patient population with HR 0.837 (96.3% CI, 0.622 to 1.297), or among the 1,070 (82%) patients with PD-L1 positive baseline biopsies with HR 0.883 (97.8% CI, 0.604 to 1.291). Gr 3/4/5 event rates were as follows: HDI 69/9/0%, ipi10 43/5/0.5% and pembrolizumab 17/2/0.3%.

Conclusions:  Pembrolizumab improves RFS but not OS compared to HDI or ipi10 in the adjuvant treatment of patients with high-risk resected melanoma. Pembrolizumab is a better tolerated adjuvant treatment regimen than HDI or Ipi10.  Clinical trial information: NCT02506153.

See study below! 

Propensity weighted indirect treatment comparison of nivolumab (NIVO) versus placebo (PBO) as adjuvant therapy for resected melanoma: A number needed to treat and overall survival analysis.  Weber, Poretta, Stwalley, et al.  ASCO 2021.

Background:  The CheckMate 238 trial demonstrated that NIVO improved recurrence free survival (RFS) vs. ipilimumab (IPI). The EORTC 18071 trial demonstrated that IPI improved RFS and overall survival (OS) vs. PBO. The current study pooled data from these two trials to indirectly assess the RFS and OS of NIVO vs. PBO and the numbers needed to treat (NNTs) for one additional recurrence-free survivor and survivor over 4 years.

Methods:  Patients with resected AJCC 7th edition stage IIIB/C cutaneous melanoma from CheckMate 238 (NIVO vs. IPI) and EORTC 18071 (IPI vs. PBO) were pooled together with inverse probability weighting to balance between-trial differences in baseline characteristics. NNTs were calculated for RFS and OS comparing NIVO vs. IPI and PBO over 4 years. To account for improved post-recurrence survival over time, a sensitivity analysis that adjusted for post-recurrence survival in the PBO arm of EORTC 18071 was performed.

Results:   A total of 278, 643, and 365 patients treated with NIVO, IPI, and PBO, respectively, were included. In the weighted samples, patients treated with NIVO had consistently higher RFS rates than those treated with IPI (HR [95% CI]: 0.69 [0.56, 0.85]) and PBO (HR: 0.49 [0.39, 0.61]). NIVO was associated with similar OS as IPI (HR: 0.80 [0.60, 1.08]) and superior OS compared to PBO (HR: 0.45 [0.33, 0.60]). At 4 years, the weighted RFS rate was 53.1% for NIVO, 41.8% for IPI, and 29.1% for PBO. The NNT to achieve one additional recurrence-free survivor was 4.2 for NIVO vs. PBO and 8.9 for NIVO vs. IPI. The NNT to obtain one additional survivor was 4.8 for NIVO vs. PBO and 22.2 for NIVO vs. IPI. The OS rate for PBO after adjusting for differences in post-recurrence treatments at 4 years was 64.1%, and the corresponding NNT of OS comparing NIVO vs. adjusted PBO was 8.5.

Conclusions:  In patients with resected AJCC 7th edition stage IIIB/C cutaneous melanoma, this indirect comparison showed that NIVO improved RFS and OS vs placebo, with OS improvement maintained after adjustment for post-recurrence therapy.

Like so much in melanoma, adjuvant therapy is not a sure thing.  Still, I am certain adjuvant nivo saved my life as a Stage IV patient spiraling into met after met in untenable physiologic locations.  

Thanks to all the mice and ratties who light our way.  I continue to hold ever so many, to whom my debt of gratitude will never be repaid, in my heart.  A few are remembered here ~ Oh, the people you'll meet...

And here:  Artie...a beautiful soul, an amazing knight. Merde!

And here:  Heavy heart, heavy lifting ~ for he was all of us...

I sill think of Steven, Joshie and all the others.  And today, news that I will never meet our dear Julie in person.  Even so, I will love her still, forever in appreciation of her wide smile, her incredible goodness and common sense.  I imagine she is looking down on us, from a beautiful vista, alongside her beloved camper that will never need repairs, on trips unspoiled by earthly troubles.  Be at peace, my dear friend.  We will always love you. Shalom. ~ les

Running Thoughts - Shades of Gray.

She was gray.  Completely.  Her hair.  Likely prematurely, given the bright and vivacious appearance of her mother who had driven her to the vaccination site.  Her eyes.  Once, they must have been mesmerizing; sparkling when she smiled. Today they were flat, resigned, without luster.  Her skin.  Sickly, coarsened, vaguely damp.  Her t-shirt.  Fashion clearly no longer mattered. Her tee had been chosen that morning because it was softened, almost thread bare, from many washings and sat easier than other garments on a frame that ached deep within her bones and burned like fire on the surface of her skin.

I was called to her car that morning due as much to the alarm her appearance and history caused among the nurses there to administer the vaccine, as to answer her questions.  

"Hello."

"Yes, mam."

Capecitabine.  Oxaliplatin.  Colon cancer.  Between treatments.  

Information exchanged.  History completed.  Answers, sorely limited in scope, given to the best of my ability.  Nurses advised to proceed with administration.  

As I walked back through the waiting cars, attaining a thumbs up from the occupants, I met the nurse with whom I worked, doing the same.

"I gave a 30 minute wait to a gray Chevy.  The passenger is in the midst of chemo.  If she feels faint, no cold compress or beverage."

A quizzical look.  "Okay," he said.

"Given the drugs she's taking, contact with cold items - within or without - can cause severe pain."

"I understand."

We parted to continue our rounds through the patients waiting in our lot.

It struck me as I walked away.  Understanding is very much a matter of degree.

                                                       ----------

I will not forget you, my dear.  May color return to your world. ~ les

ASCO 2021 - Outcomes of treatments on advanced disease - Reasons for HOPE!!!!!

 As disheartening as it can be to experience treatment that does not do all that we need it to or have dear ones who do not respond to current melanoma treatments - therapies for melanoma have come a long way, baby!!!!  Not only are more folks than ever before responding to therapy - these responses are proving durable!  Here are some outcome studies ~

Five-year overall survival from the anti-PD1 brain collaboration (ABC Study): Randomized phase 2 study of nivolumab (nivo) or nivo+ipilimumab (ipi) in patients (pts) with melanoma brain metastases (mets).  Georgina V. Long, Victoria Atkinson, Serigne Lo, et al.  ASCO 2021.

Background:  Preliminary data from the ABC (76 pts) and CheckMate 204 (94 pts) trials showed that nivo and nivo+ipi have activity in active melanoma brain metastases, with durable responses in a subset of pts. Here, we report updated 5-yr data from all pts enrolled on the ABC trial (NCT02374242).

Methods:  This open-label ph2 trial enrolled 3 cohorts of pts with active melanoma brain mets naïve to anti-PD1/PDL1/PDL2/CTLA4 from Nov 2014-Apr 2017. Pts with asymptomatic brain mets with no prior local brain therapy were randomised to cohort A (nivo 1mg/kg + ipi 3mg/kg, Q3Wx4, then nivo 3mg/kg Q2W) or cohort B (nivo 3mg/kg Q2W). Cohort C (nivo 3mg/kg Q2W) had brain mets i) that failed local therapy, ii) with neuro symptoms and/or iii) with leptomeningeal disease. Prior BRAF inhibitor (BRAFi) was allowed. The primary endpoint was best intracranial response (ICR) ≥wk12. Key secondary endpoints were IC PFS, overall PFS, OS, & safety.

Results: A total of 76 pts (med f/u 54 mo) were enrolled; median age 59y, 78% male. For cohorts A, B and C: elevated LDH 51%, 58% and 19%; V600BRAF 54%, 56% and 81%; prior BRAFi 23%, 24%, 75%. Efficacy and toxicity are shown in the table. There were no treatment-related deaths. 1/17 deaths in cohort A & 4/16 in cohort B were due to IC progression only.

Conclusions:  Nivo monotherapy and ipi+nivo are active in melanoma brain mets, with durable responses in the majority of patients who received ipi+nivo upfront. A study of upfront ipi+nivo+/-SRS is underway (NCT03340129).Clinical trial information: NCT02374242.

My takeaway - Immunotherapy works for brain mets!  BUT - most folks need the combo!!!!

As was mentioned briefly in yesterday's post - the ipi/nivo combo can be a rough road in regard to side effects and a good 40% of patients cannot tolerate all of the approved doses.  However, as far back ASCO 2016 we knew that folks who had to stop therapy early due to side effects, responded about as well as those who completed all doses:  ASCO 2016 - Nivo plus ipi, CheckMate 069 trial....18 month OS similar even if you stop meds due to side effects!!!  This study wanted to see if those responses were durable ~

Survival outcomes associated with fewer combination ipilimumab/nivolumab doses in advanced-stage melanoma.  Ma, Sun, Sitto, et al.  ASCO 2021.

Background:  Standard combination ipilimumab/nivolumab (I/N) is given as 4 induction doses for advanced stage melanoma. While many patients receive less than 4 doses due to treatment-related toxicities, it is unclear if fewer doses of I/N may still provide long term clinical benefit. Our aim is to determine if response assessment after 1 or 2 doses of I/N can predict long-term survival and if fewer doses of I/N can achieve similar survival outcomes.

Methods:  We performed a single-center, retrospective analysis on a cohort of patients with metastatic or unresectable melanoma from 2012 to 2020 who were treated with standard I/N. Cox regression of progression free survival (PFS) and overall survival (OS) models were performed to assess the relationship between response assessment after 1 or 2 doses of I/N and risk of progression and/or death. Clinical benefit response (CBR) was assessed, defined as SD (stable disease) + PR (partial response) + CR (complete response) by imaging or physical examination. Among patients who achieved a CBR after 1 or 2 doses of I/N, a multivariable Cox regression of survival was used to compare 3 or 4 vs 1 or 2 doses of I/N adjusted by age, gender, pre-treatment LDH level, BRAF mutation status, primary melanoma site, time to initial assessment, brain metastasis, and liver metastasis.

Results:  199 patients were identified and considered evaluable in our study. Median follow up was 28.8 months. Patients with CBR after 1 dose of I/N had improved PFS and OS compared to progressive disease (PD). Patients with CBR (vs PD) after 2 doses of I/N also had improved PFS and OS. The survival risk comparing 3 or 4 vs 1 or 2 doses of I/N were HR 0.82 for PFS and HR 0.56 for OS.

Conclusions:  Clinical benefit response (CBR) after 1 or 2 doses of I/N may be predictive of long-term survival in advanced stage melanoma. Patients who have CBR after 1 or 2 doses of I/N may achieve a similar survival benefit with fewer doses of I/N. Longer follow up and prospective studies are warranted to validate our findings.

Per this report, it looks as though those who showed benefit to therapy early, did indeed have similar survival, even when they took fewer that the 4 recommended combo doses!

This study looked at the characteristics of peeps who lived 5 years past immunotherapy for melanoma ~

Characteristics and probability of survival for patients with advanced melanoma who live five or more years after initial treatment with immune checkpoint blockade (ICB).  Loo, Goldman, Panageas, …Chapman…Wolchok…Postow, et al.  ASCO 2021.

Methods:  We retrospectively reviewed all patients treated at Memorial Sloan Kettering for unresectable stage III/IV melanoma who survived at least five years following their first dose of ICB (N = 151). Demographics, disease characteristics, and nature of progression were examined. Overall survival (OS) was calculated from 5 years post-ICB. Time to Treatment failure (TTF) was calculated conditionally from 5 years out until next therapy, progression, or death.

Results:  Of the 151 long-term survivors, median age at first ICB treatment was 62 years (range 22-83), with 101 (66.9%) male and 50 (33.1%) female patients. Stage at first ICB treatment was unresectable stage III (26, 17.2%), M1a (21,13.9%), M1b (39, 25.8%), M1c (52, 34.4%), M1d (13, 8.6%). Melanoma subtype was cutaneous (122, 80.8%), unknown primary (24, 15.9%), mucosal (3, 2%), and acral (2, 1.3%). First ICB was ipi (108, 71.5%), PD-1 (nivo or pembro) (5, 3.3%), and nivo+ipi (37, 24.5%). The best overall response to first ICB was CR (76, 50.3%), PR (27, 17.9%), SD (16, 10.6%) and PD (32, 21.2%). Of the patients who progressed after initial ICB, 38 received subsequent systemic treatment as follows: PD-(L)1 in 20 (53%), BRAF ± MEK in 9 (23.7%), ipi in 7 (18.4%), and chemotherapy in 2 (5.3%). Median duration of follow-up among survivors (N = 138) was 93 months (range 60-192). From 5 years post-ICB, 85% (95% CI: 73-92%) survived an additional 5 years. In those who made it to 5 years without treatment failure (N = 72), the probability of remaining failure-free was 92% (95% CI: 86-99%) at 7 years. Of the 151 patients, only 4 patients (2.6%) experienced disease progression after 5 years. Three patients had radiographic or pathologic disease progression in the lymph nodes and one in the subcutaneous tissue. No patients progressed in the lungs, visceral organs, or CNS after 5 years. At time of analysis, 13 (8.6%) patients died after 5 years post ICB, none died of progressive melanoma. 6 patients died of unknown causes, 2 died of other causes, and 5 died of other non-melanoma cancer-related causes.

Conclusions:  Patients who survive five years after their initial immunotherapy have excellent overall survival and treatment failure-free survival. Given the anxiety surrounding survivorship and late progression, long-term survivors should be reassured of their excellent prognosis. These data suggest that aggressive follow-up schedules and imaging of melanoma patients after 5 years of survival may not be required.

WHOOP!  WHOOP!!!  The C-word (NO!  Not cancer!  CURE!!) was not used, but this data on peeps 5 years out who may no longer need scans to follow up and can carry on with their lives is AWESOME!  On a personal note, Weber let me off the hook for continued follow-up for melanoma at 8 years post my Stage IV diagnosis. I am currently 11 years out.

This study looked at peeps treated with nivo alone vs the ipi/nivo combo.  Now we are blessed to look at 6.5 year outcomes. These reports would not exist without the lives and dedication of all the ratties; and sometimes a special mouse!!!  Thanks, Edster!!!!

CheckMate 067: 6.5-year outcomes in patients (pts) with advanced melanoma. Wolchok, Chiarion-Sileni, Gonzalez, et al.  ASCO 2021.

Background: In the phase 3 CheckMate 067 trial, a durable and sustained clinical benefit was achieved with nivolumab (NIVO) + ipilimumab (IPI) and NIVO alone vs IPI at 5-y of follow-up (overall survival [OS] and progression-free survival [PFS] rates: 52%, 44%, 26% and 36%, 29%, 8%, respectively). Here we report 6.5-y efficacy and safety outcomes.

Methods:  Eligible pts with previously untreated unresectable stage III or IV melanoma were randomly assigned in a 1:1:1 ratio and stratified by PD-L1 status, BRAF mutation status, and metastasis stage. Pts received NIVO 1 mg/kg + IPI 3 mg/kg for 4 doses Q3W followed by NIVO 3 mg/kg Q2W (n = 314), NIVO 3 mg/kg Q2W + placebo (n = 316), or IPI 3 mg/kg Q3W for 4 doses + placebo (n = 315) until progression or unacceptable toxicity. Co-primary endpoints were PFS and OS with NIVO + IPI or NIVO vs IPI. Secondary endpoints included objective response rate (ORR), descriptive efficacy assessments of NIVO + IPI vs NIVO alone, and safety.

Results:  With a minimum follow-up of 6.5 y, median OS was 72.1 mo with NIVO + IPI, 36.9 mo with NIVO, and 19.9 mo with IPI (table). Median time from randomization to subsequent systemic therapy was not reached with NIVO + IPI, 25.2 mo with NIVO, and 8.0 mo with IPI; 36%, 49%, and 66% of pts, respectively, received any subsequent systemic therapy. Median treatment-free interval (which excluded pts who discontinued follow-up prior to initiation of subsequent systemic therapy) was 27.6 mo (range, 0–83.0), 2.3 mo (range, 0.2–81.6), and 1.9 mo (range, 0.1–81.9) with NIVO + IPI, NIVO, and IPI, respectively. Of the pts alive and in follow-up, 112/138 (81%; NIVO + IPI), 84/114 (74%; NIVO), and 27/63 (43%; IPI) were off treatment and never received subsequent systemic therapy; 7, 8, and 0 pts, respectively, were still on treatment. Grade 3/4 treatment-related adverse events were reported in 59% of NIVO + IPI-treated pts, 24% of NIVO-treated pts, and 28% of IPI-treated pts. Since the 5-y analysis, no new safety signals were observed and no additional treatment-related deaths occurred.

Conclusions:  This 6.5-y analysis represents the longest follow-up from a phase 3 melanoma trial in the modern checkpoint inhibitor combination therapy and targeted therapy era. The results show durable improved outcomes with NIVO + IPI and NIVO vs IPI in pts with advanced melanoma. We observed improvement in OS, PFS, and ORR with NIVO + IPI over NIVO alone. Clinical trial information: NCT01844505.

My takeaway - AGAIN - though nivo alone works for many (look at me!!) - BUT - data shows responses and durability were better with the ipi/nivo combo.  Way to rock it out, ratties!!  Thanks, dear Ed!

Finally, a non-ASCO report from earlier this year looking at folks who chose to stop anti-PD-1 monotherapy with nivo (Opdivo) or pembro (Keytruda) at 1 year of therapy ~

Real-world experience with elective discontinuation of PD-1 inhibitors at 1 year in patients with metastatic melanoma.  Pokorny, McPherson, Haaland, et al.  J Immunother Cancer.  Jan 2021.

Background: Randomized trials evaluating programmed cell death protein 1 (PD-1) inhibitors in metastatic melanoma either permitted treatment for 2 years (pembrolizumab) or more (nivolumab). The optimal duration of therapy is currently unknown due to limited data, and shorter therapies may be effective.

Methods: Data of patients with metastatic cutaneous melanoma treated with single-agent PD-1 inhibitors at Huntsman Cancer Institute from January 1, 2015, to December 31, 2018, was reviewed to identify a continuous series of patients who made the joint decision with their provider to electively discontinue therapy at 1 year (greater than 6 months and less than 18 months) in the setting of ongoing treatment response or disease stability. Patients were excluded if they received PD-1 inhibitors with other systemic therapy, had prior exposure to PD-1 therapy, or discontinued treatment due to disease progression or immune-related adverse event. Best objective response (BOR) per RECIST V.1.1 at treatment discontinuation, progression-free survival (PFS), and retreatment characteristics was analyzed.

Results: Of 480 patients who received PD-1 inhibitors, 52 met the inclusion criteria. The median treatment duration from first to the last dose was 11.1 months (95% CI 10.5 to 11.4). BOR was complete response in 13 (25%), partial response in 28 (53.8%), and stable disease in 11 (21.2%) patients. After a median follow-up of 20.5 months (range 3-49.2) from treatment discontinuation, 39 (75%) patients remained without disease progression, while 13 (25%) had progression (median PFS 3.9 months; range 0.7-30.9). On multivariable analysis, younger age, history of brain metastasis, and higher lactate dehydrogenase at the time of anti-PD-1 discontinuation were associated with recurrence. Patients with recurrent melanoma were managed with localized treatment, anti-PD-1 therapies, and BRAF-MEK inhibitors. All patients except one were alive at data cutoff.

Conclusion: In this large real-world, observational cohort study, the majority of patients with metastatic melanoma after 1 year of anti-PD-1 therapy remained without progression on long-term follow-up. The risk of disease progression even in patients with residual disease on imaging was low. After prospective validation, elective PD-1 discontinuation at 1 year may reduce financial and immunotherapy-related toxicity without sacrificing outcomes.

In my 2010, nivo as a single agent, phase 1 study, we took nivo for 2 1/2 years on a rather different schedule than is utilized currently (every 2 weeks for 6 months, then every 3 months for 2 years) and at dosages of 1mg/kg (my cohort), 3 mg/kg, and 10 mg/kg.  The 3mg/kg dosage is basically what is used today.  Still, even with all that, Weber often said that he felt we were treated too long and explained that while a certain amount of drug would be helpful, beyond that, benefit was nil and the risk of side effects was increased.  Today - whether we are looking at anti-PD-1 as a single agent or the ipi/nivo combo - researchers are still trying to figure out exactly what that "certain amount" is.  It is likely that the answer may vary person to person.  As this study pointed out, the ratties who elected to stop therapy at one year had experienced treatment response or stable disease.  Clearly, that is an important factor.  Additionally, in this rather small study of 52 patients, recurrence was associated with those who were younger, had a history of brain mets and elevated LDH when therapy ceased.  Interesting, in that I was 39 at diagnosis and 46 with brain mets at the start of my trial.  However, I took nivo for 2 1/2 years, never had an elevated LDH and have yet to have a melanoma recurrence.  So many variables.  So many different peeps.  It is a hard road to walk, much less to predict.

Hang tough, guys.  There is hope! - c  

New treatments - kinda. Anti-LAG-3 plus anti-PD-1 to boost response. Ipi/nivo plus tocilizumab to decrease side effects.

Unfortunately, as mentioned in yesterday's post, current melanoma treatments do not meet the needs of all melanoma patients.  Also as mentioned, a great deal of current research is building on existing immunotherapies - attempting to fortify response rates by adding a wide variety of pharmaceuticals to existing products.

Here is another study looking at combining an anti-LAG-3 product with yet another anti-PD-1 product: (Note:  Yesterday's post includes a link to previous data and info about anti-LAG-3 generally.)

Clinical activity of fianlimab (REGN3767), a human anti-LAG-3 monoclonal antibody, combined with cemiplimab (anti-PD-1) in patients (pts) with advanced melanoma.  Hamid, Wang, Kim, et al.  ASCO 2021.

Background:  Fianlimab and cemiplimab are two high-affinity, fully human, hinge-stabilized IgG4 monoclonal antibodies. In a Phase 1 dose escalation study, fianlimab combined with cemiplimab showed an acceptable safety profile and some clinical activity in pts with advanced malignancies. Here, we present safety and clinical activity data from two expansion cohorts of pts with advanced melanoma (anti–programmed cell death/ligand-1 [anti–PD-(L)1] naïve or experienced) who were treated with fianlimab + cemiplimab and had an opportunity for first on-treatment tumor assessment (cut-off date: Jan 4, 2021).

Methods:  Pts with advanced melanoma who had no prior anti–PD-(L)1 treatment (naïve) or prior anti–PD-(L)1 treatment within 3 months of screening (experienced) received fianlimab 1600 mg + cemiplimab 350 mg by IV infusion every 3 weeks. Tumor measurements were performed every 6 weeks for the first 24 weeks and subsequently every 9 weeks per RECIST v1.1.

Results:  48 pts with advanced melanoma were treated with the combination therapy: 33 were anti–PD-(L)1 naïve and 15 were anti–PD-(L)1 experienced (median age: 69 years vs 59 years; male: 66.7% vs 46.7%; Caucasian: 87.9% vs 60%). The safety profile (including immune-related adverse events [AEs]) of fianlimab + cemiplimab combination therapy was similar to that of anti–PD-1 monotherapy with one exception. The rate of adrenal insufficiency, 8.3% (4/48) of pts, is similar to the rate previously observed with anti–PD-1 + anti–cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) combination therapy but higher than that observed with anti–PD-1 monotherapy. Grade greater than/= to treatment-emergent AEs (TEAEs) occurred in 35.4% (17/48) of patients; Grade greater than/= to serious TEAEs occurred in 22.9% (11/48) of patients; 8.3% (4/48) of patients discontinued treatment due to a TEAE. The most common TEAEs were fatigue (n = 15, 31.3%) and rash (n = 11, 22.9%). By investigator assessment, objective response rate (includes unconfirmed complete [CR] and partial responses [PR]) was 63.6% (3 CRs and 18 PRs) for anti–PD-(L)1 naïve pts and 13.3% (1 CR and 1 PR) for anti–PD-(L)1 experienced pts. Median progression-free survival and median duration of response for the anti–PD-(L)1 treatment naïve cohort have not been reached. Prognostic clinical markers and tumor biomarkers such as expression of LAG-3, PD-L1, and major histocompatibility complex II are being evaluated. Recruitment is ongoing.

Conclusions:  The safety profile of fianlimab + cemiplimab is similar to that observed with cemiplimab monotherapy and other anti–PD-1s, with the exception of higher rate of adrenal insufficiency. Fianlimab + cemiplimab combination has shown clinical activity for pts with advanced melanoma that is similar to anti–PD-1 + CTLA-4 combination therapy, but with lower demonstrated rates of TEAEs. Clinical trial information: NCT03005782.

Fingers crossed!

With its 50%+ response rate and durable results, the ipi/nivo combo has thus far been the best thing going for melanoma patients.  However, side effects caused by the treatment force roughly 40% of patients to discontinue therapy. (With that in mind, you may find this report from 2017 of interest:  40% of melanoma patients stop ipi/nivo due to side effects...BUT...efficacy is about the same!!!)  Anyhow, in an effort to DECREASE those side effects, this trial is adding tocilizumab - a monoclonal antibody that blocks interleukin 6 and is often used to treat rheumatoid arthritis - to the combo.  Interesting too, to look back on the addition of leflunomide (another drug used for RA) to targeted therapy as noted in this post:  An anti-rheumatic drug that increases the effect of vemurafenib and selumetinib?)  

Ipilimumab, nivolumab and tocilizumab as first-line therapy for advanced melanoma.  Mehmi, Hamid, Hodi, et al.  ASCO 2021.

Background:  Interleukin 6 (IL-6) functions in the maintenance of hepatocytes, haemotopoietic progenitor cells, a variety of other tissues, and regulates the innate and adaptive immune system. IL-6 may play a role as a chronic inflammatory mediator in altering levels of acute phase proteins synthesized by the liver and circulating myeloid cells which have been shown to be associated with short survival with checkpoint inhibition and which are immune suppressive. The immunomodulatory properties of interleukin-6 may in part also be responsible for immune related adverse events, given the reversal of those toxicities observed with IL-6 receptor blockade in clinical practice. To assess if blockade of IL-6 binding is associated with a decrease in irAEs and/or an increase in efficacy defined as overall response rate (ORR) at week 24 in patients receiving ICB, we added tocilizumab to ipilimumab and nivolumab therapy.

Methods:  The current phase II trial is a two-stage design to assess the safety, tolerability, and grades 3-5 immune related toxicities of tocilizumab administered every 6 weeks up to week 24 in combination with ipilimumab at 1 mg/kg and nivolumab at 3 mg/kg every 3 weeks for 4 doses each during a 12 week induction period, then administered every 6 weeks with nivolumab at 240 mg flat dose every 2 weeks in maintenance for up to 24 weeks, and nivolumab alone will be given at 480 mg flat dose every 4 weeks thereafter for up to 2 years. Eligible patients include those age 18 or older with measurable and unresectable stages III/IV melanoma (cutaneous, acral, mucosal), without prior systemic treatment for metastatic disease. Adjuvant therapy (IFN-alpha, ipilimumab and/or nivolumab, or pembrolizumab) is allowed. Patients with metastatic melanoma of brain are allowed, if neurologically stable and off immunosuppressive steroids. A total of 18 patients will be treated in the first stage, and 49 additional patients in the second stage for a total of 67. The comparator data are from the N3I1 arm of Checkmate-511 trial, in which treatment-related grades 3-5 irAEs were 33.9% with a 45.6% response rate (1). Prespecified activity goal for the first stage of accrual has been met; second stage accrual began in January 2021.  Clinical trial information: NCT03999749.

For what it's worth.  - c

P.S. With great thanks to the Edster - this link, that includes an explanatory video from the Wizard Weber, gives important background on the whys and wherefores related to IL-6 in this instance and indicates that adding an IL-6 blockade may not only decrease side effects from immunotherapy but ADD effectiveness - Elevated Levels of Serum CRP and IL-6 Are Biomarkers of Poor Prognosis in Patients Receiving Immune Checkpoint Inhibitors.  Gotta love a man in a bow tie who can elucidate the difference between predictive and prognostic!!!!  - c

Outcomes and options in advanced melanoma after resistance to standard therapy

What to do, when what was supposed to work does not?  A heart rending question for anyone always!  Sadly, in melanoma, there are still no clear answers.  Clinical trials are an option.  As always, I advocate searching this site:  ClinicalTrials.gov  From there you can enter your disease and stage, as well as click on the box for active/recruiting trials.  Once your list pops up, when you click on each trial, you can look through the drugs to be used and the inclusion/exclusion requirements.  At the bottom, you will find a list of locations in which the trial is offered and usually, contact information for the trial coordinator.  MY EXHORTATION is this:  If you are remotely interested in a trial, even if you think you may not be allowed or even desire participation in, CALL!!!!!  Call the facility, ask for info on the trial.  You never know what options you may attain from there!  

Here are just a few of the current treatment options via trials for melanoma patients with advanced disease:

LOTS of things paired with immunotherapy!!!!!

NKTR-214 - which I have reported on here:  NKTR- 214 (bempegaldesleukin) with Opdivo

Many of the current offerings being paired with immunotherapy are as yet an alphabet soup, much like Nivolumab - first MDX-1106, then  BMS-936558, then nivolumab and now Opdivo - not sure the names are any better!!! - was in my phase 1 trial back in 2010.  Here are just a few:  CMP-001.  BGB324.  APX005M.  APG-115.  HBI-8000.  V937.  SX-682.  AV-MEL-1.  Anti-VEGF.  NOVO TTF-200A.  IL6 (Tocilizumab).  Azacitidine.  High dose IL-2.  Olaparib.  Denosumab.  Something I've been reporting on since 2014 - propranolol.

There's radiation with everything.  There is TBX-3400 on its own.  Fecal transplants - more on that here.  Tazemetostat with BRAF/MEK inhibitors.  And much more.  I am not touting the feasibility (or not) of any of these, but they are available for your consideration.

Anti-LAG-3 is a promising new/additional therapy.  You can check out posts here:  Anti-LAG-3

I have posted on response rates and outcomes of advanced melanoma peeps as well as results when immunotherapy is followed by immunotherapy as well as targeted therapy after immunotherapy. Here are a couple posts with links within:

From 2020:  Five year survival reports in melanoma after various targeted and immunotherapies

How to deal with recurrence on or after anti-PD-1 as adjuvant or treatment for active melanoma disease

After progression on anti-PD1 / anti-PDL1 treatment of melanoma

There is this report:  Advanced Melanoma - A smattering of 2020 literature for Stage IV peeps which includes one report on using antiangiogenic drugs as salvage therapy when other treatments have not been successful. Which brings us here - old school chemo options, alone or combined with immunotherapy, to consider:

Potential therapeutic effect of low-dose paclitaxel in melanoma patients resistant to immune checkpoint blockade: A pilot study.  Gebhardt, Simon, Weber, et al.  Cell Immunol. Feb 2021.

The low dose application of chemotherapeutic agents such as paclitaxel was previously shown to initiate anti-tumor activity by neutralizing myeloid-derived suppressor cells (MDSCs) in melanoma mouse models. Here, we investigated immunomodulating effects of low-dose paclitaxel in 9 metastatic melanoma patients resistant to prior treatments. Three patients showed response to therapy (two partial responses and one stable disease). In responding patients, paclitaxel decreased the frequency and immunosuppressive pattern of MDSCs in the peripheral blood and skin metastases. Furthermore, paclitaxel modulated levels of inflammatory mediators in the serum. In addition, responders displayed enhanced frequencies of tumor-infiltrating CD8+ T cells and their activity indicated by the upregulation of CD25 and TCR ζ-chain expression. Our study suggests that low-dose paclitaxel treatment could improve clinical outcome of some advanced melanoma patients by enhancing anti-tumor immunity and might be proposed for combined melanoma immunotherapy.

Chemotherapy combined with antiangiogenic drugs as salvage therapy in advanced melanoma patients progressing on PD-1 immunotherapy.  Wang, Xu, Si, et al. Transl Oncol. Jan 2021.

Background: This study aimed to evaluate the effect of salvage therapy with nab-paclitaxel (nab-p) or temozolomide (TMZ) combined with antiangiogenic drugs in programmed death 1 (PD-1) inhibitor-resistant patients with unresectable metastatic melanoma.

Methods: We conducted a retrospective review of 69 metastatic melanoma patients who received nab-p or TMZ combined with antiangiogenic drugs after developing PD-1 inhibitor resistance and were treated at the Beijing Cancer Hospital between 2016 and 2019. The disease control rate (c-DCR) and progression-free survival (c-PFS) of salvage CA (chemotherapy combined with antiangiogenic drugs) regimens were investigated. Univariate and multivariate analyses were performed to evaluate the clinical pathological factors affecting the outcomes. Then, a nomogram was formulated to predict the probability of 3-month and 6-month c-PFS based on the multivariate analysis results.

Results: The c-DCR was 63.8%, and the median c-PFS was 3.0 months. In the univariate analysis, factors associated with the c-DCR were included the melanoma subtype, baseline platelet-to-lymphocyte ratio (PLR) and best response status to PD-1 inhibitors. Factors influencing c-PFS included age, baseline lactic dehydrogenase, PLR, neutrophil-to-lymphocyte ratio (NLR), PFS duration of anti-PD-1 therapy (p-PFS), and the best response and progression pattern of PD-1 inhibitors. In the multivariate analysis, age <65 years, heterogeneous progression pattern and baseline PLR<200 were significantly associated with improved c-PFS. The concordance index (C-index) of the nomogram was equal to 0.65.

Conclusions: CA regimens demonstrated promising effects in PD-1 inhibitor-resistant patients. The nomogram could be a valuable predictive module for salvage therapy choice in PD-1 inhibitor-resistant patients.

In plain English, these researchers attempted to created an algorithm to predict what amount of time the chemo cocktail would give a person.  It is not clear how accurate their predictions were.

From ASCO, there is this:

Lenvatinib (len) plus pembrolizumab (pembro) for patients (pts) with advanced melanoma and confirmed progression on a PD-1 or PD-L1 inhibitor: Updated findings of LEAP-004.  Arance, Cruz-Merino, Petrella, et al.  ASCO 2021.

Background:  Initial results of the open-label, single-arm, phase 2 LEAP-004 study (NCT03776136) showed that len and pembro in combination had promising efficacy and manageable safety in pts with unresectable stage III-IV melanoma and confirmed PD on a PD-(L)1 inhibitor given alone or in combination. ORR was 21.4% with a 6.3-mo median DOR; ORR was 31.0% in patients with PD on prior anti–PD-1 + anti–CTLA-4. We present updated data from LEAP-004 and additional ORR subgroup analyses.

Methods:  Eligible pts with PD confirmed per iRECIST within 12 wk of the last dose of a PD-(L)1 inhibitor given alone or with anti–CTLA-4 or other therapies for greater than/= to 2 doses received len 20 mg/d once daily plus less than/= to 35 doses of pembro 200 mg Q3W until PD or unacceptable toxicity. Primary end point is ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary end points are PFS and DOR per RECIST v1.1 by BICR, OS, and safety. ORR was calculated for pts with PD on prior anti–PD-1 + anti–CTLA-4, pts whose only prior anti–PD-(L)1 was in the adjuvant setting, pts with primary resistance (ie, best response of SD or PD to prior anti–PD-(L)1 in the advanced setting) and pts with secondary resistance (ie, PD following best response of CR or PR on prior anti–PD-(L)1 in the advanced setting).

Results:  103 pts were enrolled. Median age was 63 y, 68.0% of pts had stage M1c/M1d disease, 55.3% had LDH greater than ULN, 58.3% received greater than or = to 2 prior treatments, 94.2% received therapy for advanced disease, and 32.0% received BRAF ± MEK inhibition. With median study follow-up of 15.3 mo (range 12.1-19.0), 17.5% of pts were still receiving study drug. ORR by BICR remained 21.4%, although the number of CRs increased from 2 to 3. DCR was 66.0%. Median DOR increased to 8.2 mo, and the KM estimate of DOR greater than/= to 9 mo was 37.2%. ORR was 33.3% in pts with PD on prior anti–PD-1 + anti–CTLA-4 (n = 30), 18.2% in pts whose only prior anti–PD-1/L1 was in the adjuvant setting (n = 11), 22.6% in pts with primary resistance (n = 62), and 22.7% in pts with secondary resistance (n = 22). Median PFS and OS in the total population were 4.2 mo (3.8-7.1) and 14.0 mo; 12-mo PFS and OS estimates were 17.8% and 54.5%. Incidence of treatment-related AEs was as follows: 96.1% any grade, 45.6% grade 3-4, 1.0% grade 5 (decreased platelet count), 7.8% led to discontinuation of len and/or pembro, and 56.3% led to len dose reduction.

Conclusions:  The combination of len and pembro continues to show clinically meaningful, durable responses in pts with advanced MEL with confirmed progression on a prior PD-(L)1 inhibitor, including those with PD on anti–PD-1 + anti–CTLA-4 therapy, and regardless of primary or secondary resistance to prior anti–PD-(L)1 therapy. The safety profile was consistent with prior studies of len + pembro. These data support len + pembro as a potential regimen for this population of high unmet need.

Still hoping for therapies that rid disease from ALL melanoma peeps!  Hang tough, dear ones.  Hang tough! - c

Intratumoral or Intralesional therapy for melanoma - again. Yep, AGAIN!!! ASCO 2021, here we go!

Intralesional (intratumoral) therapies have come a loooooong way, baby!  I first began reporting on them in 2014.  Here's a link to a zillion articles and posts:  More than you ever wanted to know about intralesional therapy for melanoma! 

As I embark on posting the things I feel are important from ASCO this year, I will add articles I have been collecting on each topic.  We will start here, with all things intralesional ~ 

The following link takes you to a pretty good review of current state of the data regarding intralesional therapy.  PV-10, Toll-like receptor agonists (TLR's), Intratumoral oncolytic viruses - to include:  CAVATAK, Pexastimogene Devacirepvec (Pexa-Vec), HF10, PVS-RIPO, and TVEC are covered.  Lots of interesting charts and trial results/status are covered, including data (when it exists) on combining these therapies with systemic treatments.   

Intratumoral Immunotherapy Update 2019. Hamid, et al. Oncologist March 2020.

And here:

An Update on the Role of Talimogene Laherparepvec (T-VEC) in the Treatment of Melanoma: Best Practices and Future Directions.  Larocca, LeBoeuf, Silk, et al.  Am J Clin Dermatol, 2020 Dec 21.

Talimogene laherparepvec (T-VEC) is the first agent approved for cancer in the emerging class of oncolytic viral therapies. While T-VEC was approved for the treatment of advanced melanoma in 2015, clinical utilization has been hampered by rapid changes in the therapeutic landscape of melanoma related to advances in both immune checkpoint blockade and targeted therapy, cumbersome logistics involved in T-VEC administration, biosafety concerns, and a perception that T-VEC has limited impact on uninjected, visceral disease. However, with further survival follow-up from the phase III OPTiM (OncovexGM-CSF Pivotal Trial in Melanoma), along with new real-world data and consensus guidelines on safe administration of oncolytic viruses, a roadmap for when and how to use T-VEC has been emerging. In addition, preliminary data have demonstrated improved therapeutic responses to T-VEC in combination with immune checkpoint blockade in patients with melanoma without additive toxicity. This review provides an update on recent data with T-VEC alone and in combination with other agents. The emerging data provide guidance for how to better utilize T-VEC for patients with melanoma and identifies critical areas for clinical investigation to expand the role of T-VEC in combination strategies for the treatment of melanoma and perhaps other cancers.

There is this:

Oligoprogression After Checkpoint Inhibition in Metastatic Melanoma Treated With Locoregional Therapy: A Single-center Retrospective Analysis.  Comito, Leslie, Boos, et al.   J Immunother, 2020 Oct.

Checkpoint inhibitors (CPIs) have demonstrated a heterogenous spectrum of response and disease progression that may not be fully captured by conventional response criteria, such as a limited degree of progression, known as oligoprogression, which could benefit from local treatment. We retrospectively analyzed data from all patients diagnosed with metastatic melanoma, who received CPI between January 2006 and March 2018 at Royal Marsden. We enrolled 36 patients who experienced progression in a maximum of 3 metastatic sites, after achieving disease control from therapy with CPI, and were radically treated with the locoregional approach. We carried out Kaplan-Meier analysis to obtain progression free-survival post-first oligoprogression (PFS-PO1), overall survival (OS) post-first oligoprogression, and OS estimates. The median time to oligoprogression from the start of CPI was 12 months. At a median follow-up of 34 months, the median PFS-PO1 was 32 months, with 50% of patients not progressed at the time of the data cutoff. The median OS-post-first oligoprogression was not reached. At a median follow-up of 52 months (from the first cycle of CPI), the median OS was not reached, with 75% of patients alive at the time of analysis. Univariate and multivariate analyses demonstrated that baseline American Joint Committee on Cancer stage IV M1a or M1b is associated with a longer PFS-PO1 compared with stage M1c or M1d. We observed that local therapy for oligoprogression after CPI can result in durable disease control, suggesting that locoregional treatment should be considered in patients being treated with immunotherapy. However, prospective evaluation, perhaps in randomized trials, is needed. 

And this:

Durability of Complete Response to Intralesional Interleukin-2 for In-Transit Melanoma.  Khoury, Knapp, Fyfe, et al.  J Cutan Med Surg.  Feb 2021.

Background: Intralesional injection of interleukin-2 (IL-2) for in-transit melanoma (ITM) is associated with a high rate of complete response. However, there is a paucity of data on treatment durability and long-term outcomes.

Methods: Consecutive patients with ITM, treated with intralesional IL-2 therapy, at the Tom Baker Cancer Center were identified from April 2009 to August 2019. All patients received at least 4 cycles (every 2 weeks) of IL-2 (5 MIU/mL). Complete response was defined as sustained (ie, 3 months) clinical complete remission of all known in-transit disease.

Results: Sixty-five patients were treated with curative intent for in-transit disease with intralesional IL-2. Complete clinical response was identified in 44.6% (29/65). In this subset of patients, the median number of lesions per patient was 9 (range 1-40). The median total dose of IL-2 was 0.8 mL (IQR 0.4-1.5) per lesion. One patient received isolated limb infusion and 13.8% (4/29) received systemic immunotherapy as part of their initial management. At a median follow-up of 27 months (IQR 16-59), 34.5% (10/29) developed recurrent disease. Of these patients, 50.0% (5/10) presented with synchronous in-transit and distant metastases. The median time to recurrence was 10.5 months (IQR 5.8-16.3).

Conclusion: With long-term follow-up, 65.5% of complete responders have a durable response to intralesional IL-2 therapy. In this cohort of patients, local in-transit recurrence is most likely to occur within 12 months and is often associated with concomitant distant disease.

And finally, there is this from ASCO:

Talimogene laherparepvec with systemic immunotherapy in melanoma: A real-world experience.  Behera, Chen, Song, et al.  ASCO 2021.

Background: Talimogene laherparepvec (TVEC) is an FDA approved oncolytic herpes virus for intralesional therapy in unresectable metastatic melanoma. Real world data is sparse regarding the efficacy of TVEC in combination with other systemic therapies used in melanoma. We present outcomes of the largest single institution observational study of the off-label use of TVEC in combination with systemic immunotherapy.

Methods:  Patients with metastatic melanoma receiving TVEC simultaneously with ipilimumab-nivolumab (Ipi/Nivo) or single agent immunotherapy (either nivolumab or pembrolizumab) were evaluated. The demographics, clinicopathological characteristics, responses to injected lesions and remote metastatic lesions were evaluated. Clinical documentation was used to assess improvement in injected lesion size; time points for initial response and best response were identified. Review of imaging by a radiologist was evaluated to assess responses in remote metastatic lesions.

Results:  A total of 67 patients receiving TVEC from 2016 to 2020 were evaluated, of which 50 remained evaluable after excluding Merkel cell carcinoma, patients on clinical trial, TVEC monotherapy or those on BRAF-MEK inhibitors, and patients lost to follow up. In total, 29 received systemic immunotherapy simultaneously with TVEC and had been followed for at least a year, with a median follow-up time of 34 months (range, 12-56). At the time of analysis, 14 of 29 patients were alive. 6 of the 29 patients had received prior lines of therapy. Four patients received Ipi/Nivo, while 25 patients received monotherapy including 9 on nivolumab and 16 on pembrolizumab. The median number of TVEC doses received was 6 (range, 2-55) with median average TVEC dose being 3.47 ml (0.5-4 ml). Median time to initial local response was 6 weeks, whereas time to best local response was 14 weeks. Overall response rate in the injected target lesions was in 19 (66%), with complete local response (CR) in 12 (41%), partial response (PR) in 7 (24%), and progressive disease (PD) in 8 (28%). The response rate in distant non-injected lesions was 4 out of 16 (25%), 2 of which had previously progressed on prior systemic therapy. Stable disease was observed in 8 (50%) patients, and progression of disease in 4 (25%). The 1-year overall survival rate in patients receiving TVEC with systemic monotherapy was 80%. Progression free survival at 1-year in the monotherapy group was 71.6%.

Conclusions:  This is the largest single institution, real world experience to our knowledge, which assesses the efficacy of TVEC in combination with systemic immunotherapy. Our cohort suggests that TVEC is an effective treatment in combination with systemic immunotherapy, with a better overall survival observed with combination TVEC and anti-PD1 than seen with historical data from clinical trials of anti-PD-1 monotherapy.

As this mix of reports suggests, intralesional therapy can be used in several ways - as a treatment for one stubborn or new lesion in a person otherwise responding to their therapy; as an add on to pembro (Keytruda) or nivo (Opdivo) for folks with a relatively low burden of disease; or full bore combined with the ipi/nivo combo for those with more advanced disease.  The response rates are not 100%, but they are something!  And we all know, every bit helps!

Gonna shoot for getting a post up daily til done with ASCO (family, work and general life obligations withstanding)!  My fearless and determined bestie had the tough job of going through ALL the ASCO reports!!  When searching for intel on TWO cancers, that task is NOT for the faint of heart.  I have gone through his collection and broken them down into topics.  The reports will follow the pattern I have used here:  Collected, but unshared articles, followed by the selection from ASCO 2021, with my thoughts in red. 

I hope they will be of some use to a few of you.  Take good care. - c 

May Reads

Much like the members of The Guernsey Literary and Potato Peel Pie Society, a happy astonishment of my life has been how one book leads to the revelations of another.  I prefer to think of the linkage of character's lives to mine as fate, destiny and explanations unfolding as they should, rather than coincidence or mere noticing.  Such was the world and thoughts of Isabel Dalhousie, protagonist of Alexander McCall Smith's Sunday Philosophy Club series.  On the heels of A Column of Fire, the history of the Scots was familiar and made revealingly relevant.  But it was the musings of Isabel herself that gave me pause, and smiles, in the way the best characters bring.  Her view of Jimmy Carter as a human too good to be terribly successful in the political scrum.  Her appreciative notice of the prickliness of mahonias.  Her ready acceptance of the fox in her garden as an integral part of her world.  The way she allowed her breath to be taken with the fullness in her heart when touched by her abiding love for her dear ones.  

Relatively light reading that, at least for me, held so much more.  In May, I read the entire series and made note of quotes I especially enjoyed ~

The Sunday Philosophy Club

              “She was tuned into a different station than most people and the tuning dial was broken.”

              “There were two classes of persons upon whom a duty of virtually absolute confidentiality rested:  doctors and lovers.”

              “There was a distinction between lying and telling half-truths, but it was a very narrow one.”

Friends Lovers Chocolate

              “But don’t we often lie to people we love, or not tell them things, precisely because we love them?”

              “But that’s exactly the problem…  We’re all stuck with the same tires and trusted ideas.  IF we refused to entertain the possibility of something radically different, then we’d never make any progress – ever.”

              “She had been seized with a sudden existential horror.  The house had white carpets and white furniture and, most significantly, no books.”

              “There were countless injustices and difficulties in this world, but small points of light too, where the darkness was held back.”

The Right Attitude to Rain         

              “When you are with somebody you love the smallest, smallest things can be so important, so amusing because love transforms the world, everything.”

              “We never realize how transparent we are.”

              “The azalea was next to a mahonia bush, with its yellow flowers and those spikey leaves.”

The Careful Use of Compliments

              “Our possessing of our world is a temporary matter:  we stamp our ownership upon our surrounding, give familiar names to the land about us, erect statues of ourselves, but all of this is swept away, so quickly, so easily.  We think the world is ours forever, but we are little more than squatters on it.”

              “Do not act meanly, do not be unkind, because the time for setting things right may pass before your heart changes course.”

The Comfort of a Muddy Saturday

              “We like to think that we plan what happens to us, but it is chance, surely, that lies behind so many of the great events of our lives - - the meeting with the person whom we are destined to spend the rest of our days, the receiving of a piece of advice which influences our choice of career, the spotting of a particular house for sale, all of these may be put down to  chance, and yet they see how our lives work out and how happy - - or unhappy - - we are going to be.”

The Lost Art of Gratitude

              “Gratitude was a lost art, she felt.  People accepted things, took them as their right, and had forgotten how to give proper thanks.”

              “…virtues are best cultivated in discretion and silence, away from the gaze of others, known only to those who act virtuously and to those who benefit from what is done.”

The Charming Quirks of Others

              “Anger disfigured…  We are disfigured by anger and must avoid it.  We must, no matter how much we seethe.”

              “Gravity was there, and we felt it, but did anybody, other than theoretical physicists, actually understand it?  What if goodness were the same sort of force:  something that was there, could not be seen or tasted, but was still capable of drawing us into its orbit?  Perhaps we understood that, even if we acted against it, even if we denied it.  And that force could be called anything, God being one name people gave it.”

The Forgotten Affairs of Youth

              “She would never accept things as they were.  That was what made her do what she did…and what made her, and everybody else who thought about the world and its unkindness, do battle for understanding, for sympathy, for love, in small ways, perhaps, but ways that cumulatively made a difference.”

              “Cads, as they used to be called, do very well.  They thrive.  They live happily ever after.  It was enough to make one want to believe in the place below, where they’d get a good roasting for their efforts.  It would make the rest of use feel so much better, wouldn’t it?”

The Perils of Morning Coffee

              “Time, she felt, made quite enough claims on us, without our conniving in its relentless tyranny."

The Uncommon Appeal of Clouds

              “A single word, a phrase, a sentence or two could have such extraordinary power; could end a world, break a heart or, as in this case, consign another to moral purdah.”

              “The physical world—the world of stone and brick—is indifferent to our suffering, to our dramas, she thought. Even a battlefield can be peaceful, can be a place for flowers to grow, for children to play; the memories, the sadness, are within us, not part of the world about us.”

              “She liked a conversation that went in odd directions; she liked the idea of playfulness in speech. People could be so depressingly literal.”

              “…all the good things that we have in life are on temporary loan, at best, and can be taken away from us in an instant.”

The Novel Habits of Happiness

              “That was what counted, she told herself: those unexpected moments of appreciation, unanticipated glimpses of beauty or kindness - any of the things that attached us to this world, that made us forget, even for a moment, its pain and its transience.”

              “Biscuits are trivial, but lies are not.”

A Distant View of Everything

“Remember what you have and the other person doesn't. It was simple--almost too simple--advice and yet, like all such home advice, it expressed a profound truth.”

The Quiet Side of Passion

              “I know that we’re encouraged these days to make much of victimhood, but I believe in bouncing back.  And I don’t think we should allow people to make use miserable – that gives the victory to them.”

              “They held one another gently, as we should all hold those whom we love, as we should all hold the world.”

The Geometry of Holding Hands

              “Perhaps it was only a prolonged education, coupled with the security it brought, that encouraged nuanced thinking.  Isabel sometimes wondered whether liberalism was most enthusiastically practiced by those who could afford it:  you could be generous to others if the likelihood of your ever wanting for anything was remote; you could be kind to asylum seekers if they would never take up resources you would need yourself; you could be tolerant of crime if there was not much of it in your neighborhood.  And so on…”

              “He opened the book at random and found what he was looking for.  Three figures, in a typical Celtic circle, held hands with one another, arms in a complicated pattern of intermingling. “I love that,” he said.  “I think it says everything there is to be said about helping one another and loving one another and being part of…well, I suppose of being part of something bigger than oneself.”

              Isabel looked.  “The geometry of holding hands,” she said.”                                                           ______________________________________________                                                                           

I miss her.  ~ les