Future of Immunotherapy in Melanoma to Focus on Overcoming Resistance, Personalizing Regimens

With an estimated 5-year survival rate of 50% and an ongoing issue of resistance, Georgina Long, AO, BSc, PhD, MBBS, FRACPP, FAHMS, said that the next steps with immunotherapy in melanoma will focus on stratifying patients, personalizing therapy, and refining localized regimens.

Moreover, ongoing first-line studies will show a small, if any, incremental benefit in patients with advanced disease, Long projected in a presentation during the virtual 17th International Congress of the Society for Melanoma Research.¹

“We have benchmarks for our standard treatments; we can explore more new, novel therapies, look at [patients’] pathologic complete response rates within 6 weeks, and then make decisions on whether they need further development. This is the future,” said Long, who is co-medical director of Melanoma Institute Australia, and chair of Melanoma Medical Oncology and Translational Research at MIA and Royal North Shore Hospital, The University of Sydney. “We’re now at the stage where we have to stratify and personalize therapy.”

The best way to summarize where the field is now with immunotherapy in melanoma, Long said, is to review the current overall survival (OS) rates yielded with this approach. Five-year OS rates with BRAF inhibitors combined with MEK inhibitors, PD-1 inhibitors alone, and PD-1 plus CTLA-4 inhibitors are 34%,² 44%,3 and 52%,³ respectively, leaving room for improvement.

Triplet regimens with immunotherapy were a natural next step in this paradigm in an attempt to further improve outcomes, although results have been modest, according to Long.

For example, in the phase 2 KEYNOTE-022 trial, pembrolizumab (Keytruda) was evaluated in combination with dabrafenib (Tafinlar) and trametinib (Mekinist) in patients with treatment-naive BRAF V600E/K–mutant, advanced melanoma compared with dabrafenib/trametinib plus placebo. At 24 months of follow-up, the triplet led to a 47% reduction in the risk of disease progression or death compared with the doublet therapy (HR, 0.53; 95% CI, 0.34-0.83).⁴

Similarly, in the IMspire150 trial, frontline atezolizumab (Tecentriq) was evaluated in combination with vemurafenib (Zelboraf) and cobimetinib (Cotellic) in patients with unresectable advanced BRAF V600 mutation–positive melanoma. Results showed that the triplet led to a 22% reduction in the risk of disease progression or death versus vemurafenib/cobimetinib plus placebo (HR, 0.78; 95% CI, 0.63-0.97; P = .025).⁵

Most recently, an updated analysis of part 3 of the phase 3 COMBI-i trial showed that spartalizumab plus dabrafenib/trametinib in patients with untreated BRAF V600–mutant unresectable or metastatic melanoma did not meet its primary end point of investigator-assessed progression-free survival (PFS). However, although OS was not formally tested, a hazard ratio of 0.785 was observed in favor of the spartalizumab plus dabrafenib and trametinib combination.⁶

“In summary, for these triplet therapies, the [results with] immune and targeted therapy together [were modest] said Long. “There is a clinically minor added benefit, however with significant toxicity.”

Perhaps the “sandwich approach” would be optimal, suggested Long. This strategy was used in the phase 2 SECOMBIT [Sequential COMB Immuno and Targeted Therapy] study and was presented during the 2020 ESMO Virtual Congress. Patients with untreated metastatic BRAF V600–mutant melanoma were randomized 1:1:1 to encorafenib/binimetinib until disease progression, followed by nivolumab/ipilimumab (arm A); nivolumab/ipilimumab until disease progression, followed by encorafenib/binimetinib (arm B); or encorafenib/binimetinib for 8 weeks, followed by nivolumab/ipilimumab until disease progression, followed by encorafenib/binimetinib (arm C).

Results showed that the median PFS was 15.8 months, 7.2 months, and 11.4 months in arms A, B, and C, respectively.⁷ While these data differed, the 2-year PFS rates were similar at 35%, 38%, and 39%, respectively.

More data are needed from this trial before applying any of these approaches to clinical practice, Long concluded.

Looking ahead, read outs from the ongoing first-line combination trials are anticipated, including the phase 3 KEYNOTE-034 study (NCT02263508) of pembrolizumab with or without talimogenelaherparepvec (T-VEC; Imlygic) in patients with unresectable stage IIIB to IVM1c melanoma; a phase 2 trial (NCT04552223) of nivolumab plus relatlimab in patients with metastatic melanoma who have not received prior immunotherapy; and the phase 3 LEAP-003 trial (NCT03820986) of pembrolizumab plus lenvatinib (Lenvima) in patients with advanced disease.

“I don’t believe they will be much better than ipilimumab/nivolumab,” said Long. “[These combinations] may be less toxic, but I’m not sure they will reach that bar.”

Immunotherapy in the Locally Advanced Setting

Regarding checkpoint inhibitors, nivolumab, pembrolizumab, and ipilimumab are all available for use in the adjuvant setting, along with the combination of dabrafenib and trametinib. Yet, the optimal use of adjuvant treatment is still unclear, according to Long.

“The big question in adjuvant therapy is: Should we be treating now with this adjuvant therapy, or should we treat later when we definitely have recurrence?” Long asked.

Some clues to answering that question may come from the phase 3 CheckMate-238 trial, in which 906 patients who were undergoing complete resection of stage IIIB, IIIC, or IV melanoma were randomized to receive either nivolumab at 3 mg/kg every 2 weeks or ipilimumab at 10 mg/kg every 3 weeks for 4 doses and then every 12 weeks.

The 12-month rate of recurrence-free survival (RFS) was 70.5% (95% CI, 66.1-74.5) with nivolumab and 60.8% (95% CI, 56.0-65.2) with ipilimumab (HR, 0.65; 97.56% CI, 0.51-0.83; P < .001).⁸ In longer follow-up, looking at the secondary end point, the 4-year OS rate was 77.9% and 76.6% with nivolumab and ipilimumab, respectively (HR, 0.87; 95% CI, 0.66-1.14; P = .315).⁹

“We still need 100 or so events to analyze this properly, but it suggests that perhaps we can treat [patients] later,” Long added.

Combination adjuvant immunotherapy with nivolumab and ipilimumab also showed an improvement in relapse-free survival versus nivolumab alone or a double-matching placebo group (HR, 0.23; 95% CI, 0.13-0.14) in patients with resected stage IV melanoma in the double-blind, placebo-controlled phase 2 German IMMUNED study.¹⁰

Moreover, the combination of nivolumab and ipilimumab was evaluated again in the phase 3 CheckMate-915 trial—this time, in patients with resected stage IIIB/CD, or IV cutaneous or mucosal melanoma. Patients were randomized to receive nivolumab at 480 mg every 4 weeks or nivolumab at 240 mg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks. However, topline results showed that the combination compared with nivolumab alone did not meet its primary end point of RFS.¹¹

“Why [was this not a positive study]?” Long asked. “We don’t know yet, but could it be a dosing issue of ipilimumab, or could it be a protocol issue? If you develop toxicity on the nivolumab/ipilimumab arm, you couldn’t continue on nivolumab alone [on this trial], so maybe these patients received much less immunotherapy than needed due to toxicity. We do not do that in practice.”

Resistance to Immunotherapy

Resistance to checkpoint inhibitors is an active area of investigation, especially as Long noted that 50% of patients progress on immunotherapy within 6 months, which presents as primary progression, tends to be homogeneous, and is generalized.

However, recent research may provide some context to this difficult-to-treat scenario. At the virtual 2020 ESMO Virtual Congress, findings from the phase 2, single-arm LEAP-004 trial showed that the combination of lenvatinib and pembrolizumab elicited a confirmed ORR by blinded independent central review of 21.4% in patients with advanced melanoma that has progressed on a PD-1/PD-L1 inhibitor.¹²

Additional areas of exploration for response and resistance to immunotherapy in melanoma include collection of tumor and tumor fragments/dissociates, blood, and feces and skin, Long explained. Moreover, she looked to the neoadjuvant setting, where 6 weeks of preoperative therapy could be “the perfect model”—with pathologic complete response rate as a key measure.

References

1. Long GS. Immunotherapy: where are we now and where to next? Presented at: 17th International Congress of the Society for Melanoma Research; October 28, 2020; virtual.
2. Robert C, Grob JJ, Stroyakovskiy D, et al. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N Eng J Med. 2019;381(7):626-636. doi:10.1056/NEJMoa1904059
3. Larkin J, Chiarin-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Eng J Med. 2019;381(16):1535-1546.
   doi:10.1056/NEJMoa1910836
4. Ferucci P, Ascierto PA, Maio M. Updated survival in patients (pts) with BRAF-mutant melanoma administered pembrolizumab (pembro), dabrafenib (D), and trametinib (T). Presented at: 16th International Congress of the Society for Melanoma Research; November 20-23, 2019; Salt Lake City, UT.
5. Gutzmer R, Stroyakovskiy D, Gogas H, et al. Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020;395(10240):1835-1844. doi:10.1016/S0140-6736(20)30934-X
6. Nathan PD, Dummer R, Long GV, et al. Spartalizumab plus dabrafenib and trametinib (Sparta-DabTram) in patients (pts) with previously untreated BRAF V600–mutant unresectable or metastatic melanoma: results from the randomized part 3 of the Phase III COMBI-i trial. Ann Oncol. 2020;31(suppl_4):S1142-S1215. doi:10.1016/annonc/annonc325
7. Ascierto PA, Mandalá M, Ferrucci PF, et al. First report of efficacy and safety from the phase II study SECOMBIT (SEquential COMBo Immuno and Targeted therapy study). Ann Oncol. 2020;31(suppl_4):S1142-S1215. doi:10.1016/annonc/annonc325
8. Weber J, Mandalá M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage iii or iv melanoma. N Eng J Med. 2017;377(19):1824-1835. doi: 10.1056/NEJMoa1709030
9. Ascierto PA, Vecchio MD, Mandalá M, et al. 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. Lancet Oncol. Published online September 19, 2019. doi:10.1016/S1470-2045(20)30494-0
10. Zimmer L, Livingstone E, Hassel JC, et al. Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2020;395(10236):1558-1568. doi: 10.1016/S0140-6736(20)30417-7
11. Bristol Myers Squibb announces update on CheckMate -915 evaluating Opdivo (nivolumab) plus Yervoy (ipilimumab) versus Opdivo in resected high-risk melanoma patients. News release. Bristol Myers Squibb. October 2, 2020. Accessed October 29, 2020. https://bit.ly/2TCbXOy
12. Arance Fernandez AM, O’Day SJ, de la Cruz Merino L, et al. Lenvatinib (len) plus pembrolizumab (pembro) for advanced melanoma (MEL) that progressed on a PD-1 or PD-L1 inhibitor: Initial results of LEAP-004. Ann Oncol. 2020;31(suppl_4):S1142-S1215. doi: 10.1016/annonc/annonc325