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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.

“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%,

 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 

 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).

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; 

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 

 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.

“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 

 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.

 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; 

 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; 

“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.

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.

“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 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.

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.

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.

Robert C, Grob JJ, Stroyakovskiy D, et al. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. 

. 2019;381(7):626-636. doi:10.1056/NEJMoa1904059

Larkin J, Chiarin-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. 

. 2019;381(16):1535-1546.
doi:10.1056/NEJMoa1910836

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.

Gutzmer R, Stroyakovskiy D, Gogas H, et al. Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced 

V600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. 

. 2020;395(10240):1835-1844. doi:10.1016/S0140-6736(20)30934-X

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. 

. 2020;31(suppl_4):S1142-S1215. doi:10.1016/annonc/annonc325

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). 

Weber J, Mandalá M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage iii or iv melanoma. 

. 2017;377(19):1824-1835. doi: 10.1056/NEJMoa1709030

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. 

. Published online September 19, 2019. doi:10.1016/S1470-2045(20)30494-0

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. 

. 2020;395(10236):1558-1568. doi: 10.1016/S0140-6736(20)30417-7

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

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. 

. 2020;31(suppl_4):S1142-S1215. doi: 10.1016/annonc/annonc325

With an estimated 5-year survival rate of 50% and an ongoing issue of resistance,  next steps with immunotherapy in melanoma will focus on stratifying patients, personalizing therapy, and refining localized regimens.   

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

The addition of anti–PD-1/PD-L1 to combination BRAF and MEK inhibition has been shown to improve progression-free survival (PFS) and duration of response (DOR) in patients with BRAF-mutated melanoma, suggesting potential to overcome resistance to targeted approaches, said Grant McArthur, MBBS, PhD, in a presentation during the 

Targeted therapies, such as BRAF and MEK inhibitors, offer an advantage of rapid and high response rates in patients with advanced melanoma harboring a BRAF mutation. However, the limitation of this approach is the development of resistance, according to McArthur. Most of the patients who receive BRAF/MEK inhibition in this setting will experience disease progression. 

“If we were able to overcome resistance to targeted therapies, this would be a major benefit for patients,” noted McArthur, who is executive director of the Victorian Comprehensive Cancer Centre, inaugural Lorenzo Galli Chair of Melanoma and Skin Cancers at the University of Melbourne, Australia, and a senior principal research fellow.

Several approaches have been explored in an attempt to overcome resistance to targeted treatment approaches, such as targeting acquired mechanisms of resistance, the development of novel BRAF inhibitors, overcoming early drug adaptation or tolerance, and the enhancement of antitumor immunity.

“[It has been shown] that the combination of BRAF and MEK inhibition could induce an influx of CD8 and CD4 T cells in the tumor and generate a favorable tumor microenvironment with a reduction in T-reg and myeloid-derived suppressor cells,” said McArthur. “This has led to the hypothesis that it might be possible to overcome resistance to targeted therapies by enhancing this immune response in the tumor through the addition of immune checkpoint inhibitors.”

In his presentation, McArthur walked the virtual audience through 3 pivotal trials that further evaluated this hypothesis: the phase 2 KEYNOTE-022 trial (NCT02130466), the phase 3 IMspire150 trial (NCT02908672), and the phase 3 COMBI-i trial (NCT02967692).

 enrolled a total of 120 patients with histologically confirmed unresectable or metastatic stage IV BRAF V600E/K–mutated melanoma. Patients had to be treatment naïve, have measurable disease, and an ECOG performance status of either 0 or 1 to be eligible. Participants were stratified based on performance status (0 vs 1) and

lactic acid dehydrogenase (LDH) level (greater than 1.1 x upper limit of normal [ULN] vs 1.1 or less x ULN).

In the trial, patients were randomized 1:1 to receive either pembrolizumab (Keytruda) at 2 mg/kg once every 3 weeks plus dabrafenib (Tafinlar) at 150 mg twice daily and trametinib (Mekinist) at 2 mg once daily for up to 2 years (n = 60) or placebo with the same dose and schedule of dabrafenib/trametinib (n = 60). The primary end point of the trial was PFS.

Results showed that the median PFS in the triplet arm was 16.9 months (95% CI, 11.3-27.9) versus 10.7 months (95% CI, 7.2-16.8) with the targeted therapy alone (HR, 0.53; 95% CI, 0.34-0.83). The 12-month PFS rates in the investigational and control arms were 62% and 47%, respectively; at 24 months, these rates were 41% and 16%, respectively.

The benefit was found to extend to all subsets of patients examined, irrespective of age, sex, ECOG performance status, LDH, and PD-L1 expression.

“If the triplet combination was overcoming resistance to the targeted therapy one would anticipate an improved DOR and this was, indeed, seen in the KEYNOTE-022 trial,” noted McArthur. The median DOR with the triplet regimen was 25.1 months (95% CI, 14.1–not reached) versus 12.1 months with the doublet (95% CI, 6.0-15.7; HR, 0.32; 95% CI, 0.17-0.59). The 24-month DOR rates with the triplet and doublet regimens were 55% and 16%, respectively.

The overall survival (OS) data remain immature but a trend to improved survival favoring the triplet arm was observed (HR, 0.64; 95% CI, 0.38-1.06). The 24-month OS rate was 63% with the triplet versus 52% with the doublet.

“One useful parameter to look at how tolerable a treatment is, is the rate of treatment discontinuation,” said McArthur. “This was, in fact, higher in the triplet arm compared with the combination targeted therapy arm, with 30% of patients discontinuing versus approximately 17%, respectively.”

Key treatment-related adverse effects (TRAEs) that occurred in 15% or more patients in either treatment arm included rash, arthralgia, and diarrhea—all known toxicities associated with anti–PD-1 treatment, said McArthur.

Patients with previously untreated, advanced, BRAF V600–mutated melanoma with an ECOG performance status of 0 or 1 and measurable disease per RECIST v1.1 criteria were enrolled to the 

 In this trial, patients were stratified by geographic region along with centrally evaluated LDH level.

Here, participants were randomized 1:1 to receive either a triplet regimen comprised of atezolizumab (Tecentriq) at 840 mg on days 1 and 15 plus vemurafenib (Zelboraf) at 720 mg twice daily and cobimetinib (Cotellic) at 60 mg once daily on days 1 to 21 or placebo with vemurafenib/cobimetinib administered at the same dosing and schedule.

“This study had an important difference to the KEYNOTE-022 trial in that there was a 28-day lead-in with targeted therapy alone before the anti–PD-L1 drug was added,” noted McArthur.

The primary end point of the trial was PFS per investigator assessment, while key secondary end points included PFS per independent review committee, objective response, DOR, and OS.

This trial also met its primary end point, showing an improvement in investigator-assessed PFS that favored the triplet regimen. The median PFS was 15.1 months (95% CI, 11.4-18.4) with the triplet versus 10.6 months (95% CI, 9.3-12.7) with the doublet (log-rank 

 = .0249). The PFS rates at 6 months in the investigational and control arms were 72.8% versus 74.2%, respectively; the 12-month PFS rates were 54.0% versus 45.1%, respectively, while the 18-month PFS rates were 43.6% versus 31.6%, respectively. Again, all subsets of patients who were analyzed achieved benefit with the triplet.

The addition of atezolizumab to the targeted therapy combination was also found to prolong DOR compared with the doublet regimen, at 21.0 months (95% CI, 15.1–not evaluable [NE]) versus 12.6 months (95% CI, 10.5-16.6), respectively. The DORs at 12 months in the investigational and control arms were 69.4% versus 50.8%, respectively.

Moreover, although the OS data are still immature, the OS favored the triplet arm. The median OS in the atezolizumab arm was 28.8 months (95% CI, 27.4-NE) versus 25.1 months (95% CI, 22.3-NE) in the control arm. The 12-month OS rate in the triplet arm was 76.1% versus 76.7% in the doublet arm; these rates were 60.4% and 53.1%, respectively, at 24 months.

Regarding safety, the most prominent toxicities observed were pyrexia and arthralgia, which were more commonly reported on the triplet arm, as were abnormalities in liver function tests and thyroid dysfunction, according to McArthur.

“There was a similar rate of discontinuation, however, between the 2 arms, possibly related to the fact that there was the 1 cycle lead-in without the anti–PD-L1 therapy,” added McArthur.

 enrolled a total of 532 treatment-naïve patients with BRAF V600–mutated unresectable or metastatic melanoma who did not have active brain metastases and had an ECOG performance status of 2 or less. Participants were stratified by performance status and LDH level and they were randomized to either spartalizumab at 400 mg every 4 weeks plus dabrafenib at 150 mg twice daily and trametinib at 2 mg once daily or placebo with dabrafenib/trametinib given at the same dose and schedule.

The primary end point of the trial was investigator-assessed PFS in accordance with RECIST v1.1 criteria, while secondary end points included OS, objective response rate, DOR, disease control rate, safety, patient-reported outcomes, and pharmacokinetics.

“In this study, we saw a trend toward improvement in PFS in the triplet-therapy arm, but it did not reach statistical significance,” said McArthur. “However, there was an approximately similar magnitude of benefit seen with this triplet therapy versus the doublet therapy similar to KEYNOTE-022 and IMspire150.”

The median PFS in the spartalizumab arm was 16.2 months (95% CI, 12.7-23.9) versus 12.0 months (95% CI, 10.2-15.4) in the doublet arm (HR, 0.82; 95% CI, 0.655-1.027; 1-sided 

 =.042). The PFS rates in the investigational and control arms at 12 months were 58% versus 50%, respectively; at 24 months, these rates were 44% versus 36%, respectively. 

The triplet was beneficial in all subsets analyzed. “Notably, patients with multiple sites of metastatic disease of 3 or more or patients with high disease burden as measured by the sum of lesions diameters at baseline achieved significant benefit from the triplet therapy; that may potentially identify a subset that may get greater benefit from this approach,” said McArthur.

A trend toward OS favoring the triplet therapy was observed in this trial, as well, although the median OS had not been reached in either arm (HR, 0.785; 95% CI, 0.589-1.047). The OS rate at 12 months with the spartalizumab combination was 84% versus 79% with the doublet; the 24-month OS rates were 68% versus 62%, respectively.

With regard to safety, patients in the spartalizumab arm experienced more AEs that led to treatment discontinuation than those in the doublet arm. Specifically, 15.7% of patients in the triplet arm experienced all-grade AEs that resulted in discontinued treatment versus 9.1% of those in the doublet arm; 12.4% and 8.0%, respectively, were related to treatment. The toxicities reported were in line with what had previously been reported with these agents, including diarrhea, pyrexia, and abnormalities in liver function tests.

“The COMBI-i study looked at subsets of patients with high tumor mutational burden (TMB) and showed a relatively greater benefit in patients with high TMB,” added McArthur. “[Additional results showed] that patients who had an inflamed tumor microenvironment had higher PFS versus those who did not.”

Although combining immune checkpoint inhibition with targeted therapy has shown promise in potentially overcoming resistance to targeted therapy in this patient population, further follow-up is needed to understand the impact of these combinations on OS, said McArthur.

“However, I do point out to you that when one looks at the PFS curves, there's no sign yet of a plateau,” McArthur emphasized. “If this approach was a robust mechanism to overcome resistance, then one would anticipate a plateau in the PFS curves. Ongoing follow up with regard to this will be important.”

McArthur G. Overcoming resistance to targeted therapy. Presented at: 2020 SMR Virtual Congress; October 28, 2020; Virtual.

McArthur GA, Stroyakovskiy D, Gogas H, et al. CT012 — Evaluation of atezolizumab (A), cobimetinib (C), and vemurafenib (V) in previously untreated patients with BRAFV600 mutation-positive advanced melanoma: primary results from the phase 3 IMspire150 trial. Presented at: the 2020 AACR Annual Virtual Meeting I; April 27-28, 2020. Abstract CT012.

Nathan P, 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 3 COMBI-i trial. 

. 2020;31(suppl 4):S1172. doi:10.1016/j.annonc.2020.08.2273

The addition of anti–PD-1/PD-L1 to combination BRAF and MEK inhibition has been shown to improve progression-free survival and duration of response in patients with BRAF-mutated melanoma, suggesting potential to overcome resistance to targeted approaches.

Novel Triplets May Overcome Resistance to Targeted Therapy in BRAF+ Melanoma

Despite the recent advancements with BRAF-targeted therapies and PD-1 checkpoint inhibitors, there is still much to learn in the field of melanoma, especially with regard to disease biology, according to Jason J. Luke, MD, FACP, who added that this understanding is needed to inform development and sequencing strategies, as emphasized during the 2020 SMR Virtual Congress.

“We need to gain a better understanding of the biology of melanoma. Over the past decade, we have seen tremendous progress with the development of BRAF-targeted therapies, the identification of CTLA-4, and PD-1 checkpoint blockade; however, this is not enough for at least half of our patients,” said Luke. “We need to better understand some of the differences in these melanoma tumors to know what kinds of combination therapies should be developed or what sequence of treatment would be needed to optimize treatment for each patient. Over the years, we've learned a lot from several large clinical trials. Even so, I believe we need to go back to the basic translational realm to learn more about the biology of this disease to identify new targets and improve the way that we use the treatments that we have available now.”

®, Luke, an associate professor of medicine in the Division of Hematology/Oncology, who is also the director of the Cancer Immunotherapeutics Center Immunology and Immunotherapy Program at the University of Pittsburgh Medical Center Hillman Cancer Center, highlighted key research presented during the 2020 SMR Virtual Congress and beyond.

®: Could you spotlight some of the key topics that were discussed during the SMR meeting?

 Due to this very unusual year, the SMR meeting was conducted virtually. However, even so, the agenda was very exciting. Some of the research that I am most excited about has to do with how melanoma develops and evolves over time, especially in relation to the treatments we administer in the metastatic setting. This research could lead to the next generation of therapeutic targets.

We see the progression of melanoma from very early, dysregulated melanocytes, all the way through to refractory metastatic disease. Understanding what those biological processes are help that transition might nominate a place where we can intervene, even before people develop melanoma. A number of the talks during the meeting focused on that biology; [by understanding this better, we will] hopefully be able to push the field into new directions.

What is currently known about the molecular pathogenesis of melanoma?

We have seen a number of elegant studies conducted by investigators like Boris C. Bastian, MD, and Hunter A. Shain, MD, that have looked at the progression of melanocytes, picking up serial dysregulated oncogenes, and the overexpression of certain pathways.

One of the surprising features about melanoma is that 

, which we target with BRAF-targeted therapies, actually develops very early in melanocytes. Even moles harbor 

 mutations, although we know that moles are not melanoma.

It's now becoming clear that there's a series of stages that these lesions go through, which points to our ability to potentially intervene therapeutically. We continue to learn more about this.

One of the talks dissected the melanoma tumor. As we continue to learn about which cells, and at which stages, are developing dysregulated pathways, this may help us better understand when different treatments are needed to avoid the development of metastatic melanoma over time.

Could you expand on the importance of testing for

 is a foundational mutation that is discovered in about half of the melanomas that arise. However, it has to happen in conjunction with some other mutations or dysregulations in the tumor. Even so, it’s considered foundational because it was one of the targets in early targeted therapy drug development. In melanoma, half of our treatment paradigm is targeting 

 mutations with the 3 FDA approved BRAF and MEK inhibitor combinations. We now also have the combination of BRAF/MEK inhibitors and PD-1 antibodies.

 is very important, biologically, in the sense that it drives the development of about half of the melanoma cases out there. It’s also important therapeutically because it’s integrated into the treatment paradigm in half of our patients and truly dictates how we select and sequence therapies.

What is the significance of HLAs in melanoma?

HLAs are genes that help the immune system to show within the immune system to different parts of the immune system, molecules come that it comes into contact with. As such, having a diversity of HLA is important in terms of having a diverse immune response. It has become quite clear after analyzing immune checkpoint blockade, or PD-1–blocking antibody clinical trials, that patients who have diversity of their HLA status are more likely to benefit from immunotherapy. This is presumably because the immune system is able to show more cancer particles to different cells of the immune system.

Melanoma is a diverse cancer type, which often develops from sun damage. As such, many different molecules could be present, which is both good and bad. A patient might be more likely to have a better immune response against the tumor if their HLA is more diverse. It will be interesting to hear new data that will hopefully answer a few questions for us, such as how HLA relates to patient outcomes, along with the implications of therapeutic strategies like BRAF inhibitors and PD-1 antibodies.

COMBI-AD trial? How have these data impacted your own personal practice?

The COMBI-AD trial was a randomized, phase 3 clinical trial in the adjuvant, stage III setting.

Patients with melanoma who had lymph node involvement were randomized to receive either placebo or the combination of dabrafenib plus trametinib (Mekinist).

Notably, there was some skepticism with regard to this clinical trial when it initially started because, at that time, there were no reports of long-term benefit with targeted therapy in the adjuvant setting. Over the past couple of years of follow-up, however, it has become clear that in the patients who received the combination, there has been a real and stable improvement in relapse-free survival (RFS) compared with those who received the placebo.

As we expected, there's an initial tremendous benefit over the first year of treatment; however, this starts to drop around years 2 and 3, similar to [what we see with] the placebo. Once you get a few years out, then you see a stable difference, meaning that patients who were treated with this approach had an absolute improvement in RFS. We believe this is very meaningful because, in the adjuvant setting, we're hoping to decrease relapses.

Although there is some initial toxicity with this regimen, once patients get past the initial fever, they are able to tolerate this very well. This could be an important foundational treatment in melanoma, and we plan to build upon this in the future.

You are currently involved in the KEYNOTE-716 trial examining adjuvant pembrolizumab (Keytruda) in stage II disease. Could you speak to the goals of this research?

An area that I've been interested in is investigating earlier stages of melanoma. [Patients with] stage II melanoma are those who have deep, primary disease on the skin but do not have lymph node involvement. For a long time, these patients have not been treated with adjuvant therapy.

We recently completed accrual of the KEYNOTE-716 trial, which was a randomized, phase 3 trial that evaluated pembrolizumab in patients with stage II melanoma. I helped design and lead that study.

The risk for patients with the stage II melanoma is actually as high as some of the patients who already have FDA approval for the use of immunotherapy. As such, this has been a jarring clinical problem that we aren’t able to treat these patients. I'm very excited to see the results of KEYNOTE-716 as they become more mature, because those patients deserve to have the option at least to consider treatment in that setting. This trial would potentially be the first to offer that opportunity.

How has melanoma treatment been impacted by the coronavirus disease 2019 (COVID-19) pandemic?

With the approvals of checkpoint inhibitors at extended schedules, such as nivolumab (Opdivo) to 1 month and pembrolizumab to 6 weeks, at least in the academic community, we’ve been pushing to create less visits for patients. So, we have shifted to more extended schedules.

Also, accrual to clinical trials really slowed down in light of the pandemic, especially large, randomized, phase 3 studies and adjuvant studies. My hope is that, as we near the end of the year, we will see an improvement in the COVID-19 pandemic and these trials will pick back up again. These trials are very important in terms of advancing the field and moving toward the next generation of treatments.

What challenges are faced in the field of melanoma?

A major challenge, especially for metastatic melanoma, is trying to identify which patients need an aggressive approach up front, versus those for whom we can serially use the therapies that we already have.

We can use some clinical biomarkers such as lactate dehydrogenase or the presence of brain metastases to look at that; they could be very powerful in terms of stratification. However, on a molecular level, it's out there and we could understand it.

Data presented during the SMR meeting provided insight on who could benefit from an aggressive approach, and future analyses will continue to expand on this. Fully understanding this is important because aggressive approaches are associated with more toxicities.

Finally, there is still a whole segment of the melanoma population that doesn't do well. Those patients need new treatments and we need to better understand what the therapeutic targets are for this subset. I'm very excited though because we have the tools to find this information.

What are some of the ongoing research efforts being made that are generating excitement?

There is so much going on. Currently, we have 4 randomized, phase 3 trials in the frontline setting for immunotherapy, 2 randomized trials in the second-line setting, as well as another single-arm trial [that may lead to the] potential approval of another therapy. So, we have 7 new therapies that could potentially become available in the next couple of years.

While we've made tremendous progress with our treatments over the past 10 years, the next 10 years look very bright, as well. This emphasizes the importance of continued clinical trial participation. With participation, we could expand the benefits of therapy and improve overall survival for our patients in the long term.

Jason J. Luke, MD, discusses the recent advancements with BRAF-targeted therapies and PD-1 checkpoint inhibitors in melanoma. 

 

Deeper Understanding of Disease Biology Needed in Melanoma to Move the Needle Forward

Jason J. Luke, MD, FACP, an associate professor of medicine in the Division of Hematology/Oncology and director of the Cancer Immunotherapeutics Center Immunology and Immunotherapy Program at the University of Pittsburgh Medical Center Hillman Cancer Center, discusses the importance of BRAF in melanoma.

, found in half of all patients with melanoma, is a foundational mutation that was 1 of the seminal targets for early targeted agents, says Luke. 

 mutations also have to occur in conjunction with other mutations or dysregulations of the tumor. 

In melanoma, half of the treatment paradigm is targeting 

 3 different FDA-approved BRAF/MEK inhibitor combinations. Now, BRAF/MEL inhibitors are even being combined with PD-1 antibodies, Luke adds.

 is very important biologically, as it drives the development of about half of the melanoma cases, says Luke; it is almost important therapeutically, as it is integrated into the treatment paradigm for half of patients with the disease and dictates how treatments are selected and sequenced, concludes Luke.

Jason J. Luke, MD, FACP, discusses the importance of BRAF in melanoma.

Dr. Luke on the Importance of BRAF in Melanoma

Jeffrey S. Weber, MD, PhD, the deputy director of NYU Langone Health’s Perlmutter Cancer Center; Laura and Isaac Perlmutter Professor of Oncology in the Department of Medicine at NYU Grossman School of Medicine; and the 2016 Giant of Cancer Care

 in Melanoma, discusses the results of the phase 3 COMBI-AD trial with dabrafenib (Tafinlar) plus trametinib (Mekinist) in patients with resected, stage III 

The COMBI-AD trial results are impressive, with a plateau in the 5-year relapse-free survival (RFS) curve, according to Weber. After a median follow-up of 60 months, the data show a 5-year RFS of 

 for patients treated with dabrafenib plus trametinib, says Weber.

The phase 3 CheckMate-238 trial was an adjuvant trial that randomized patients with resected stage IIIB/C or stage IV melanoma to receive either nivolumab (Opdivo) or ipilimumab (Yervoy). If the results from COMBI-AD are compared with the 4-year results from the CheckMate-238 trial, the 4-year survival seen with nivolumab is the same as the 5-year survival seen with dabrafenib/trametinib, notes Weber. However, a large number of patients with stage IIIA disease included in the COMBI-AD trial  did well but were not included in CheckMate-238. Additionally, patients with stage IV resected disease were included in the CheckMate-238 trial and would probably not do well with the COMBI-AD regimen, explains Weber.

Nonetheless, evidence of a plateau in the RFS curve is encouraging, according to Weber. Finally, when looking at the survival of any of the prognostic factors in the COMBI-AD trial, there appears to be a clear benefit for patients with stage IIIA-C disease, concludes Weber. 

Jeffrey S. Weber, MD, PhD, discusses the results of the phase 3 COMBI-AD trial with dabrafenib plus trametinib in patients with resected, stage III BRAF V600E/K–mutant melanoma.

Dr. Weber on Results of the COMBI-AD Trial in Stage III BRAF-Mutant Melanoma

A triplet combining the PD-1 inhibitor spartalizumab with dabrafenib (Tafinlar) and trametinib (Mekinist) led to a 12-month overall survival (OS) rate of 86.1% for patients with previously untreated advanced 

 V600—mutant melanoma, according to pooled findings from the phase III COMBI-i trial presented during the 16th International Congress of the Society for Melanoma Research.

Furthermore, the 3-drug regimen showed promising efficacy in patients with elevated lactate dehydrogenase (LDH) levels and stage IV M1c disease—populations that generally have poor outcomes.

“With that combination, we saw that everybody had some tumor reduction—which was incredible,” study co-author Georgina V. Long, MBBS, PhD, co-medical director of the Melanoma Institute Australia (MIA) and chair of Melanoma Medical Oncology and Translational Research at MIA and Royal North Shore Hospital, stated in an interview with 

. “That does give us the idea that this triplet could be used in patients who have the poorest of poor prognosis, particularly when we saw that no one actually progressed, everyone had some tumor reduction or at least stable disease, and a very good response rate.”

Results from previous trials showed that adding spartalizumab to treatment with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib led to improved objective response rates (ORRs) compared with the doublet alone.

In the ongoing COMBI-i trial (NCT02967692), investigators are evaluating 400 mg of spartalizumab administered every 4 weeks plus 150 mg of twice-daily dabrafenib and 2 mg of daily trametinib in patients with unresectable or metastatic 

 V600—mutant melanoma. Treatment is continued until disease progression, death, unacceptable toxicity, loss to follow-up, or withdrawal of consent.

Part 1 of the phase III trial is a safety run-in phase, and part 2 is a biomarker cohort. The median follow-up was 19.9 months (range, 16.5-25.1), and treatment was ongoing in 36% of patients (n = 13).

Pooled baseline characteristics from part 1 and part 2 showed that the median age was 55 years (range, 23-76), 61% of patients were male, and 92% of patients were white. Most (69%) patients had an ECOG performance status of 0, and 56% of patients had ≥3 disease sites.

In data presented at the 2019 ASCO Annual Meeting, the triplet was associated with an ORR of 78% by investigator assessment in the overall population and a complete response (CR) in 42% (15/36) at a median follow-up of 19.9 months.

 CR was ongoing in 10 of 15 patients. The median duration of response (DOR) was 20.7 months and the 12-month DOR rate was 80.3%. OS was not evaluable in results presented at the 2019 ASCO Annual Meeting.

The updated findings presented at SMR, which include the 86.1% (95% CI, 70-94) 12-month OS rate, are from the total 36 patients (9 from part 1 and 27 from part 2), with a data cutoff of April 8, 2019. Overall, the 12-month PFS rate was 66.7% (95% CI, 49-80) and the 12-month DOR was 80.3% (59-91).

Among those with elevated LDH (n = 15), the 12-month DOR rate was 64.8% (95% CI, 25-87). At 12 months, the progression-free survival (PFS) rate was 33.3% (95% CI, 12-56) and the OS rate was 66.7% (95% CI, 37.5-85).

In patients with stage IV M1c disease (n = 20), the DOR rate was 67.7% (95% CI, 35-86.5) at 12 months, with a 12-month PFS rate of 50.0% (95% CI, 27-69) and an OS rate of 75.0% (95% CI, 50-89).

Moreover, investigators determined that patients with elevated circulating tumor DNA, low tumor mutational burden (TMB), high levels of immunosuppressive factors in tumor microenvironment (TME), and/or low T-cell—inflamed gene expression levels were more likely to experience a PFS event in the first 12 months (n = 5; 23%). In their poster, they noted that the predictive implications of linking TMB and T-cell–inflamed gene expression levels with other TME markers require further validation.

Updated safety findings showed that all patients experienced ≥1 any-grade adverse event (AE), the most common being pyrexia (n = 32), cough (n = 18), arthralgia (n = 18), rash (n = 17), chills (n = 17), and fatigue (n = 16). Six patients experienced grade ≥3 pyrexia, and treatment-related serious AEs occurred in 36% (n = 13) of patients. There were no treatment-related deaths.

Dummer R, et al. Spartalizumab (S) + dabrafenib (D) + trametinib (T) in first-line treatment (tx) of BRAF V600-mutant melanoma: clinical outcomes and biomarker analyses from COMBI-1 parts 1 and 2. Presented at: 16th International Congress of the Society for Melanoma Research; November 20-23, 2019; Salt Lake City, UT.

Long GV, Weber JS, Infante JR, et al. Overall survival and durable responses in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib combined with trametinib. 

. 2016;34:871-878. doi: 10.1200/JCO.2015.62.9345.

Long GV, Lebbe C, Atkinson V, et al. The anti—PD-1 antibody spartalizumab (S) in combination with dabrafenib (D) and trametinib (T) in previously untreated patients (pts) with advanced BRAF V600–mutant melanoma: updated efficacy and safety from parts 1 and 2 of COMBI-i. 

. 2019;37(suppl; abstr 9531). doi: 10.1200/JCO.2019.37.15_suppl.9531.

View more from the 2019 International Congress of the Society for Melanoma Research

A triplet combining the PD-1 inhibitor spartalizumab with dabrafenib and trametinib led to a 12-month overall survival rate of 86.1% for patients with previously untreated advanced BRAF V600–mutant melanoma.

Spartalizumab Plus Dabrafenib/Trametinib Impresses in BRAF+ Melanoma With Poor Prognosis

Although multiple combinations of BRAF and MEK inhibitors have been approved by the FDA for the treatment of patients with melanoma, more trials are underway to identify regimens of targeted agents plus immunotherapies to better benefit this patient population, according to Ryan J. Sullivan, MD.

Dabrafenib (Tafinlar) plus trametinib (Mekinist) was the first BRAF/MEK combination to receive regulatory approval for use in patients with melanoma. About 70% of patients have major responses to these agents, said Sullivan, associate director of the Melanoma Program at Massachusetts General Hospital Cancer Center.

Five-year survival outcomes with the combination were confirmed in a pooled analysis of the phase III COMBI-d and COMBI-v trials. Results showed that the OS rates were 37% and 34% at 4 and 5 years, respectively. Specifically, the 5-year OS rate with dabrafenib plus trametinib in patients who had a complete response (CR) was 71% compared with 32% in those with a partial response (PR) and 16% in those with stable disease. However, investigators are still looking for other potential combinations to improve upon this efficacy, said Sullivan.

For example, investigators are now looking to pair immunotherapeutic agents with targeted therapies. The PD-1 inhibitor spartalizumab is being examined in combination with dabrafenib and trametinib, and the PD-L1 inhibitor atezolizumab (Tecentriq) is being evaluated in combination with vemurafenib (Zelboraf) and cobimetinib (Cotellic).

 during the he 16th International Congress of the Society for Melanoma Research, Sullivan, who is also an assistant professor of medicine at Harvard Medical School, discussed the rationale for BRAF/MEK combinations and immunotherapeutic combinations in melanoma and ongoing research examining triplet regimens.

: What is the rationale for using BRAF/MEK inhibitor combinations in melanoma?

: About 40% to 50% of patients with melanoma have a mutated gene called 

, which is a critical signaling pathway initiator. When that is active, uncontrolled signaling occurs that is associated with cancer. 

 mutations and are found in a significant minority of patients with cancer.

 was made not that long ago, in the early 2000s. Inhibitors of 

 V600 mutations have been tested now for well over a decade, and when given as an individual drug, we have seen responses in about half of patients, though most have reductions in tumor volume. However, the pathway inhibition by 

 mutation is usually not enough to be associated with durable benefit in the majority of, or even a significant minority of patients.

Blocking the same pathway with a protein called MEK, is also associated with benefit. In the early 2010s, there were approvals of vemurafenib, which is a BRAF inhibitor; dabrafenib, another BRAF inhibitor; and trametinib, a MEK inhibitor. All were approved for use as single agents because they improved responses, progression-free survival, and overall survival (OS).

As with everything, when you have 2 drugs that work, you always wonder if combining them is going to be an important next step. In fact, preclinical models support the combination [of BRAF and MEK inhibitors]. Interestingly, there was some suspicion that the combination may not be more toxic, rather that it might mediate some of the toxicities [seen with both agents alone]. If you give a BRAF inhibitor, the agent actually enhances signaling in those cells. It’s also true when patients develop hand-foot syndrome and thickened callouses that are associated with the use of BRAF inhibitors by themselves. MEK inhibitors cause AEs by blocking the pathway. When you combine the 2 inhibitors in a cell that is not mutated, that signals to the pathway, and actually balances out the toxicity. It became quite clear even before vemurafenib was approved in 2011 that combination therapy was likely going to be better. Not only does there appear to be mediation of toxicity, but there is also superior efficacy with this approach.

To date, 4 randomized phase III trials have been done in patients with metastatic melanoma and 

 mutations that have demonstrated the superiority of combination BRAF/MEK versus a BRAF inhibitor alone. Three combinations have received FDA approval, including vemurafenib plus cobimetinib, dabrafenib plus trametinib, and encorafenib (Braftovi) plus binimetinib (Mektovi). We don’t use single-agent BRAF or MEK inhibitors, unless some weird scenario dictates it in a patient with 

Ryan J. Sullivan, MD, discusses the rationale for BRAF/MEK combinations and immunotherapeutic combinations in melanoma and ongoing research examining triplet regimens.

SMR Congress | Conference

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

Novel Triplets May Overcome Resistance to Targeted Therapy in BRAF+ Melanoma

Deeper Understanding of Disease Biology Needed in Melanoma to Move the Needle Forward

Dr. Luke on the Importance of BRAF in Melanoma

Dr. Weber on Results of the COMBI-AD Trial in Stage III BRAF-Mutant Melanoma

Spartalizumab Plus Dabrafenib/Trametinib Impresses in BRAF+ Melanoma With Poor Prognosis

Expert Weighs in on Targeted and Immunotherapy Combinations in Melanoma

Expert Highlights Potential Markers of Nivolumab/Ipilimumab Response in Melanoma

Cobimetinib/Vemurafenib OS Benefit Sustained at 5 Years in BRAF+ Melanoma

CR With Dabrafenib/Trametinib Linked to Long-Term Survival in BRAF+ Melanoma