Experts Examine Emerging Approaches in Melanoma Management

As new data emerge in the melanoma treatment landscape, novel combinatorial regimens are boosting responses in harder to treat subgroups of patients and innovative approaches such as tumor-infiltrating lymphocyte (TIL) therapies and bispecific antibodies are also gaining ground.

In a special OncLive video program, The Board, several experts came together to discuss key melanoma data that were presented during the 2020 ASCO Virtual Scientific Program. Omid Hamid, MD, chief of Translational Research and Immunotherapy and director of Melanoma Therapeutics at The Angeles Clinic, led the dynamic discussion, which featured insights from the following panelists:

• Sunandana Chandra, MD, MS: medical oncologist and assistant professor of medicine (hematology and oncology) at Northwestern Feinberg School of Medicine
• Pauline Funchain, MD: director of melanoma and genomics at Cleveland Clinic
• Geoffrey T. Gibney, MD: co-leader of the Melanoma Disease Group at the Lombardi Comprehensive Cancer Center and MedStar Cancer Network, member of the Developmental Therapeutics (Phase I) program, and medical oncologist at MedStar Georgetown Cancer Institute
• Ragini Kudchadkar, MD: medical oncologist, associate professor in the Department of Hematology and Medical Oncology, and medical director of the skin program at Emory University School of Medicine, and chair of the Clinical and Translational Review Committee at Winship Cancer Institute of Emory University
• Jason Luke, MD, FACP: associate professor of medicine in the Division of Hematology/Oncology and the director of the Cancer Immunotherapeutics Center within the Cancer Immunology and Immunotherapy Program at UPMC Hillman Cancer Center
• Evan J. Lipson, MD: associate professor of oncology at Johns Hopkins Kimmel Cancer Center
• Anna C. Pavlick, DO: professor in the Department of Medicine and the Ronald O. Perelman Department of Dermatology at NYU Grossman School of Medicine, director of High Reliability Organization Initiatives at Perlmutter Cancer Center, and co-director of the Melanoma Program at NYU Langone Health
• Tara C. Mitchell, MD: associate professor of medicine at the Abramson Cancer Center of the University of Pennsylvania

As part of the discussion, the panel discussed some of the encouraging data on emerging modalities presented during the meeting and shared how they might apply that information to clinical practice.

Dual Immunotherapy Shows Benefit in Mucosal Melanoma

In the phase 3 CheckMate-067 trial (NCT01844505), investigators randomized a total of 945 treatment-naïve patients with stage III or IV unresectable or metastatic melanoma 1:1:1 to receive nivolumab (Opdivo) plus ipilimumab (Yervoy; n = 314), nivolumab alone (n = 316), or ipilimumab alone (n = 315).¹

The co-primary end points of the trial were progression-free survival (PFS) and overall survival (OS) in the treatment arms containing nivolumab compared with ipilimumab alone. Secondary end points of the trial included objective response rate (ORR) per RECIST v1.1 criteria, correlation of PD-L1 with survival end points, and safety.

A total of 79 patients with mucosal melanoma received treatment; 28 received the combination, 23 received nivolumab monotherapy, and 28 receive ipilimumab monotherapy. Long-term results presented during the ASCO meeting showed a higher 5-year PFS rate with nivolumab/ipilimumab compared with nivolumab or ipilimumab alone in this patient subgroup, at 29% versus 14% and 0%, respectively. The combination also led to a higher 5-year OS rate at 36% compared with 17% with nivolumab monotherapy and 7% with ipilimumab monotherapy.

The ORRs in the mucosal and intent-to-treat populations were 43% and 58%, respectively, with the combination; with nivolumab alone, ORRs were 30% and 45%, respectively, and 7% and 9%, respectively, for ipilimumab alone.

“I think this supports what many of us have always suspected, which is that patients with mucosal disease are more difficult to treat with immunotherapy than patients with cutaneous disease,” said Lipson. “It also suggests that we have a lot more work to do with regard to understanding what does drive antitumor immunity in the setting of mucosal melanoma.”

VEGF/Immunotherapy Combination Shows Promise in Mucosal Melanoma

In a single-arm, open-label phase 1b trial (NCT03086174), investigators set out to examine the safety and efficacy of axitinib (Inlyta) in combination with the humanized IgG4 monoclonal antibody against PD-1, toripalimab, in patients with advanced mucosal melanoma.²

To participate, patients had to have pathologically confirmed metastatic mucosal disease, at least 1 measurable lesion per RECIST v.1.1 criteria, acceptable organ and bone marrow function, and an ECOG performance status of 0 to 1.

The primary end point of the trial was dose-limiting toxicity, while key secondary end points included adverse effects, pharmacokinetic (PK) profile of toripalimab in the combination study, ORR, disease control rate (DCR), duration of response (DOR), PFS, OS, and PD-L1 status, among others.

Results presented during the meeting showed that by May 2, 2020, the ORR with the combination was 48.5%; this included 1 complete response (CR) and 15 partial responses (PRs). Moreover, the median DOR with the combination was 13.7 months. Axitinib plus toripalimab had a median PFS of 7.5 months (95% CI, 3.9-14.8), with 1- and 2-year PFS rates of 41.4% and 13.8%, respectively. The median OS with the combination was 20.7 months (95% CI, 10.2–not evaluable [NE]); 1- and 2-year OS rates were 65.5% and 44.8%, respectively.

“If you numerically compare, and it’s tough to numerically compare across trials, we’re seeing a response rate of 48%,” said Funchain. “When you think of the CheckMate-067 data, the 5-year response rate was 43%, so this is numerically higher. We could probably say that this is at least as effective as that approach. I don’t know whether we can say it’s better, but these are some very promising data for a combination other than CTLA-4 plus a PD-1 inhibitor.”

With regard to safety, the combination was very well tolerated, with no dose-limiting toxicities reported in the first 6 patients examined in the dose-findings portion of the research. Moreover, axitinib was not found to have an effect on the PK parameters of toripalimab versus toripalimab alone. Although 97% of participants experienced treatment-related adverse effects (AEs), most were grade 1 or 2 in severity.

“I really think that VEGF is coming. We already see the signal with VEGF plus immunotherapy in renal cell cancer; there’s some signal in glioblastoma and there are signals in many tumor types, but this is one place where melanoma has been a bit slower,” said Funchain. “But there’s activity in a histology that we know is tougher to treat than cutaneous melanoma. I think that this is the beginning of other trials with VEGF/immunotherapy combinations.”

Luke noted that although he believes that this might offer a strong option in the relapsed/refractory setting, he feels more cautious about using it up front, as ipilimumab and nivolumab is available and triplet regimens are being explored. “Is this going to be better than those combinations? I don’t know,” admitted Luke.

TIL Therapy Boosts Responses in Heavily Pretreated Metastatic Disease

In the phase 2 multicenter Iovance C-144-01 trial (NCT02360579), investigators set out to examine the safety and efficacy of the autologous tumor-infiltrating lymphocyte (TIL) lifileucel (LN-144) in patients with metastatic melanoma.³

To be eligible to participate, patients had to have unresectable or metastatic melanoma that was treated with at least 1 prior systemic therapy, including a PD-1 inhibitor, and if BRAF V600 mutation–positive, a BRAF inhibitor or BRAF/MEK combination. Cohort 1 (n = 30) received the non-cryopreserved TIL product (Gen 1), cohort 2 (n = 60) received the cryopreserved TIL product (Gen 2), cohort 3 (n = 10) received retreatment with TIL therapy, and cohort 4 (n = 75) received the cryopreserved TIL product (Gen 2).

“In this study, they were able to get the processing time down to 22 days, which is quite impressive,” said Gibney. “Results from cohort 2 were presented during the meeting, and everyone received the standard cryopreserved TIL; this means that after it was processed, the TIL was frozen, shipped, and then delivered to the patient at each center. This makes it a very attractive option that could be viable for centers across the country and across the world.”

Results from cohort 2 showed that the TIL treatment resulted in an ORR of 36.4%, which included 2 CRs and 22 PRs; 29 patients achieved stable disease, while 29 patients experienced disease progression. The DCR with the TIL was 80.3% and after a median follow-up of 18.7 months, the median DOR had not yet been reached.

Notably, responses were reported across a wide age range, even in participants who had previously progressed on a CTLA-4 inhibitor or BRAF inhibitor. Responses proved to occur regardless of BRAF mutations and occurred equally in patients with high or low PD-L1 levels.

“This is a very exciting time to see this therapy emerging as a potential viable standard of care going forward, if it does meet FDA criteria for approval,” added Gibney. “However, I want to ensure that everyone is aware that this is not an easy course for patients. There is a high toxicity rate, although it is short lived. Ninety-seven percent of patients experienced a grade 3 or 4 event, which included thrombocytopenia, anemia, and pyrexia.”

However, these toxicities are often short lived, and occur within the first 2 weeks of treatment, noted Gibney.

Kudchadkar added that this is just the beginning of the TIL story. “The science in growing these cells and figuring out which cells to give is really exploding right now,” said Kudchadkar. “I think this is a great start, but I think we are going to perfect this process over the next 5 to 10 years to make it more accessible. This is just the beginning.”

Bispecific DART Molecules Burst Onto the Landscape

The first-in-human phase 1 trial of MGD013, an investigational DART protein targeting PD-1 and LAG-3 with a single molecule, is examining the safety and tolerability of the agent, as well as its PK, immunogenicity, and preliminary activity.⁴

“The search for immune checkpoints that can be targeted in patients who have progressed on an anti–PD-1 therapy has been a little difficult,” said Lipson. “A checkpoint that’s really successful has been a bit elusive. However, LAG-3 does seem to be emerging as 1 of the potential candidates and I think data from the study back this up.”

Results showed encouraging monotherapy activity in several different tumor types, such as triple-negative breast cancer, mesothelioma, and gastric cancer, with baseline LAG-3 expression and interferon-gamma signature linked with objective response. Moreover, MGD013 was found to have encouraging preliminary combinatorial activity with margetuximab, showing an ORR of over 40% in patients with low PD-L1 expression and HER2-positive tumors.

“High levels of LAG-3 in the tumor microenvironment strongly correlated with treatment response, and that was even in the PD-1–refractory setting,” said Luke, who was the first author. “Patients retained an interferon-associated gene expression profile at baseline prior to treatment, despite being PD-1–refractory, and still responded to the treatment.”

Is There a Place for GSK-3β Inhibitors in Melanoma?

In a phase 1 trial (NCT03678883), investigators examined the GSK-3β inhibitor 9-ING-41 administered intravenously twice weekly as a single agent or in combination with gemcitabine plus nab-paclitaxel (Abraxane), carboplatin, carboplatin/paclitaxel, doxorubicin, lomustine, or irinotecan in patients who were previously treated with the same chemotherapy.⁵

Results showed that the agent had dose-proportional pharmacokinetics and that it was well tolerated with no attributable severe AEs. The agent was found to have antitumor activity when used as a monotherapy, with 1 ongoing CR reported in a patient with refractory BRAF-mutated melanoma.

“The reason I found this abstract interesting is that they looked at a number of histologies— gastrointestinal, thoracic, gliomas, breast, to name a few—but they showed a beautiful response in a patient with melanoma,” said Chandra. “The patient was aged 55 years, had a BRAF V600k mutation and refractory disease to previous immunotherapy. The patient achieved a CR and had complete resolution of their brain metastases, as well.”

She noted that although conclusions cannot be drawn, the signal of activity with this approach was intriguing. “There must be something with that biology that perhaps we should be looking at,” Chandra concluded.

References

1. Shoushtari AN, Wagstaff J, Ascierto PA, et al. CheckMate 067: Long-term outcomes in patients with melanoma. J Clin Oncol. 2020;38(suppl 15):10019. doi:10.1200/JCO.2020.38.15_suppl.10019
2. Sheng X, Yan X, Chi Z, et al. Overall survival and biomarker analysis of a phase 1b combination study of toripalimab, a humanized IgG4 mAb against programmed death-1 (PD-1) with axitinib in patients with metastatic mucosal melanoma. J Clin Oncol. 2020;38(suppl 15):10007. doi:10.1200/JCO.2020.38.15_suppl.10007
3. Sarnaik A, Khushalani NI, Chesney JA, et al. Long-term follow up of lifileucel (LN-144) cryopreserved autologous tumor infiltrating lymphocyte therapy in patients with advanced melanoma progressed on multiple prior therapies. J Clin Oncol. 2020;38(suppl 15):10006. doi:10.1200/JCO.2020.38.15_suppl.10006
4. Luke JJ, Patel MR, Hamilton, EP, et al. A phase I, first-in-human, open-label, dose-escalation study of MGD013, a bispecific DART molecule binding PD-1 and LAG-3, in patients with unresectable or metastatic neoplasms. J Clin Oncol. 2020;38(suppl 15):3004. doi:10.1200/JCO.2020.38.15_suppl.3004
5. Carneiro BA. Cavalcante L, Bastos BR, et al. Phase I study of 9-ing-41, a small molecule selective glycogen synthase kinase-3 beta (GSK-3β) inhibitor, as a single agent and combined with chemotherapy, in patients with refractory tumors. J Clin Oncol. 2020;38(suppl 15):3507. doi:10.1200/JCO.2020.38.15_suppl.3507