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  

ASCO 2017: Nivo or Ipi/Nivo combo in melanoma after progression on ipi or anti-PD-1

Despite a heavy heart, I begin my annual journey through the ASCO reports.  Great thanks to B for funneling the most pertinent of the entire meeting my way.  I will do my best to give you the unvarnished abstracts, any relevant history I have, and my take on what the expert's jargon is really saying.  As usual, my commentary will be in red.  However, there are many sources through which you can read them (as well as see videos) for yourself and I certainly encourage you to do so.  At any rate, in honor of Jamie and Josh - here we go....

Can you get a response to nivo (Opdivo) alone or the ipi/nivo combo after you've been treated with ipi or anti-PD-1 and progressed?????  Yes, you can!!!!!

Here patients who have poor prognostic factors as well as progression after ipi are treated with nivo alone:

Efficacy and safety of nivolumab (NIVO) in patients with advanced melanoma (MEL) and poor prognostic factors who progressed on or after ipilimumab (IPI): Results from a phase II study (CheckMate 172).

ASCO 2017. J Clin Oncol 35, 2017. Schadendorf, Ascierto, Haanen, et al.

Background: In the phase III CheckMate 037 study, NIVO improved the objective response rate and progression-free survival with less toxicity vs chemotherapy in patients (pts) with MEL who progressed after prior IPI treatment. We report the first efficacy and updated safety data from pts with MEL in CheckMate 172, including those with rare melanoma subtypes (uveal, mucosal), brain metastases, or an ECOG performance status (PS) of 2. Methods: In this ongoing phase II, single-arm, open-label, multicenter study, pts with MEL who progressed on or after IPI were treated with NIVO 3 mg/kg Q2W for up to 2 years until progression or unacceptable toxicity. We report efficacy and updated safety data from 734 treated pts with greater than/= to 1 year of follow-up. Results: Of 734 pts, 50% had LDH greater than ULN, 7% ECOG PS 2, 66% M1c disease, 15% a history of brain metastases, and 23% received greater than/= to 3 prior therapies. Overall, 593 pts (81%) received more than 4 doses of NIVO. Overall, response rate at 12 weeks was 32%, with a complete response in 1%. The 1-year overall survival (OS) rate was 63%. Any grade and grade 3/4 treatment-related adverse events (AEs) occurred in 66% and 17% of pts, respectively. Discontinuations due to treatment-related AEs occurred in 4% of pts. The most common treatment-related select (potentially immune-related) AEs were diarrhea (12%), hypothyroidism (9%), and pruritus (7%). Conclusions: CheckMate 172 is the largest study of NIVO efficacy and safety in pts with MEL who progressed on or after IPI. NIVO demonstrated a safety profile consistent with that of prior clinical trials. Efficacy outcomes were encouraging in some difficult-to-treat subgroups of pts with poor prognostic factors, such as mucosal melanoma and brain metastases. 

	Total pt (n=734)	ECOG PS 2 (n=48)	Uveal (n=75)	Mucosal (n=52)	CNS (n=112)
response rate at 12 weeks, % (n)	32 (123/386)	15 (2/13)	6 (2/34)	21 (5/24)	43 (20/47)
Med OS (mo)	19 (17-NR)	2 (1-4)	11 (7-15)	13 (6-NR)	13 (9-NR)
1-yr OS rate, %	63 (60-67)	14 (2-26)	47 (34-59)	53 (38-67)	51 (40-60)

* assessed in evaluable pts on tx for greater than/= to 12 weeks; NR = not reached.

Here patients who advanced after a variety of immunotherapy were treated with the ipi/nivo combo:

Salvage combination ipilimumab and nivolumab after failure of prior checkpoint inhibitor therapy in patients with advanced melanoma.

ASCO 2017. J Clin Onco 35, 2017. Gaughn, Petroni, Grosh, et al.

Background: The combination of Ipilimumab and Nivolumab is standard initial therapy in patients with advanced melanoma based on trials involving treatment-naïve patients. The benefit in those previously managed with checkpoint monotherapy is not well defined. Methods: We identified metastatic melanoma patients from our Immunotherapy database managed with combination Ipilimumab/Nivolumab after progression on prior checkpoint monotherapy. Baseline clinical factors, treatment history, combination therapy outcome by RECIST v1.1 and toxicity data were collected. Descriptive statistics were used to summarize the data. Given the small sample size and limited numbers of deaths, it is too early to look for preliminary associations between outcomes and clinicopathologic factors. Results: We identified 19 patients treated with combination Ipilimumab/Nivolumab after progression on prior checkpoint monotherapy. The cohort included 15 men and 4 women with an average age of 63 years. Thirteen patients had M1c disease, and 7 had a BRAF mutation. Patients had received up to four lines of prior immunotherapy including 9 treated with both prior anti-PD1 and anti-CTLA4 monotherapy. Seven patients completed all four doses of combination therapy with 6 proceeding onto maintenance nivolumab. Eight patients stopped treatment due to toxicity and 4 due to progressive disease. Thirteen patients had clinically significant toxicity, with rash, colitis, hepatitis, and hypophysitis reported most frequently. There were no treatment-related deaths. Overall, 2/19 patients (10.5%,) had an objective response (CR+PR) and 9/19 patients (47.4%) had disease control (CR+PR+SD). Four of the patients had stable disease for over 6 months. Six of the 19 patients went on to receive subsequent treatment. Median follow-up for patients still alive was 7 months (range 1 to 20 months) and median survival was not reached. Six-month survival was 68.5%. Conclusions: The combination of Ipilimumab and Nivolumab can result in melanoma control in patients with progression on prior checkpoint monotherapy with an expected toxicity profile.

While response rates were not nearly what we'd like them to be, patients DID respond to both nivo after ipi and the Ipi/Nivo combo after prior treatments of ipi and anti-PD-1 alone.  Side effects were no worse than what we already know them to be on the respective immunotherapies. Hang tough ratties.  Much love and hope to each of you.  - c

Nivo after nivo? Or nivo after progression? Can melanoma patients still attain a response???

A question frequently asked...with no absolute answer is.... What if I take nivo after I've progressed....having already been on nivo....or if currently on nivo??????  These reports begin an answer:

Efficacy and safety of retreatment with nivolumab in metastatic melanoma patients previously treated with nivolumab. Nomura, Otasua, Konda, et al.  Cancer Chemother Pharmacol. 2017 Oct 5. 

Nivolumab is a monoclonal antibody directed against programmed death-1 that has been shown to improve survival in patients with metastatic melanoma. However, the efficacy of nivolumab and other agents in melanoma remains limited. The objective of this study was to evaluate the efficacy and safety of retreatment with nivolumab in metastatic melanoma patients who previously progressed on nivolumab.

A retrospective review was performed on eight consecutive metastatic melanoma patients retreated with nivolumab who progressed on previous nivolumab. These patients received nivolumab 2 mg/kg every 3 weeks. Best responses to each treatment were assessed using RECIST 1.1.

Of eight metastatic melanoma patients, three patients received chemotherapy before first nivolumab. The median first nivolumab treatment period was 4.1 months. During first nivolumab, 3 (37.5%) patients achieved a partial response and 3 (37.5%) patients achieved stable disease as their best response. First nivolumab was discontinued due to disease progression in seven patients and grade 3 colitis in 1 patient. Patients were subsequently treated with ipilimumab (n = 6), vemurafenib (n = 1), or no other medical treatment (n = 1). The median treatment period between first and second nivolumab was 3.0 months. Four patients received radiation therapy between first and second nivolumab. The median second nivolumab treatment period was 4.3 months. Among the eight patients who received second nivolumab, 2 (25%) patients achieved a partial response and 3 (37.5%) patients achieved stable disease as their best response. Second nivolumab was discontinued due to disease progression in seven patients. One patient continues to receive second nivolumab. Among the four patients treated with ipilimumab and radiotherapy between first and second nivolumab, the response rate was 50% and the disease control rate was 75%.

This study showed that retreatment with nivolumab is an option for select metastatic melanoma patients after previous nivolumab treatment.

Here, 8 patients were given nivo (3 of them had chemo beforehand).  37.5% had a partial response.  37.5% had stable disease.  Nivo was stopped due to progression in 7 of the patients and colitis in 1.  6 were subsequently treated with ipi.  1 was given vemurafenib.  4 got radiation at that point.  Then...these 8 folks were given a new round of nivo.  2 attained a partial response.  3 attained stable disease. Eventually, 7 of them had to stop nivo again due to progression.  Interestingly, it sounds as though those that had radiation between therapies did better....at least for a while - though that is not entirely spelled out here.  

So, it seems that round two of nivo can give patients a reprieve.  Though for these 8 patients it doesn't sound as though it lasted long enough!

And....there's also this....

Nivolumab for Patients With Advanced Melanoma Treated Beyond Progression: Analysis of 2 Phase 3 Clinical Trials. Long, Weber, Larkin, ….Hodi, Wolchok.  JAMA Oncol. 2017 Jun 29.

Immune checkpoint inhibitors have demonstrated atypical response patterns, which may not be fully captured by conventional response criteria. There is a need to better understand the potential benefit of continued immune checkpoint inhibition beyond progression.

To evaluate the safety and potential benefit of nivolumab (anti-programmed cell death receptor 1) monotherapy beyond Response Evaluation Criteria in Solid Tumors (RECIST) v1.1-defined progression.

Pooled, retrospective analysis of data from phase 3 trials of nivolumab in treatment-naive patients with advanced melanoma (CheckMate 066 or CheckMate 067) conducted at academic and clinical cancer centers. Participants were patients treated beyond first disease progression, defined as those who received their last dose of nivolumab more than 6 weeks after progression (TBP group); and patients not treated beyond progression, who discontinued nivolumab therapy before or at progression (non-TBP group). Data analyses were conducted from November 6, 2015, to January 11, 2017.  Nivolumab (3 mg/kg every 2 weeks) administered until progression or unacceptable toxic effects. Patients could be treated beyond progression if deriving apparent clinical benefit and tolerating study drug, at the investigator's discretion.  Tumor response and safety in TBP and non-TBP patients.

Among 526 randomized patients (39% [n = 203] female; median age, 62 years [range, 18-90 years]), 306 (58%) experienced disease progression, including 85 (28%) TBP patients and 221 (72%) non-TBP patients. Twenty-four (28%) of the TBP patients had a target lesion reduction of greater than 30% after progression compared with baseline (TBP greater than 30% group). At the time of this analysis, 65 (76%) TBP patients and 21 (87%) TBP greater than 30% patients were still alive; 27 (32%) and 11 (46%), respectively, continued to receive treatment. Median (range) time from progression to last dose of treatment was 4.7 (1.4-25.8) months for TBP patients and 7.6 (2.4-19.4) months for TBP greater than 30% patients. Median (range) time from progression to greater than 30% tumor reduction was 1.4 (0.2-7.0) months. Treatment-related select grade 3 to 4 adverse events were similar in the TBP and non-TBP groups (5 [6%] and 9 [4%], respectively).

A substantial proportion of selected patients treated with frontline nivolumab who were clinically stable and judged to be eligible for treatment beyond RECIST v1.1-defined progression by the treating investigators derived apparent clinical benefit without compromising safety. Further analysis will help define the potential benefit of continued nivolumab treatment beyond progression.

Here they looked at the outcomes of 3 trials in which nivo was used....in 526  patients.  306 had progression.  But 85 of those who progressed were given nivo more than 6 weeks AFTER their known progression, while 221 were not. Of those 85 patients "treated beyond progression", 24 "had a target lesion reduction of greater than 30% after progression compared to baseline."  And at follow-up further down the line, many of those were still alive.

There is much we still don't understand about immunotherapy.  But, I think the statement Agarwala and Weber made to, "Be patient with the patient!" still holds.  Hang tough, ratties! And, thanks!  - 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

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

Ipilimumab or ipi/nivo combo after recurrence in patients previously treated with immunotherapy ~

How to treat a melanoma recurrence when you have already been treated with ipi or anti-PD-1 (nivo/Opdivo or pembro/Keytruda) as single agents or the ipi/nivo combo has been a question for sometime now.  From 2017 there were these:

Response to ipi or ipi/nivo after failing anti-PD1 as single agent in Stage IV melanoma

ASCO 2017: Nivo or Ipi/Nivo combo in melanoma after progression on ipi or anti-PD-1

ASCO 2017: ipi plus pembro, ipi after pembro and identifying markers for outcome with pembro for advanced melanoma

There was this in 2020:  How to deal with recurrence on or after anti-PD-1 as adjuvant or treatment for active melanoma disease

And also, this:  After progression on anti-PD1 / anti-PDL1 treatment of melanoma

Now, there are these:

Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study.  Da Silva, Ahmed, Reijers, et al.  Lancet Oncol.  June 2021.

Background: Anti-PD-1 therapy (hereafter referred to as anti-PD-1) induces long-term disease control in approximately 30% of patients with metastatic melanoma; however, two-thirds of patients are resistant and will require further treatment. We aimed to determine the efficacy and safety of ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab) compared with ipilimumab monotherapy in patients who are resistant to anti-PD-(L)1 therapy (hereafter referred to as anti-PD-[L]1).

Methods: This multicentre, retrospective, cohort study, was done at 15 melanoma centres in Australia, Europe, and the USA. We included adult patients (aged greater/= to 18 years) with metastatic melanoma (unresectable stage III and IV), who were resistant to anti-PD-(L)1 (innate or acquired resistance) and who then received either ipilimumab monotherapy or ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab), based on availability of therapies or clinical factors determined by the physician, or both. Tumour response was assessed as per standard of care (CT or PET-CT scans every 3 months). The study endpoints were objective response rate, progression-free survival, overall survival, and safety of ipilimumab compared with ipilimumab plus anti-PD-1.

Findings: We included 355 patients with metastatic melanoma, resistant to anti-PD-(L)1 (nivolumab, pembrolizumab, or atezolizumab), who had been treated with ipilimumab monotherapy (n=162) or ipilimumab plus anti-PD-1 (n=193) between Feb 1, 2011, and Feb 6, 2020. At a median follow-up of 22·1 months, the objective response rate was higher with ipilimumab plus anti-PD-1 (60 of 193 patients) than with ipilimumab monotherapy (21 of 162 patients). Overall survival was longer in the ipilimumab plus anti-PD-1 group (median overall survival 20·4 months) than with ipilimumab monotherapy (8·8 months). Progression-free survival was also longer with ipilimumab plus anti-PD-1 (median 3·0 months) than with ipilimumab (2·6 months). Similar proportions of patients reported grade 3-5 adverse events in both groups (59 [31%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 54 [33%] of 162 patients in the ipilimumab group). The most common grade 3-5 adverse events were diarrhoea or colitis (23 [12%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 33 [20%] of 162 patients in the ipilimumab group) and increased alanine aminotransferase or aspartate aminotransferase (24 [12%] vs 15 [9%]). One death occurred with ipilimumab 26 days after the last treatment: a colon perforation due to immune-related pancolitis.

Interpretation: In patients who are resistant to anti-PD-(L)1, ipilimumab plus anti-PD-1 seemed to yield higher efficacy than ipilimumab with a higher objective response rate, longer progression-free, and longer overall survival, with a similar rate of grade 3-5 toxicity. Ipilimumab plus anti-PD-1 should be favoured over ipilimumab alone as a second-line immunotherapy for these patients with advanced melanoma. 

In this report, it is evident that the ipi/nivo combo did better as follow-up to progression on anti-PD-1 as a single agent, than the response that was provided by ipi alone.

Now, what to do if you took the combo from the start?

Re-induction ipilimumab following acquired resistance to combination ipilimumab and anti-PD-1 therapy.  Hepner, Atkinson, Larkin, et al.  Eur J Cancer.  Aug 2021.

Purpose: Combination immunotherapy with nivolumab and ipilimumab has a high initial response rate in advanced melanoma; however, up to 55% of patients later progress. The efficacy and safety of ipilimumab re-induction in the setting of acquired resistance (AR) to combination immunotherapy is unknown.

Methods: Patients with advanced melanoma who initially achieved a complete response, partial response or sustained stable disease to induction combination immunotherapy then progressed and were reinduced with ipilimumab (alone or in combination with anti-PD-1) and were analysed retrospectively. Demographics, disease characteristics, efficacy and toxicity were examined.

Results: Forty-seven patients were identified from 12 centres. The response rate to reinduction therapy was 12/47 (26%), and disease control rate was 21/47 (45%). Responses appeared more frequent in patients who developed AR after ceasing induction immunotherapy (30% vs. 18%). Time to AR was 11 months. After a median follow-up of 16 months, responders to reinduction had a median progression-free survival of 14 months, and in the whole cohort, the median overall survival from reinduction was 17 months. Twenty-seven (58%) immune-related adverse events (irAEs) were reported; 18 (38%) were grade 3/4, and in 11 of 27 (40%), the same irAE observed during induction therapy recurred.

Conclusions: Reinduction with ipilimumab ± anti-PD-1 has modest clinical activity. Clinicians should be attentive to the risk of irAEs, including recurrence of irAEs that occurred during induction therapy. Future studies are necessary to determine best management after resistance to combination immunotherapy.

This report notes that despite failing the ipi/nivo combo, a repeated course can provide response and disease control.

Here's something to consider if serious adverse reactions have been an impediment to repeating treatment using immunotherapy ~

Low-dose ipilimumab combined with anti-PD-1 immunotherapy in patients with metastatic melanoma following anti-PD-1 treatment failure.  Klee, Kurzhals, Hagelstein, et al.  Melanoma Res. July 2021.

Combined immunotherapy is associated with a significant risk of severe and potentially fatal immune-related adverse events (irAEs). Therefore, we retrospectively analyzed the side profile and efficacy of low-dose ipilimumab (1 mg/kg, IPI1) combined with anti-PD-1 immunotherapy in patients who progressed after anti-PD-1 monotherapy. Nine patients with unresectable stage III or IV melanoma treated with combined low-dose ipilimumab (1 mg/kg, IPI1) and anti-PD-1 immunotherapy, following progression after anti-PD-1 treatment, were identified. Treatment response and irAEs were recorded. Grade 3 irAEs occurred in one-third of patients. Interestingly, there were no grade 4 or 5 irAEs. In fact, four out of the nine patients experienced no irAEs at all. One patient discontinued combined immunotherapy due to immune-related colitis. The mean time to the onset of grade 3 irAEs was 14.3 weeks. The objective response rate was 33.3% and a disease control rate of 66.7% was achieved. Median progression-free survival (PFS) was 5.7 months and median overall survival (OS) was 21.6 months. The median PFS when IPI1 and anti-PD-1 treatment was administered in the second-line setting was not reached, but only 2.8 months when used in subsequent treatment settings. Combined IPI1 and anti-PD-1 immunotherapy was well tolerated. Its use in the third-line or above setting was associated with a significantly poorer prognosis than in the second-line setting. Larger, prospective studies are required to evaluate the safety and efficacy of this dosing regimen following anti-PD-1 treatment failure.

After progressing on anti-PD-1, these patients were treated with a low dose ipi/usual dose nivo combo.  Side effects were decreased and responses were attained.

Hang tough, peeps.  Melanoma doesn't make it easy, but there is hope.  - c

FDA approves Relatlimab plus Nivolumab (Opdivo) for advanced melanoma patients - the down and dirty on Opdualag!!!!

Finally, an additional FDA approved treatment for melanoma!!  With FDA approvals for the first immunotherapy and targeted therapy in melanoma in 2011, the addition of Nivo and Pembro in 2014, a few additional BRAF/MEK combo's in 2013 and 2018, T-VEC approved as an intralesional in 2015, immunotherapy approved as adjuvant in 2017, targeted as such in 2018 - that's been about it for new melanoma therapies.  I recently reported on study results for Relatlimab combined with Nivolumab (Opdivo) for treatment of advanced melanoma in February:  Relatlimab plus Nivolumab in advanced melanoma patients - better than Nivo (Opdivo) alone!  The main take-away from the data being:

1.  The combination of the anti-LAG-3 product relatlimab with anti-PD-1 agent Nivolumab provided better progression free survival than when melanoma patients with advanced disease were treated with nivo alone - "The median progression-free survival was 10.1 months (6.4 to 15.7) with relatlimab-nivolumab as compared with 4.6 months (3.4 to 5.6) with nivolumab. Progression-free survival at 12 months was 47.7% (41.8 to 53.2) with relatlimab-nivolumab as compared with 36.0% (30.5 to 41.6) with nivolumab. Progression-free survival across key subgroups favored relatlimab-nivolumab over nivolumab."

2.  Nivo and Pembro when used as single agents are both known (through data collection over many years) to have an approximate response rate of 40%.  The second article in the link above addressing relatlimab combined with nivo notes (though tallied as PFS):  "Median progression-free survival was 10.1 months in the combination arm and 4.6 months in the monotherapy arm. After 12 months’ follow-up, progression-free survival rates were 47.7% in the combination arm versus 36% in the monotherapy arm..."  The ipi/nivo combo is recognized to have a response rate of 50%+.  The fourth article in this 2021 post - ASCO 2021 - Outcomes of treatments on advanced disease - Reasons for HOPE!!!!! - notes:  "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)."  But, we know that PFS and OS is higher earlier on after treatment, so in the first article from this 2017 report - Do melanoma peeps with side effects to immunotherapy have a better response? - it notes:  " The 3-year OS rate of 63% is the highest observed for this patient population and provides additional evidence for the durable clinical activity of immune checkpoint inhibitors in the treatment of advanced melanoma."

3.  Though the combo had greater side effects than when nivo was taken alone - "Grade 3 or 4 treatment-related adverse events occurred in 18.9% of patients in the relatlimab-nivolumab group and in 9.7% of patients in the nivolumab group."  - we know that about 40% of patients on ipi/nivo have to stop the combo due to side effects, with about 55% experiencing grade 3/4 adverse events. 

4.  This post reviewed the Relativity trial of relatlimab and nivo in 2021 - Something "new" in melanoma treatment???? Anti-LAG-3! Again....  Despite the new data and having been reporting on anti-LAG-3 since 2014, I think my summation there still stands:

My take:  It seems that the combination of relatlimab and nivolumab (Opdivo) has a response rate that is slightly less than that of the ipi/nivo (Ipilimumab/Yervoy and Nivolumab/Opdivo) combo which has proven to be around 50+ percent, but one that is possibly better than the 40% response rate when anti-PD-1 (nivo or pembro) is used alone. Perhaps the two most important things these (still preliminary - after all these years) reports tell us is that ~

1.  Side effects, that can be so devastating and difficult in the ipi/nivo combo may be much decreased in the relatlimab/nivo combo.

2.  For reasons we don't fully understand, melanoma responds differently to the same treatment in different folks.  For me, thus far, nivolumab alone was 100% effective.  Obviously that is not the case for most melanoma patients.  So having another effective immunotherapy combination, that may well be far less than 100% effective in all of us, may still be completely effective in some.

And, finally, as ever - the drug company did not see fit to configure the trial such that the new combo went up against the old one directly.  Why not BMS?  Why not????  Why not three arms?  One with nivo alone.  One with the ipi/nivo combo? And the third with relatimab/nivo?  WHY???

5.  We still don't have durability of response data to this combo - but I would presume (given the durability we know about responses to nivo) they would be good.

SOooooooooooooooo - there you have it - a newly FDA approved combo for melanoma dubbed - OPDUALAG!!!!  (Seriously, these names!  My word!)

Now, this:

FDA Approves Relatlimab Plus Nivolumab for Unresectable or Metastatic Melanoma

March 18, 2022  Krista Rosa OncLive

The FDA has approved the fixed-dose combination of relatlimab plus nivolumab (Opdualag) for the treatment of adult and pediatric patients who are 12 years of age or older and who have unresectable or metastatic melanoma.1

The regulatory decision is based on data from the phase 2/3 RELATIVITY-047 trial (NCT03470922), which showed that the doublet (n = 355) resulted in a median progression-free survival (PFS) of 10.1 months vs 4.6 months with single-agent nivolumab (n = 359; P = .0055).

“Since the approval of the first immune checkpoint inhibitor more than 10 years ago, we’ve seen immunotherapy, alone and in combination, revolutionize the treatment of patients with advanced melanoma,” F. Stephen Hodi, MD, director of the Melanoma Center and the Center for Immuno-Oncology at Dana-Farber Cancer Institute, stated in a press release. “Today’s approval is particularly significant, as it introduces an entirely new combination of two immunotherapies that may act together to help improve anti-tumor response by targeting two different immune checkpoints — LAG-3 and PD-1.”

To be eligible for enrollment to RELATIVITY-047, patients had to have previously untreated, unresectable, or metastatic melanoma and an ECOG performance status of 0 or 1.

A total of 714 patients were randomized 1:1 to receive the fixed-dose combination of relatlimab at 160 mg and nivolumab at 480 mg administered every 4 weeks vs single-agent nivolumab at the same dose and schedule.

Patients were stratified by LAG-3 expression on immune cells in the tumor microenvironment, PD-L1 expression on tumor cells, BRAF mutational status, and AJCC v8 M stage.

The primary end point of the trial was PFS per blinded independent central review (BICR). Secondary end points included overall survival (OS) and ORR per BICR. End points were tested in hierarchy, with PFS evaluated first, followed by OS, and then objective response rate (ORR).

Baseline characteristics were well balanced between the arms. The median age of participants was 63 years, 41.7% were female, and 66.9% had an ECOG performance status of 0. The serum lactate dehydrogenase level was above the upper limit of normal in 36.1% of patients.

LAG-3 expression was 1% or higher in 75.2% of patients, and it was lower than 1% in 24.8% of patients. PD-L1 expression was at least 1% in 41.0% of patients, and lower than 1% in 59.0% of patients. Moreover, 38.5% of patients had BRAF-mutated disease, and 61.5% had BRAF wild-type disease. Lastly, 65.7% of patients had AJCC M stage of M0/M1any[0], and 34.3% had M1any[1].

Data presented during the March 2022 ASCO Plenary Series showed that at a median follow-up of 19.3 months, the median OS with the doublet had not yet been reached vs 34.10 months with nivolumab monotherapy.  Although this benefit was not found to be statistically significant, it was considered to be clinically meaningful.

Additional data showed that PFS rates continued to be higher in the doublet arm vs the monotherapy arm. At 12 months, these rates were 48.0%  and 36.9%, respectively; at 24 months, these rates were 38.5% and 29.0%, respectively.

Notably, PFS and OS benefit favored the doublet over the monotherapy across all stratification factors that were assessed.

In the investigative arm, the complete response rate achieved was 16.3%, the partial response rate was 26.8%, and 17.2% of patients experienced stable disease. Additionally, 29.6% of patients in this arm had disease progression.

The median duration of response had not yet been reached in both the relatlimab/nivolumab arm and the control arm. Moreover, the disease control rate achieved with the doublet was 62.8% vs 50.7% with the monotherapy.

Notably, fewer patients who received the doublet went on to receive subsequent therapy vs those who received single-agent nivolumab, at 40.8% and 42.6%, respectively. Specifically, fewer patients in the investigative arm received systemic therapy vs those in the control arm, at 32.7% vs 34.5%, respectively. Additionally, 11.8% of patients who received relatlimab/nivolumab went on to receive PD-L1 and/or CTLA-4 inhibitors vs 15.9% of those who received nivolumab monotherapy.

Specifically, 4.2% of patients on the relatlimab/nivolumab arm went on to recive nivolumab and ipilimumab (Yervoy), 4.2% received nivolumab monotherapy, 3.7% received ipilimumab, 1.7% received pembrolizumab (Keytruda) monotherapy, and no patients received single-agent avelumab (Bavencio); these rates were 6.7%, 5.6%, 5.3%, 2.8%, and 0.3%, respectively.

Additionally, 12.4% of patients on the investigative arm went on to receive BRAF and/or MEK inhibitors vs 14.8% of those on the control arm. Other subsequent treatment was received by 13.8% of those who received the doublet vs 12.3% of those who were given the monotherapy. Slightly more patients on the investigative arm received radiotherapy at 14.6% vs 12.3% on the control arm; however, more patients on the control arm underwent surgery, at 8.1% vs 7.0%, respectively.

The fixed-dose combination is associated with severe and fatal immune-mediated adverse reactions such as pneumonitis, colitis, hepatitis, endocrinopathies, nephritis with renal dysfunction, dermatologic adverse reactions, myocarditis, and other immune-mediated adverse reactions; infusion-related reactions. The doublet is also linked with complications of allogeneic hematopoietic stem cell transplantation and embryo-fetal toxicity.

“While we have made great progress in the treatment of advanced melanoma over the past decade, we are committed to expanding dual immunotherapy treatment options for these patients,” Samit Hirawat, chief medical officer of global drug development at Bristol Myers Squibb, added in the press release. “Inhibiting LAG-3 with relatlimab, in a fixed-dose combination with nivolumab, represents a new treatment approach that builds on our legacy of bringing innovative immunotherapy options to patients. The approval of a new medicine that includes our third distinct checkpoint inhibitor marks an important step forward in giving patients more options beyond monotherapy treatment.”

An updated "Primer of Melanoma Treatments" to be posted soon.  Hang tough, peeps! - c

IPI/NIVO - results - in melanoma brain mets and long term follow-up in advanced melanoma

Yes.  I think the results ratties provided have finally gotten it through most researchers heads (though not the heads of all oncologists) that targeted therapy (via the BRAF/MEK combo for BRAF positive melanoma peeps) and immunotherapy WORK IN THE BRAIN!!!!  I have been reporting on this trial CheckMate 204 since 2015.  Now, there's this:

Efficacy and safety of the combination of nivolumab (NIVO) plus ipilimumab (IPI) in patients with symptomatic melanoma brain metastases (CheckMate 204).  2019 ASCO.  Tawbi, Forsyth, Hodi...Hamid...Postow, Pavlick...et al. J Clin Oncol 37, 2019 (suppl; abstr 9501)

Background: We previously reported efficacy and safety of NIVO+IPI in patients (pts) with untreated, asymptomatic, melanoma brain metastases (MBM) from the CheckMate 204 study. Here, we provide the first report of NIVO+IPI in pts with symptomatic MBM, and report updated data in pts with asymptomatic MBM. Methods:In this phase II trial, pts with  greater than/= to 1 measurable, nonirradiated MBM 0.5–3.0 cm were enrolled into two cohorts: (1) those with no neurologic symptoms or steroid Rx (asymptomatic; cohort A); and (2) those with neurologic symptoms, whether or not they were receiving steroid Rx (symptomatic; cohort B). In both cohorts, pts received NIVO 1 mg/kg + IPI 3 mg/kg Q3W × 4, then NIVO 3 mg/kg Q2W until progression or toxicity. The primary endpoint was intracranial clinical benefit rate (CBR; proportion of pts with complete response [CR] + partial response [PR] + stable disease [SD]  greater than/= to 6 mo). As of the clinical cutoff date on May 1, 2018, all treated pts (101 in cohort A and 18 in cohort B) had been followed for ~6 mo or longer. Results: In this updated analysis of cohort A (median follow-up of 20.6 mo), the CBR was 58.4% (Table). In cohort B, pts received a median of 1 NIVO+IPI dose and 2 of 18 pts (11%) received all 4 doses. At a median follow-up of 5.2 months in cohort B, intracranial objective response rate was 16.7% and the CBR was 22.2%. Grade 3/4 adverse events occurred in 54.5% of pts in cohort A and in 55.6% of pts in cohort B (6.9% and 16.7% in the nervous system, respectively), with one death related to treatment in cohort A (immune-related myocarditis). Conclusions: In pts with asymptomatic MBM, our updated results show a high rate of durable intracranial responses, further supporting NIVO+IPI as a first-line treatment in this population. Intracranial antitumor activity was observed with NIVO+IPI in pts with symptomatic MBM, but further study is needed to understand the biologic mechanisms of resistance to immunotherapy and to improve treatments in this challenging population. Clinical trial information: NCT02320058

Intracranial response	Asymptomatic (Cohort A; n = 101)	Symptomatic (Cohort B; n = 18)
Best overall response, n (%)
CR	29 (29)	2 (11)
PR	26 (26)	1 (5.6)
SD ≥6 mo	4 (4)	1 (5.6)
CBR, % (95% CI)	58.4 (48.2–68.1)	22.2 (6.4–47.6)

While I am glad to note those responses, you would be hard pressed to convince me to go with ipi/nivo alone...given all we have learned about the positive response systemic therapy COMBINED with radiotherapy provides.  You can read a zillion articles on the combo here:  
Radiation for melanoma

I am not even going to try to note ALL the posts and discussions I have reported regarding the ipi/nivo combo!  We have long known that the 15% response rate to ipi alone and the 40% average response rate to either anti-PD-1 product alone jumps to around 50+% with the ipi/nivo combo.  Just put "ipi/nivo" in the search bar to read the history for yourself.  Now, there's this:

Long-term follow-up of CA209-004: A phase I dose-escalation study of combined nivolumab (NIVO) and ipilimumab (IPI) in patients with advanced melanoma.  2019 ASCO.  Akins, Kirkwood, Wolchok, ..., Postow, ...Sznol.  J Clin Oncol 37, 2019.

Background: We previously reported a 3-year overall survival (OS) rate of 63% with NIVO+IPI concurrent therapy in the initial phase I dose-escalation study for the combination, conducted in patients (pts) with advanced melanoma. Here, we report OS after 5 years of overall study follow-up and assess survival rates after stopping treatment. Methods: Adults with previously treated or untreated unresectable stage III or IV melanoma, and ECOG performance status of 0 or 1, received NIVO + IPI Q3W × 4 as mg/kg in one of the following cohorts: (1) NIVO 0.3 + IPI 3; (2) NIVO 1 + IPI 3; (2a) NIVO 3 + IPI 1; (3) NIVO 3 + IPI 3; (8) NIVO 1 + IPI 3. Cohorts 1-3 received maintenance with NIVO Q3W × 4, then NIVO + IPI Q12W × 8 at assigned doses; cohort 8 received NIVO Q2W for up to 96 weeks. Patients were followed for the primary endpoint of safety and the secondary endpoints of response and progression-free survival for up to 2.5 years, then for the survival exploratory endpoint for up to an additional 3 years, for a maximum study participation of 5.5 years. Results: At a median follow-up of 43.1 months in all cohorts (N = 94), the 4- and 4.5-year OS rates were both 57%. The 4-year OS rates for pts with normal (n = 58) versus elevated LDH (n = 36) were 62% versus 49%; for pts with wild-type (n = 66) and mutant (n = 24) BRAF tumors, 4-year OS rates were 54% and 61%, respectively. Following the last dose of study drug (for any reason), overall post-treatment 1-, 2-, and 3-year OS rates were 74%, 65%, and 56%, respectively; in pts who discontinued due to study drug toxicity (n = 32), post-treatment 1-, 2-, and 3-year OS rates were 84%, 75%, and 65%, respectively, and in pts who discontinued for disease progression (n = 30), these were 52%, 34%, and 24%, respectively. Conclusions: This updated analysis from study CA209-004 showed favorable survival outcomes with NIVO+IPI, regardless of BRAF or LDH status, and provided evidence of long-term survival following discontinuation of treatment in pts with advanced melanoma. Clinical trial information: NCT01024231

Yep.  "...analysis from study CA209-004 showed favorable survival outcomes with NIVO+IPI, regardless of BRAF or LDH status, and provided evidence of long-term survival following discontinuation of treatment in pts with advanced melanoma."  NOW!  Let's make these numbers even better!!!

We are beautiful before, during, and after...

...the storm. ~ c