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Table of Contents
ONCOLOGY UPDATE
Year : 2020  |  Volume : 3  |  Issue : 3  |  Page : 594-597

Melanoma at American Society of Clinical Oncology 2020 – An update and its implications in the Indian setting


1 Department of Medical Oncology, Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
2 Department of Radiodiagnosis, ABVIMS and DR. RML Hospital, New Delhi, India

Date of Submission11-Jul-2020
Date of Decision27-Jul-2020
Date of Acceptance06-Aug-2020
Date of Web Publication19-Sep-2020

Correspondence Address:
Sameer Rastogi
Department of Medical Oncology, Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi-110029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_239_20

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How to cite this article:
Mittal A, Gupta A, Rastogi S. Melanoma at American Society of Clinical Oncology 2020 – An update and its implications in the Indian setting. Cancer Res Stat Treat 2020;3:594-7

How to cite this URL:
Mittal A, Gupta A, Rastogi S. Melanoma at American Society of Clinical Oncology 2020 – An update and its implications in the Indian setting. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Oct 26];3:594-7. Available from: https://www.crstonline.com/text.asp?2020/3/3/594/295494




  Introduction Top


Advanced melanoma is one of the success stories of oncology. A disease with a dismal 5-year survival rate of 5% about a decade ago has been transformed by immunotherapy and targeted therapy such that 50% of the patients can now achieve long-term disease control.[1] In the past ten years, a multitude of agents have been added to the armamentarium of oncologists for the treatment of melanoma, both in advanced disease and in the adjuvant setting. In the recent American Society of Clinical Oncology (ASCO) 2020 meeting, several important studies were presented, further adding to our understanding of this disease. Although an increasing number of studies on melanoma are being reported, for India, the unavailability of drugs like ipilimumab, high cost of available immunotherapy and targeted therapy, and the lack of active clinical trials continue to remain some of the major obstacles to improving our patient outcomes. In this article, we discuss the implications of a few select abstracts from the ASCO 2020 symposium on our routine clinical practice [Table 1].
Table 1: Summary table

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  Discussion Top


COMBI AD study (adjuvant BRAF and MEK inhibitor therapy trial)

The 5-year outcomes of the use of adjuvant dabrafenib and trametinib (D + T) for 12 months in patients with resected stage III BRAF mutated melanoma were presented in this abstract.[2] This was a placebo-controlled study in which about 870 patients with stage III cutaneous melanoma were randomized to receive dabrafenib and trametinib or a matched placebo. The primary end point of this study was relapse-free survival (RFS). Majority (80%) of the patients in both the arms had stage IIIB/C disease (as per the American Joint Committee on Cancer [AJCC] 7th edition). RFS for the treatment arm at 5 years was 52%, while that for the placebo arm was 36%. The median RFS in the placebo arm was 16.6 months (95% confidence interval [CI], 12.7–22.1), whereas the median RFS for the D + T arm was not reached (NR) (95% CI, 47.9 months – NR); hazard ratio, 0.51 (95% CI, 0.42–0.61). Except for patients with stage IIIA disease and V600K mutation and patients from Australia and New Zealand (test of heterogeneity awaited), a significant benefit was observed in all the other subgroups. Although this could be attributed to the small number of patients in these subgroups, the benefit disappeared completely in stage IIIA when the results were analyzed according to the 8th edition of the AJCC staging system. This is likely because 30%–40% of the high-risk cases of stage IIIA disease according to the 7th edition of AJCC are reclassified as stage IIIB in the 8th edition of AJCC.[7] Thus, the role of adjuvant therapy in stage IIIA completely resected melanoma remains controversial (especially considering the arguable benefit from immunotherapy as well), and such patients may be spared the physical and financial toxicity of treatment. The overall survival (OS) results of this study were not presented at the symposium and are awaited. Although the prevalence of BRAF mutations in the Indian patients is unknown, it is expected to be lower than that in the western population, due to the higher prevalence of mucosal, acral, and orbital melanomas.[8] However, considering its recent availability in India, D + T remains an important therapeutic option for patients with BRAF mutation in the adjuvant setting, especially for those who have toxicity from immunotherapy, those who are unwilling for intravenous therapy, especially during the prevailing COVID-19 pandemic, and those who are not eligible for immunotherapy due to their pre-existing uncontrolled autoimmune condition.

Post anti-programmed cell death receptor 1 antibody progression – Role of immunotherapy

Two abstracts addressed the question of immune checkpoint inhibitor (ICI) re-challenge after progression on first-line, single-agent, anti-programmed cell death receptor 1 ( PD1) therapy, which is the most common approach in our routine practice as well.[3],[4] Both studies tested the combination of ipilimumab (ipi) with anti-PD1 therapy after progression on anti-PD1 therapy in the first line. Although there are preliminary data to suggest that ipi alone or in combination with anti-PD1 therapy might be beneficial in such patients, it is not the standard approach, and therapeutic options in this scenario are limited. The first abstract presented by Hauschild et al. was for a retrospective study that evaluated the response rates, progression-free survival (PFS), and OS in 355 patients who had previously received anti-PD1 monotherapy, either in the adjuvant or metastatic setting. Postprogression, 46% (n = 162) of the patients received ipi, while 54% (n = 193) received a combination of ipi with anti-PD1 therapy. There was a difference in the baseline characteristics of the patients in the two arms, as can happen in a retrospective study; the ipi arm had a higher median age (67 vs. 61 years), fewer patients with brain metastasis (26% vs. 36%), and a lower prevalence of BRAF mutations (21% vs 36%) than the combination arm. The objective response rate (ORR) in the combination arm was significantly higher than that in the single-agent arm (32% vs. 13%, P = 0.0021). The 1-year PFS was 25% in the combination arm and 13% in the single-agent arm. In addition, the OS in the combination arm was also significantly higher than that in the single-agent arm (20 vs. 8.8 months [P < 0.0001]). Moreover, the interval between first-line anti-PD1 therapy and post-progression ipi ± anti-PD1 use affected the patients' response to combination immunotherapy.

The second abstract was for a phase II single-arm trial in which 70 patients were treated with ipi and a dose of 1 mg/kg along with pembrolizumab 200 mg once-in-3-weeks after progression on anti-PD1 therapy. The ORR was 31% with a median PFS of 5 months and median OS of 24.7 months. grade 3/4 adverse events were seen in 27% of the patients, which was less than half (56%) of that seen in the checkmate 067 trial with nivolumab (nivo)-ipi. Similar findings have been reported in metastatic renal cell cancer; Gul et al. observed a 20% ORR with 16% stable disease (SD) with nivo-ipi in patients previously treated with immunotherapy with a median PFS of 4 months.[9]

Although these retrospective findings need prospective validation, they provide an answer to a very challenging and important clinical situation in patients with BRAF-negative melanoma who progress on front-line immunotherapy and BRAF-positive patients who progress on immunotherapy and targeted therapy. Given the chemoresistant nature of melanoma (10% ORR in the first-line setting),[10] this study provides important conceptual proof of the value of ICI re-challenge in patients progressing on first-line ICI monotherapy. However, the unavailability of ipilimumab in India makes the management of patients resistant to anti PD-1 therapy even more complex and is an important factor contributing to their poor outcomes.

Triple therapy (anti programmed cell death ligand-1 + BRAF inhibitor + MEK inhibitor)

Another abstract presented by Paola et al. was an exploratory analysis of the time to central nervous system (CNS) metastasis in the triple therapy arm (atezolizumab, vemurafenib, and cobimetinib [a + v + c]) as compared to the doublet arm (cobimetinib and vemurafenib [v + c]) (IMspire 150 study).[5] Previously, it had been observed that patients receiving the triple therapy (a + v + c) achieved a median PFS of 15.1 months, while those receiving the doublet therapy (v + c) achieved a median PFS of 10.6 months.[11] In addition, the triple therapy arm showed an improved duration of response; patients treated with the three-drug combination achieved a median duration of response of 21 months, whereas in the doublet arm, this duration was 12.6 months. However, almost 40% of the patients developed grade 3/4 adverse events in the triple therapy group, with sepsis or pyrexia occurring in more than two patients. The most common minor side effects included hypophosphatemia, diarrhea, arthralgia, and elevation of liver enzymes. In the current abstract, the time to CNS metastasis was numerically but not statistically lower in the triple therapy group. However, the incidence of brain metastasis was quite low in both the arms as compared to the historical control (19% in c + v vs. 16% in a + c + v arm). Currently, there are no data to compare the sequential approach of immunotherapy (single agent/combination) followed by BRAF/MEK inhibitors with triple therapy, and until such data become available, the superiority of this approach cannot be established unequivocally. In addition, considering the combined toxicity of immunotherapy and targeted therapy (both physical and financial with cobimetinib being unavailable in India), we believe that this strategy is not feasible in our population.

Optimizing ipilimumab dosing strategy

This abstract presented intriguing data on the impact of reducing the number of doses of ipilimumab on the outcome of metastatic melanoma treated with combination immunotherapy.[6] This study was conceived because of the unfavorable toxicity profile of the combination, with 56% of the patients having grade 3/4 side effects in the CheckMate 067 trial.[1] The authors omitted two doses of ipilimumab in patients who had a good anti-tumor response (complete response (CR)/partial response [PR]/SD) at the week 6 assessment. The primary end point was ORR (CR/PR) at week 12. A total of 60 patients were treated, and 68% had a favorable response at week 6 with the omission of two ipi doses. The primary end point was achieved in 48% (compared to the ORR of 60% with conventional dosing in CheckMate 067. Overall, 76% of the patients received only two doses, and yet 57% developed grade 3/4 toxicities after a median follow-up of 11 months, which is similar to the previous data (three treatment-related deaths). Another important finding was that patients who did not respond at week 6 also did not respond at week 12, indicating that imaging at week 6 could be an early marker for response in these patients. A noteworthy finding from this study for the Indian setting is that although the toxicity was not reduced with fewer doses of ipilimumab, the efficacy did not seem to be compromised either. This might help to reduce the financial burden on our patients when ipilimumab is finally launched in India.


  Conclusion Top


Although melanoma research is at an exciting juncture, there is an urgent need to bridge the gap between the bench and bedside in India.[12] Rare cancers such as melanomas need to be prioritized, Indian data regarding the prevalence of mutations and the response to newer drugs need to be generated, drugs need to be made accessible, and specialist clinics at tertiary level centers need to be promoted to provide the best quality care for this rare but lethal disease.



 
  References Top

1.
Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol 2018;19:1480-92.  Back to cited text no. 1
    
2.
Hauschild A, Dummer R, Santinami M, Atkinson V, Mandalà M, Kirkwood JM, et al. Long-term benefit of adjuvant dabrafenib+trametinib (D+T) in patients (pts) with resected stage III BRAF V600–mutant melanoma: Five-year analysis of COMBI-AD. J Clin Oncol 2020;38 (15 Suppl):10001.  Back to cited text no. 2
    
3.
Olson D, Luke JJ, Poklepovic AS, Bajaj M, Higgs E, Carll TC, et al. Significant antitumor activity for low-dose ipilimumab (IPI) with pembrolizumab (PEMBRO) immediately following progression on PD1 Ab in melanoma (MEL) in a phase II trial. J Clin Oncol 2020;38 (15 Suppl):10004.  Back to cited text no. 3
    
4.
Silva IP, Ahmed T, Lo S, Reijers IL, Weppler A, Warner AB, et al. Ipilimumab (IPI) alone or in combination with anti-PD-1 (IPI+PD1) in patients (pts) with metastatic melanoma (MM) resistant to PD1 monotherapy. J Clin Oncol 2020;38 (15 Suppl):10005.  Back to cited text no. 4
    
5.
Ascierto PA, Robert C, Lewis KD, Munhoz R, Liszkay G, de la Merino LC, et al. Time to central nervous system (CNS) metastases (mets) with atezolizumab (A) or placebo (P) combined with cobimetinib (C)+vemurafenib (V) in the phase III IMspire150 study. J Clin Oncol 2020;38 (15 Suppl):10023.  Back to cited text no. 5
    
6.
Postow MA, Goldman DA, Shoushtari AN, Warner AB, Callahan MK, Momtaz P, et al. A phase II study to evaluate the need for > two doses of nivolumab + ipilimumab combination (combo) immunotherapy. J Clin Oncol 2020;38 (15 Suppl):10003.  Back to cited text no. 6
    
7.
Isaksson K, Katsarelias D, Mikiver R, Carneiro A, Ny L, Bagge RO. A Population-Based Comparison of the AJCC 7th and AJCC 8th Editions for Patients Diagnosed with stage III Cutaneous Malignant Melanoma in Sweden. Ann Surg Oncol 2019;26:2839-45.  Back to cited text no. 7
    
8.
Chen F, Zhang Q, Wang Y, Wang S, Feng S, Qi L, et al. KIT, NRAS, BRAF and FMNL2 mutations in oral mucosal melanoma and a systematic review of the literature. Oncol Lett 2018;15:9786-92.  Back to cited text no. 8
    
9.
Gul A, Stewart TF, Mantia CM, Shah NJ, Gatof ES, Long Y, et al. Salvage Ipilimumab and Nivolumab in Patients With Metastatic Renal Cell Carcinoma After Prior Immune Checkpoint Inhibitors. J Clin Oncol. 2020 ;JCO1903315.  Back to cited text no. 9
    
10.
Hersh EM, Vecchio MD, Brown MP, Kefford R, Loquai C, Testori A, et al. A randomized, controlled phase III trial of nab-paclitaxel versus dacarbazine in chemotherapy-naïve patients with metastatic melanoma. Ann Oncol 2015;26:2267-74.  Back to cited text no. 10
    
11.
Sullivan RJ, Hamid O, Gonzalez R, Infante JR, Patel MR, Hodi FS, et al. Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients. Nat Med 2019;25:929-35.  Back to cited text no. 11
    
12.
Darling HS, Rastogi S. Rare cancers in India: A road less travelled. Indian J Cancer 2020;57:139-43.  Back to cited text no. 12
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