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
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