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
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