Results for Stage III melanoma peeps who recurred after adjuvant targeted therapy

The positive benefits noted in yesterday's update on adjuvant therapy for Stage III melanoma - utilizing immuotherapy as well as targeted therapy in the form of BRAF/MEK inhibitor combos - have been practically miraculous in preventing many melanoma patients from advancing to Stage IV and even death.  Despite the benefits, there are still those whose melanoma does recurr.  This report addresses outcomes of melanoma peeps who advanced after taking BRAF/MEKi as adjuvant targeted therapy.

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.

So - in folks who were given targeted therapy as adjuvant treatment for their Stage III melanoma - 22% recurred.  Recognizing the small numbers in this break down - responses to treatment that they were given at that relapse point follows:

anti-PD-1 garnered a 63% response rate

ipi/nivo  = 62% RR

targeted therapy rechallenge = 25% RR

ipi as a single agent = 10% RR

33% of the relapsed patient died of melanoma.  

The two year overall survival for those treated with anti-PD-1 = 84%, ipi/nivo = 92%, targeted therapy = 49%, ipi alone = 45%.

Pretty clear to me.  If you relapse, go for the ipi/nivo combo.  Not that we didn't already know that! - c

Melanoma - All things adjuvant

I have kicked and screamed about the need for adjuvant treatment for so many years (especially the more effective anti-PD-1 products vs ipi) that it was almost unbelievable when they were finally FDA approved for adjuvant use in 2017 (Opdivo) and 2019 (Keytruda).  Sadly, recent trial results for the ipi/nivo combo as adjuvant did not prove more effective - providing instead only a greater side effect profile.  Here's a history of adjuvant care in melanoma - ADJUVANT therapy for melanoma!!!!!!!!!!!!!! State of the science....   At this point, targeted therapy in the form of BRAF/MEKi combo's, for BRAF positive patients, and NEO-adjuvant treatments are also available for melanoma patients in need of such care.  Here are zillions of adjuvant related reports - Adjuvant care in melanoma

Now, there are these (my comments in red as ever):

Adjuvant Therapy is Effective for Melanoma Patients with a Positive Sentinel Lymph Node Biopsy Who Forego Completion Lymphadenectomy.  Farrow, Raman, Williams, et al.  Ann Surg Oncol, 2020 Dec 27.

Background: Multiple adjuvant therapies for melanoma have been approved since 2015 based on randomized trials demonstrating improvements in recurrence-free survival (RFS) with adjuvant therapy after surgical resection of high-risk disease. Inclusion criteria for these trials required performance of a completion lymph node dissection (CLND) for positive sentinel lymph node (pSLN) disease.

Objective: We aimed to describe current practice for adjuvant therapies in patients with pSLN without CLND (active surveillance [AS]), and to evaluate recurrence in these patients.

Methods: Melanoma patients with pSLN between 2016 and 2019 were identified at two institutions. Demographic information, disease and treatment characteristics, and recurrence details were reviewed retrospectively. Patients were stratified by recurrence and patient-, treatment- and tumor-related characteristics were compared using Fisher's exact test and t test for categorical and continuous variables, respectively.

Results: Overall, 245 SLN biopsies were performed, of which 36 (14.7%) were pSLN. Of 36 pSLN, 4 underwent CLND and 32 underwent AS, of whom 22 (68.8%) received adjuvant therapy with the anti-programmed death-1 (PD1) inhibitor nivolumab (16/22), anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor ipilimumab (3/22), or BRAF/MEK inhibitors (3/22). At a median follow up of 13.3 months, 7/32 (21.9%) patients on AS recurred, including 4/22 (18.2%) who received adjuvant therapy and 3/10 (30.0%) who did not. Tumor ulceration was significantly associated with recurrence. While not significant, acral lentiginous subtype appeared more common among those with recurrence.

Conclusion: The majority (68.8%) of patients with pSLN managed without CLND were treated with adjuvant therapy. The 1-year RFS for patients managed with adjuvant therapy without CLND was 82%, which is similar to modern adjuvant therapy trials requiring CLND.

Back in the day, including when I was first diagnosed in 2003 and when I recurred in 2007, patients were routinely treated with a complete lymphadenectomy (CLND) of the area around a positive lymph node.  I went through it twice, to both axilla.  Times have changed and the process of CLND is no longer recommended.  In fact, NEO -adjuvant treatment is being studied to see if starting treatment with the positive node in place provides better results and the data is looking positive.  In this report, researchers were looking for differences between melanoma peeps who had a complete lymphadenectomy and those who simply had the positive node removed and started adjuvant treatment.  Of 245 sentinel node biopsies they examined - 36 were positive.  Of those, 4 patients had CLND and 32 had only the positive node removed.  22 were given adjuvant treatment - 16 were treated with nivo, 3 with ipi, and 3 with BRAF/MEK.  At 13.3 months of follow-up - 7 of the 32 patients had recurred - 4 of whom had been treated with adjuvant therapy (abstract does not note which) and 3 had not.  Tumor ulceration was significantly associated with recurrence (which is not news).  Overall, the patients who had adjuvant treatment after a positive node, but NO CLND had a recurrence free survival rate of 82% which is similar to patients who were given a CLND and adjuvant therapy.  Again, this is no longer news, rather confirmation of what we have understood for some years now.

Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial.  Eggermont, Blank, Mandala, et al.  J Clin Oncol.  2020 Nov.

Purpose: We conducted the phase III double-blind European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial to evaluate pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. On the basis of 351 recurrence-free survival (RFS) events at a 1.25-year median follow-up, pembrolizumab prolonged RFS compared with placebo. This led to the approval of pembrolizumab adjuvant treatment by the European Medicines Agency and US Food and Drug Administration. Here, we report an updated RFS analysis at the 3.05-year median follow-up.

Patients and methods: A total of 1,019 patients with complete lymph node dissection of American Joint Committee on Cancer Staging Manual, stage IIIA (at least one lymph node metastasis greater than 1 mm), IIIB, or IIIC (without in-transit metastasis) cutaneous melanoma were randomly assigned to receive pembrolizumab at a flat dose of 200 mg (n = 514) or placebo (n = 505) every 3 weeks for 1 year or until disease recurrence or unacceptable toxicity. The two coprimary end points were RFS in the overall population and in those with programmed death-ligand 1 (PD-L1)-positive tumors.

Results: Pembrolizumab (190 RFS events) compared with placebo (283 RFS events) resulted in prolonged RFS in the overall population (3-year RFS rate, 63.7% v 44.1% for pembrolizumab v placebo, respectively). The impact of pembrolizumab on RFS was similar in subgroups, in particular according to AJCC-7 and AJCC-8 staging, and BRAF mutation status.

Conclusion: In resected high-risk stage III melanoma, pembrolizumab adjuvant therapy provided a sustained and clinically meaningful improvement in RFS at 3-year median follow-up. This improvement was consistent across subgroups

At three years follow up, Stage III patients of all stripes did better after treatment with Pembro than those treated with placebo - demonstrating a recurrence free survival rate of 63.7% for those treated with pembro vs 44.1% for those given placebo.  YEP.

Adjuvant Therapy Failure Patterns in the Modern Era of Melanoma Management.  Rauwerdink, Molina, Tompers, et al.  Ann Surg Oncol.  2020 Dec.

Background: The management of patients with resected stage 3 melanoma has changed significantly due to adoption of the Multicenter Selective Lymphadenectomy Trial (MSLT)-2 guidelines and to the survival benefit of adjuvant anti-PD-1 immunotherapy and BRAF/MEK-inhibitor (BRAF/MEKi) therapy. Data are scarce regarding recurrence patterns, adjuvant therapy responses, and therapy-associated adverse events (AEs) in the modern era.

Methods: This single-institution, retrospective study analyzed surgically resected stage 3 and oligometastatic stage 4 patients who received anti-PD-1, BRAF/MEKi, or surgery with active surveillance only. The primary end point of the study was recurrence-free survival (RFS). The secondary end points were the location and clinical characteristics of recurrence and therapy-associated AEs.

Results: From a cohort of 137 patients, the study enrolled 102 patients treated with adjuvant anti-PD-1 (n = 46), adjuvant BRAF/MEKi (n = 3), or surgery alone (n = 26). During a mean follow-up period of 17 months, 20% of the ani-PD-1 patients, 13% of the BRAF/MEKi patients, and 42% of the surgery-only patients experienced recurrence. Log-rank testing showed a significantly longer RFS for the patients treated with anti-PD-1 [15.3 months; interquartile range (IQR), 8.2-23.2 months] or BRAF/MEKi (17.9 months; IQR, 12.5-23 months) than for those treated with surgery alone (11.9 months; IQR, 7.0-17.6 months). In the anti-PD-1 group, AEs occurred less frequently than in the BRAF/MEKi group (54% vs 80%).

Conclusions: Adjuvant anti-PD-1 and BRAF/MEKi were associated with significantly improved RFS for the patients with resected stage 3 or 4 melanoma. The BRAF/MEKi group had significantly more AEs than the anti-PD-1 group. This is the first study to characterize real-world recurrence in the modern era of adjuvant therapy for melanoma.

This study looked at 102 resected Stage III and Stage IV patients. (Stage III patients whose positive node was removed as well as Stage IV like me when I entered my Phase 1 Nivo trial in 2010, whose metastatic disease had been removed.)  46 were given adjuvant anti-PD-1.  3 were given BRAF/MEKi.  26 had surgery alone.  At 17 months 20% of those treated with anti-PD-1, 13% treated with targeted therapy, and 42% of the surgery-only patients had recurred.  Recurrence free survival lasted an average of15 months for anti-PD-1 patients, 18 months for the BRAF/Meki group, and only 12 months for those given surgery alone.   {While this type of data analysis of outcomes of adjuvant therapy is much needed - TAKE THESE NUMBERS WITH A HUGE GRAIN OF SALT!!!!!  THE 46 patients treated with anti-PD-1 and 26 given surgery only -is barely sufficient to make valid statistical analysis possible; the THREE treated with BRAF/MEKi does NOT!!!!!!!!!!!!!!!!!!!!}

The data presented in the reports included in this October 2020 post New follow-up data confirms effectiveness for targeted and immunotherapy as adjuvant in melanoma patients!!! is much better! To whit ~ 

From Five-Year Analysis of Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma.  Drummer, Hauschild, Saninami, et al.  New England Journal of Medicine.  September 17, 2020.  

870 patients who had resected stage III melanoma with BRAF V600E or V600K mutations to receive 12 months of oral dabrafenib (at a dose of 150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos.  At 5 years, the percentage of patients who were alive without relapse was 52% with dabrafenib plus trametinib and 36% with placebo.

From Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial.  Eggermont, Blank, Mandala, et al.  J Clin Oncol.  September 18, 2020.

1,019 patients with complete lymph node dissection ofcutaneous melanoma were randomly assigned to receive pembrolizumab at a flat dose of 200 mg (n = 514) or placebo (n = 505) every 3 weeks for 1 year or until disease recurrence or unacceptable toxicity.   3-year RFS rate, 63.7% v 44.1% for pembrolizumab v placebo, respectively.

From Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial.  Ascierto, Del Vecchio, Mandala, et al.  Lancet Oncol.  September 18, 2020.

906 patients were assigned to nivolumab (n=453) or ipilimumab (n=453). Median follow-up was 51·1 months with nivolumab and 50·9 months with ipilimumab; 4-year recurrence-free survival was 51·7% in the nivolumab group and 41·2% in the ipilimumab group. With 211 (100 [22%] of 453 patients in the nivolumab group and 111 [25%] of 453 patients in the ipilimumab group) of 302 anticipated deaths, 4-year overall survival was 77·9% with nivolumab and 76·6% with ipilimumab.

NOW - even with all this - it is hard to compare THESE numbers! (Though they are clearly more statistically valid than those noted in the article I started with and also demonstrate the falseness of the claim those authors purport in the last sentence of their abstract!!!!!)  To that end,  I noted when I published them - 

So, there you go.  ALL of these adjuvant therapies provided Stage III/IV melanoma patients whose obvious disease was removed via surgery or radiation better results - no matter if they were treated with ipi, nivo, pembro or the dabrafinib/trametinib combo - than when they were left untreated.  Per these reports, here's how things panned out ~

Dabrafinib/trametinib - at 5 years, stage III melanoma patients alive without relapse was 52% with treatment vs 36% with placebo.

Pembrolizumab (Keytruda) - at 3 years, Stage III melanoma patients with recurrence free survival was 63.7% when treated with pembro, vs 44.1% for placebo.

Ipilimumab (Yervoy) - at 4 years, in Stage III and Stage IV melanoma patients, 4 year recurrence free survival was 41.2%.  4 year overall survival was 76.6%.

Nivolumab (Opdivo) - at 4 years, in Stage III and Stage IV melanoma patients, 4 year recurrence free survival was 51.7%.  4 year overall survival was 77.9%.

My thoughts:

The fact that Stage IV patients were included in the study looking at adjuvant ipi and nivo (CheckMate 238 trial) is HUGE!!!!!!  It makes comparison to the studies using pembro and the dabrafinib/trametinib combo as adjuvant in Stage III peeps ONLY, difficult to say the least.   I would really like to see an adjuvant study in Stage III melanoma patients where Keytruda and Opdivo are compared head to head, using the exact same result parameters and time frames.  I doubt there would be any significant difference in results as that has already been found to be the case when those agents are used in treatment of Stage IV melanoma patients - but still.  And finally, while the numbers for adjuvant ipi weren't that bad, and certainly much better than placebo, the side effects were greater - so I don't find ipi as a single agent a good choice for adjuvant therapy given the other options.

FYI - Time frames of follow-up matter.  As time goes on, more peeps have a chance to progress.  So data at three years is often better than outcomes reported at five years.

For instance in this article:  2017 - Nivo better than ipi as adjuvant  The data (drawn from Stage III AND Stage IV melanoma patients who took the drugs as adjuvant) demonstrates this:

Recurrence free survival at 12 months:

70.5% for nivo                    60.8% for ipi

Recurrence free survival at 18 months:

66.4% for nivo                    52.7% for ipi

That is why it is important to compare apples to apples in all aspects.  c

KEYNOTE-695 Interim Data - Pembrolizumab (Keytruda) combined with TAVO (intratumoral plasmid IL-12 ~ tavokinogene telseplasmid)

In July of 2020 I posted on the combo of TAVO and Pembro here -  Intratumoral (intralesional) therapy and a new guy in town: IL-12 Plasmid Transfection (tavo) with pembro  That is:  "intratumoral plasmid IL-12 (tavokinogene telseplasmid; "tavo") electroporation combined with pembrolizumab".

Now there is this from November 2020 ~

OncoSec Announces Positive Interim Data from KEYNOTE-695 Trial in Anti-PD-1 Checkpoint Refractory Metastatic Melanoma at SITC 2020

The report notes:

-- 30% overall response rate (ORR) and 6% complete response (CR) rate achieved 
-- 35% ORR achieved in patients with Stage IV M1c or M1d disease 
-- TAVO + pembrolizumab demonstrated durable responses for up to two years

TAVO + KEYTRUDA led to a 30% ORR in the first 54 out of 100 planned patients. This interim investigator assessed ORR is much higher than the primary efficacy endpoint for the study, which is a 20% ORR determined by blinded independent review.  The data were selected for a Poster Walk discussion and will be additionally presented in the virtual Poster Hall on Wednesday, November 11 and Friday November 13 and as part of a Company Symposium on November 11th at the Society for Immunotherapy of Cancer (SITC)'s 35th Anniversary Annual Meeting.

"Achieving an overall response rate of 30% with several complete responses and no serious adverse events is extremely encouraging for checkpoint resistant metastatic melanoma patients who currently rely on systemic administration of immune-stimulating drugs  associated with severe toxicity. The data reported, in addition to its ease of use, demonstrate the potential of TAVO in combination with pembrolizumab as a next-generation intratumoral IL-12 therapy that can induce regression of both locally treated and untreated distant and visceral lesions," said Paolo A. Ascierto, M.D., Director of the Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy at the National Tumor Institute Fondazione G. Pascale in Naples, Italy.

Key highlights of KEYNOTE-695 include:

• Of the first 54 out of 100 planned patients ~

• ORR was 30% (95%CI [18.0%, 43.6%]) (16/54)

• Complete response rate was 6% (3/54)

• All responses were confirmed by scans taken no earlier than after 6 months on study

• 9% (5/54) patients had 100% reduction of target lesions

• ORR was 35% (n=6/17) in patients with Stage IV M1c/M1d disease

• ORR was 40% (n=6/15) in patients with prior exposure to ipilimumab

• Median duration of response (mDOR) is currently 12.2 months

• Median study follow-up was 13.5 months

• Excellent safety profile resulting from intramural treatment approach

• Only 5.4% Grade 3 treatment-related AEs

• No grade 4/5 treatment-related AEs

• This study enrolled rapidly progressing patients with a short interval of 1.2 months (median) between the last dose of anti-PD-1 and study treatment

Adil Daud, M.D., a  Professor of Medicine at The University of California, San Francisco, Director of the Melanoma Clinical Research, and lead author of the study added, "the TAVO-electroporation (TAVO-EP) delivery system works by optimizing cellular uptake of DNA-based IL-12 in the tumor microenvironment, leading to local, sustained production of IL-12 in the tumor, where it matters, with negligible systemic exposure.  This recruits and primes immune cancer-fighting cells in the tumor leading to systemic immune responses without systemic toxicity. The totality of the safety and efficacy data establishes TAVO-EP as a best-in-class intratumoral therapy."

Daniel O'Connor, Chief Executive Officer of OncoSec, added "Patients with recurrent metastatic melanoma are in great need of effective treatment options. We believe this data demonstrates not only strong levels of efficacy, but also very low treatment related adverse events with the TAVO + pembrolizumab combo. This, combined with its ease of administration to accessible lesions within minutes in an outpatient setting, plus TAVO's low-cost/simple manufacturing process and its off-the-shelf availability, build a strong case that the TAVO + pembrolizumab combination, in a real-world setting, could equip clinicians with more options for their patients."

Results are still not as good as those achieved with the ipi/nivo combo.  But, for those who can't tolerate that treatment or remain in need of additional treatment, this combo may be a viable option.  For what it's worth! - c

Advanced Melanoma - A smattering of 2020 literature for Stage IV peeps

Unfortunately, though some promising trials are underway, no major breakthroughs have occurred in melanoma research of late.  Still, there are studies and data that are meaningful.  Here is a collection of reports that may be valuable to Stage IV melanoma peeps.  (My comments in red.) -

Overall Survival Improved for Contemporary Patients with Melanoma: A 2004-2015 National Cancer Database Analysis.  Farrow, Turner, Salama, Beasley.  Oncol Ther. 2020 Dec.

Introduction: Since 2011, encouraging clinical trial results have led to approval of multiple new therapies for advanced melanoma, but the impact of these therapies outside of trial populations is largely unknown. This study examines use of novel therapies and survival in contemporary patients with melanoma.

Methods: Stage I-IV melanoma patients were identified in the 2004-2015 National Cancer Database and grouped into historic (2004-2010) and contemporary (2011-2015) cohorts. Overall survival (OS) was compared using Kaplan-Meier and Cox proportional hazard modeling adjusting for patient, tumor, and facility characteristics.

Results: Of 268,668 patients, 136,828 were classified as historic and 131,840 as contemporary. Among all stages, immunotherapy utilization was significantly higher among contemporary patients. Adjusted OS was improved in the contemporary cohort. There was no difference in OS among stage I/II patients between groups, while OS was significantly improved for contemporary stage III/IV patients. Among stage III/IV patients who received immunotherapy, OS was improved for the contemporary cohort.

Conclusions: Adjusted overall survival for contemporary melanoma patients is improved. This effect is driven by improvements for those with advanced stage disease, particularly those that received immunotherapy and BRAF/MEK targeted therapies.

Confirmation of what we already know - targeted therapy (BRAF/MEK combo's) for BRAF positive melanoma patients and immunotherapy - have made a world of difference for melanoma peeps.  

Systemic Therapy for Melanoma: ASCO Guideline.  Seth, …Kirkwood, Kudchadkar…Weber, Agarwala, Ascierto, …, Faries… Robert,…Sondak, et al.  J Clin Oncol, 2020 Nov 20.

Purpose: To provide guidance to clinicians regarding the use of systemic therapy for melanoma.

Methods: ASCO convened an Expert Panel and conducted a systematic review of the literature.

Results: A systematic review, one meta-analysis, and 34 additional randomized trials were identified. The published studies included a wide range of systemic therapies in cutaneous and noncutaneous melanoma.

Recommendations: In the adjuvant setting, nivolumab or pembrolizumab should be offered to patients with resected stage IIIA/B/C/D BRAF wild-type cutaneous melanoma, while either of those two agents or the combination of dabrafenib and trametinib should be offered in BRAF-mutant disease. No recommendation could be made for or against the use of neoadjuvant therapy in cutaneous melanoma. In the unresectable/metastatic setting, ipilimumab plus nivolumab, nivolumab alone, or pembrolizumab alone should be offered to patients with BRAF wild-type cutaneous melanoma, while those three regimens or combination BRAF/MEK inhibitor therapy with dabrafenib/trametinib, encorafenib/binimetinib, or vemurafenib/cobimetinib should be offered in BRAF-mutant disease. Patients with mucosal melanoma may be offered the same therapies recommended for cutaneous melanoma. No recommendation could be made for or against specific therapy for uveal melanoma. 

YEP!

Five-Year Outcomes With Nivolumab in Patients With Wild-Type BRAF Advanced Melanoma.  Robert, Long, Brady, et al.  J Clin oncol.  2020 Nov.

Purpose: The CheckMate 066 trial investigated nivolumab monotherapy as first-line treatment for patients with previously untreated BRAF wild-type advanced melanoma. Five-year results are presented herein.

Patients and methods: In this multicenter, double-blind, phase III study, 418 patients with previously untreated, unresectable, stage III/IV, wild-type BRAF melanoma were randomly assigned 1:1 to receive nivolumab 3 mg/kg every 2 weeks or dacarbazine 1,000 mg/m2 every 3 weeks. The primary end point was overall survival (OS), and secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety.

Results: Patients were followed for a minimum of 60 months from the last patient randomly assigned (median follow-up, 32.0 months for nivolumab and 10.9 months for dacarbazine). Five-year OS rates were 39% with nivolumab and 17% with dacarbazine; PFS rates were 28% and 3%, respectively. Five-year OS was 38% in patients randomly assigned to dacarbazine who had subsequent therapy, including nivolumab (n = 37). ORR was 42% with nivolumab and 14% with dacarbazine; among patients alive at 5 years, ORR was 81% and 39%, respectively. Of 42 patients treated with nivolumab who had a complete response (20%), 88% (37 of 42) were alive as of the 5-year analysis. Among 75 nivolumab-treated patients alive and evaluable at the 5-year analysis, 83% had not received subsequent therapy; 23% were still on study treatment, and 60% were treatment free. Safety analyses were similar to the 3-year report.

Conclusion: Results from this 5-year analysis confirm the significant benefit of nivolumab over dacarbazine for all end points and add to the growing body of evidence supporting long-term survival with nivolumab mono-therapy. Survival is strongly associated with achieving a durable response, which can be maintained after treatment discontinuation, even without subsequent systemic therapies.

So over comparing any melanoma treatment with dacarbazine.  At the onset of this study, I suppose it was okay - but hopefully we are well past that now!!!  At any rate - important points are just relative to nivo only treatment and survival.  Overall response rate was 42%.  Of patients alive at five years ORR was 81%.  Of the patients on nivo with a complete response, 88% were alive at 5 years.  Of nivo treated patients alive at 5 years - 83% had needed no additional treatment, 23% were still on treatment, and 60% were treatment free.

Safety and efficacy of combination nivolumab plus ipilimumab in patients with advanced melanoma: results from a North American expanded access program (CheckMate 218).  Hodi, Chapman, Sznol, et al.  Melanoma Res.  2020 Nov.

CheckMate 218, a North American expanded access program (EAP), investigated nivolumab plus ipilimumab in patients with advanced melanoma. Safety and efficacy, including 2-year survival in clinically relevant patient subgroups, are reported. Eligible patients were aged greater than/equal to18 years with unresectable stage III/IV melanoma, an Eastern Cooperative Oncology Group performance status of 0/1, and no prior checkpoint inhibitors. Patients received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for 4 cycles (induction) followed by nivolumab 3 mg/kg every 2 weeks (maintenance) until progression or unacceptable toxicity or a maximum of 48 weeks. Safety and overall survival (OS) data were collected. This EAP included 754 treated patients from the USA (n = 580) and Canada (n = 174). Median follow-up time was 17.8 months. All-grade and grade 3-4 treatment-related adverse events were reported in 96% and 53% of patients and led to treatment discontinuation in 36% and 26% of patients, respectively. OS rates at 12 and 24 months were 82%  and 70%, respectively. Twenty-four-month OS rates were 63% in patients aged ≥75 years, 56% in patients with elevated lactate dehydrogenase levels, 73% in patients with BRAF wild-type tumors, 70% in patients with BRAF mutant tumors, and 56% in patients with mucosal melanoma. In this EAP, nivolumab plus ipilimumab demonstrated high survival rates and safety outcomes consistent with those from randomized clinical trials, further supporting the use of this combination for advanced melanoma across multiple subgroups.

Again - ipi/nivo with better survival than nivo alone, though with a more significant side effect profile.

PD-1 inhibitors might limit the development of brain metastases in patients with advanced melanoma.  Marcaillous, Linder, Chaltiel, et al.  Melanoma Res. 2020 Dec.

Brain metastases are a common and severe complication potentially leading to death in patients with metastatic melanoma. Immunotherapy and targeted therapy have significantly improved progression-free survival (PFS) and overall survival (OS) in patients with advanced melanoma. Few studies focus on patients with central nervous system (CNS) metastases, and these patients are often excluded and have a poor prognosis. It has been suggested that immunotherapy could reduce the incidence of brain metastases. We tested this hypothesis in a retrospective bicentric study. We performed a retrospective, bicentric descriptive analysis on a cohort of 293 patients treated for metastatic melanoma between May 2014 and October 2017. Patients with brain metastasis at diagnosis were excluded from the analysis. Patients were separated into two groups according to the first line of treatment: immunotherapy [immune checkpoint inhibitor (ICI)] vs other and anti-PD-1 vs other. The primary endpoint was the cumulative incidence of brain metastases, and secondary endpoints were OS and PFS. At 12 months, the cumulative incidence of brain metastases was 13.78% in the ICI group and 27.26% in the other group. The cumulative incidence was 9.49% in the anti-PD-1 group vs 30.11% in the other group . In multivariable analysis, anti-PD-1 reduced the risk of brain metastases by almost 70%. The use of ICI (anti-PD-1/PD-L1) in advanced melanomas without initial brain metastasis shows a protective effect and prevents their occurrence.

Yep.  Been yelling it for over 10 years!!!  Immunotherapy works in the brain.  Folks treated with anti-PD-1 had an incidence of brain met development of 9.49% vs 30.11% in patients not treated with anti-PD-1.  Analysis found that anti-PD-1 reduced the risk of brain mets by almost 70%.

PD-L1 blockade in combination with inhibition of MAPK oncogenic signaling in patients with advanced melanoma. Ribas, Algazi, Ascierto, et al.  Nat Commun.  2020 Dec.

Combining PD-L1 blockade with inhibition of oncogenic mitogen-activated protein kinase (MAPK) signaling may result in long-lasting responses in patients with advanced melanoma. This phase 1, open-label, dose-escalation and -expansion study (NCT02027961) investigated safety, tolerability and preliminary efficacy of durvalumab (anti-PD-L1) combined with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) for patients with BRAF-mutated melanoma (cohort A, n = 26), or durvalumab and trametinib given concomitantly (cohort B, n = 20) or sequentially (cohort C, n = 22) for patients with BRAF-wild type melanoma. Adverse events and treatment discontinuation rates were more common than previously reported for these agents given as monotherapy. Objective responses were observed in 69.2% (cohort A), 20.0% (cohort B) and 31.8% (cohort C) of patients, with evidence of improved tumor immune infiltration and durable responses in a subset of patients with available biopsy samples. In conclusion, combined MAPK inhibition and anti-PD-L1 therapy may provide treatment options for patients with advanced melanoma.

In this trial of either Durvalumab (anti-PD-L1) combined with dabrafenib/trametinib or just with trametinib or given sequentially - patients given the combination of the three drugs had a 69.2% response rate, of the 2 a response rate of 20% and in the sequential group (not clear, but I suspect that they got the three drugs) a response rate of 31.8%.  For comparison here is a report on atezo and pembro when combined with a BRAF/MEK therapy from 2019 that includes links to other reports of results when immunotherapy was combined with targeted therapy - Treating melanoma by COMBINING targeted therapy AND immunotherapy!!  When atezo and pembro were combined with a BRAF/MEK combo - responses rates were 70+%.  Of course, this treatment option is only available to about half of us as patients need to be BRAF positive.

Chemotherapy combined with antiangiogenic drugs as salvage therapy in advanced melanoma patients progressing on PD-1 immunotherapy.  Wang, Weiran, Zhihong, et al.  Transl Oncol. 2020 Nov.

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.

So these peeps created a fancy scale to determine whether a chemo cocktail would provide 3 vs 6 months of progression free survival in unresectable Stage IV melanoma folks who had become unresponsive to anti-PD-1.  Sad thing to face.  But, if this formula works, perhaps it can provide patients with knowledge that may inform their decision to accept or decline such therapy.

So there you have it.  Final 2020 reports in review for advanced melanoma patients - my take, anyway.  Over the coming days, I will plow through some other 2020 research on other topics pertinent to melanoma.  Stay safe.  Wear a mask.  Get a COVID vaccine when you can.  - c

New year, New Career??? VACCINES!!!!!

No human on the planet has been unscathed by the crazy of 2020!  My heart aches for those who have lost loved ones to the Coronavirus.  Lost jobs and homes.  Lost their own previously healthy status.  Lost the ability to visit family and friends.  Struggled to help the rest of us attain supplies and groceries.  Put forth Herculean efforts to teach our children whether in classrooms or their homes.  For those who refuse to protect themselves and those around them through simple travel restrictions and mask wearing - I have zero respect or sympathy.

I have been far more fortunate than most.  My four children remain healthy despite working on the front lines in restaurants, doctor offices and school classrooms.  And while I know many who have suffered from this unrelenting virus, some paying the ultimate price, most of those near and dear to me remain well.  Further, B and I were blessed with the option to stay home together and the wherewithal to entertain ourselves.  Through his work as a healthcare provider he was allowed a Covid vaccine a few weeks ago and is eagerly awaiting his second dose.

2021 has certainly brought more horrors as hate filled marauders invaded, looted, and vandalized our Capitol - beating and killing police officers, threatening our lawmakers, and attempting to overturn a free and fair election - just because they didn't like the outcome.  Because a horrible man with no conscience, no belief in democracy, no willingness to do anything for anyone other than himself - told them to.  2021 brought the grim total of deaths due to the Coronavirus to more than 400,000 souls - here - in the United States of America.  There are now more than 24 million cases in this country alone.

Still, I am not without hope.  With intelligent leadership and the obvious result of unchecked viral spread, I am hopeful that more Americans will wear masks, utilize common sense, show respect for their fellow man.  I am hopeful that sane leaders and peer pressure from the vast majority of Americans who believe in justice and the rule of law will tamp down the crazy that has been spread in the dark corners of the internet and from the bully pulpit.  Finally, though it will take time, I am incredibly hopeful that vaccinations will turn the tide in this epidemic.   To that end....

I am now on a team through our local health department to provide those very vaccinations!!!  There are those who say such a position is below my pay grade.  That I am over trained.  Given the current state of our world, I can't think of any better way to spend my time and skills!  I have the blessings of my peeps - albeit with some trepidation.  I was not able to attain my vaccine as a healthcare provider until AFTER I started working.  Not ideal.  But, as the powers that be won't allow healthcare workers a vaccine without proof of employment - nor are folks with risk factors (missing lung, asthma, post chemo - though I am probably out of the woods with that last - in my case) currently allowed a vaccine unless they meet some other criteria like age, etc. - that's the breaks.  Given the vaccines take place in a "drive by" fashion and the fact that I am actually trained to protect myself from communicable diseases - the Guardians of my Galaxy have relented!  It feels good to be productive.  To do SOMETHING to help.

My path over the past two years has been - well, I really don't know the words!  I left my practice of 13 years as a Pediatric Nurse Practitioner jam packed with valuable lessons, incredible friends, and amazing patients with mixed feelings.  I was sad to leave, but had great plans of a dream trip to Italy with B and finding a new position closer to home on our return.  All of that was not to be.  Instead, just days after my last work day and a few weeks before our scheduled departure - my "last scan" for melanoma revealed ex-goblet cell adenocarcinoma of the appendix.  Damn!  Trip canceled.  Multiple surgeries and multiple organ removal was followed by nasty ass chemo.  My return to health was infuriatingly slow.  Poop patrol in a manner conducive to leaving the house seemed insurmountable at times.  But through amazing care and encouragement from my peeps, endless gardening shows (Thank you, Monty Don!!!), actual gardening, sewing and gradually increasing exercise, I worked my way back!  Early plans to rejoin the workforce and land of the living in 2020 were quickly dashed with the advent of Covid.  Nevertheless, I am here!  I am well.  I am working to help as best I can, so that ALL of us can return to the lives we want.

Take good care.  Wear a mask.  And I beg you - get a Covid vaccination as soon as you are allowed!!  Much love and virtual hugs ~ les

Sew Chaotically! ~ The best dude and the quilt frame he built!!!

I casually mentioned I'd like to make a quilt.  I made it clear I didn't know HOW to make a quilt!  That I really had no idea how to proceed with such a thing.  No matter.  Within minutes B was busy!!!  He did a little research, ordered a pattern, and was off to the races!

Cutting out side supports.

Getting all those rails and gears set.

Sanding it carefully!

And there she is!!!!  Isn't she pretty?  Three rails with gears, locks and a support beam!!!

I researched various 'leaders' on both hand quilting frames and long arm machines.  I used canvas duck to create these.  B helped me mark their centers and other points I needed to help line up the quilt layers properly.  He used a staple gun to attach them to the rails.  No more excuses.  I had to quilt something!

I wasn't ready to risk all the work I've put into my sashiko squares in my first attempt!  So...

...as mentioned in my prior post, I put this 60X60 throw together using the Carolina Chain Quilt pattern from bits and pieces I'd been collecting for some time to serve as my quilting rattie!

Trying to make sure I test all aspects, I decided to go ahead and use my Hera Marker to make 'dents' for my stitching lines in the border as a test for duration of said dents through the quilting process.  My super cool new cutting mat was the perfect surface!

As B built it, I tried to figure out how to use it!!!  With so many folks using regular sewing machines, long arm quilting machines and hand quilters using hoop type frames or none at all to make their quilts, it  was a bit of a challenge to find information on these Amish style quilting frames.  While the internet can be used for ill, it also connects folks and allows us to share information of all kinds.  I owe a great deal of thanks to Shawnae Somsen for an excellent video she created after finding it difficult to load her own - Loading an Amish Quilting Frame.  I loaded mine much as she did.  AND ~ I think it'll work!

And because B is super awesome, he made a work table to go alongside - replete with shelves and inset magnetized work bowls!!!

I am pleased to embrace this new adventure.  I am incredibly fortunate and privileged to have the means, space, and access to such extravagant entertainment - the opportunity to develop new hobbies.  I am more than blessed to have a partner who will indulge my whims and play my silly games.  Thanks, B.  I love you.

May you all find peace and comfort in things large and small during this crazy time.  ~ love, les

Sew Chaotically! ~ I made a quilt!!!!

 Well - a quilt top anyway!

This quilt has been in the works for a very long time!  I have been cutting bits and remnants from all my makes into 2 inch wide strips and squares for the longest - inspired by this post of Julie Lou's Bonnie Hunter's Carolina Chain Quilt.  

I have stitched many "quilts" together in the past.  Lots of little patchwork throws for the kids when they were growing up.  I even made a full sized bed cover for Roo when she moved into her house -

They were pieced with random shaped scraps, their layers tied together with embroidery thread.  Still, having finished all my sashiko blocks - you can peep that prep here:  November's Nesting and Making - I figured I'd better learn some actual quilting skills and practice them on something a little less precious!  With all those pre-cut pieces sitting in a box, I figured they would be a good starting place.  So, last week I got busy.  I decided upon a throw measuring 60" X 60", as a gift for a dear one who just completed and moved into his first house.  I selected greys, browns, blues, and greens from my box as they match his interior.  

Before I began, I read several quilting books.  I watched dozens of quilting videos.  Things can get confusing pretty quickly as quilters are passionate about how they do things ~  Use only size 9 or smaller quilting needles.  No, use embroidery needles!  Use quilting thread.  Wax it.  No, buy pre-waxed.  Use DMC pearl cotton #5.  Press seam allowances to the 'dark' side in one direction.  Press seams open.  Cut this way.  Pin pieces this way.  And so much more!  While all those seemingly disparate techniques can be a bit over whelming to a new quilter - I am ever so grateful to all the quilters who went to the trouble to post their advice, techniques and create tutorials.  I am particularly indebted to these generous quilters for the inspiration and information they provide:

Carolyn Gibbs Quilts      Suzy Quilts      The above mentioned Just Julie Lou

Farm and Folk      Karen's Quilting      Vacilando Quilting Company  

Elizabeth of Mend Learn      Bonnie K Hunter's - Quiltville

Though slow going at first, I began to get the hang of what I was doing and managed to piece the top in about 5 days.  MANY lessons were learned!!!!

• Quilting is most certainly a 'pay me now or pay me later' sort of thing!  I had cut my stash of pieces rather hurriedly at the end of garment making and had to trim up most of them more carefully if there was to be any hope of them going together with sharp lines and points as they should.  Once the quilt top was finished I created a cardboard template for my sashiko squares, so I could press the edges under and stitch round them to create finished edges and consistent sizes.  Again, I had not put tremendous effort in cutting the rectangles perfectly knowing they were to be hemmed!!!  Given that, a good bit of fiddling and measuring to make certain the stitched designs were centered was required.  Both instances necessitated a stern conversation with my past devil-may-care self!
• Making a quilt from garment scraps is - sensible, nostalgic, earth friendly, sustainable, useful.
• Making a quilt from garment scraps is - CHALLENGING!  For this quilt I bought nothing other than a poly/cotton batting and grey linen-esq cotton to use as backing and finish out the top's border.  Finding colors that work together wasn't too difficult as my wardrobe of makes is pretty cohesive.  However, having enough contrast in the fabric I had on hand was a real challenge.  I was very worried that the 'light' and 'dark' lines would not come through as they should.  If I had selected fabric FOR this quilt, that would have been much easier.  Still, I'm pretty happy with how it turned out.  (Despite the block that is turned the wrong way!!!  We'll just call that a design element and leave it at that!!!)  Having to use fabric in a variety of textures and types created another issue.  This quilt top contains linen, tencel, various cottons, including bits of quilting cotton.  Clearly some of those fabrics have far more give than the fabric they were paired with, so it was easy for the squares to go a bit wonky!  I'm pleased enough with how I managed to keep the lines straight, though a few blocks won't tolerate close inspection!!  I just hope they will all hold together with use.  Shockingly, quilting cotton is steady as a rock and stitches together perfectly!  Who knew??? (All quilters - that's who!)
• Through trial and error, I settled on pressing seams to one side, but alternated the direction at intersections.  I found this method created a lot less bulk and I was able to match seams much more easily.  After the top was completed, further reading led me to a quilter who recommended that practice as well.

Overall, I am quite tickled with how it turned out.  I've made and installed canvas leaders onto the three rail quilting frame B made me.  It is AMAZING!!!  Blog post coming on that adventure soon! Today, I hope to get the top, batting (learning about THAT was a whole other thing!!!), and bottom loaded on it!  

New Year = New Lessons and Adventures!!  Happy New Year and Happy Making to you and yours! - love les