Novel Therapies and Combinations Augment Melanoma Treatment Arsenal

Following the February 2024 FDA accelerated approval of the first cellular therapy for patients with melanoma, the tumor-derived autologous T-cell immunotherapy lifileucel (Amtagvi), investigators are hoping to build on this and other recent gains by developing additional novel therapies for these patients who often experience resistance to other available treatments.1

“Novel agents may be helpful in overcoming primary resistance, and that still [represents] a significant proportion of our patients—40% to 50% don’t respond to initial checkpoint inhibitor therapy,” Omid Hamid, MD, director of the Melanoma Program at Cedars Sinai in Los Angeles, California, said in an interview with OncologyLive. “Novel combinations may help overcome that [resistance]. We know that because [data on] our tumor-infiltrating lymphocyte [TIL] therapies in initial trials have shown that most patients [who] responded were initially enrolled [with] primary resistance [following] progression on checkpoint [inhibitors].”

The February regulatory decision by the FDA earned lifileucel an indication for the treatment of adult patients with unresectable or metastatic melanoma previously treated with a PD-1 blocking antibody, and if BRAF V600 positive, a BRAF inhibitor with or without a MEK inhibitor. The approval was supported by findings from the phase 2 C-144-01 study (NCT02360579). The trial enrolled patients with unresectable or metastatic melanoma who previously received at least 1 systemic therapy, including a PD-1 blocking antibody, as well as a BRAF inhibitor alone or in combination with a MEK inhibitor if they had BRAF V600–mutated disease.1,2

At the time of the approval, efficacy-evaluable patients who received the recommended dose range of 7.5 x 109 to 72 x 109 viable cells (n = 73) achieved an objective response rate (ORR) of 31.5% (95% CI, 21.1%-43.4%), including a complete response (CR) rate of 4.1%. Notably, the median duration of response (DOR) was not reached (NR; 95% CI, 4.1 months-NR). Patients experienced a DOR of at least 6, 9, or 12 months at rates of 56.5%, 47.8%, and 43.5%, respectively.2

Additional findings from C-144-01 published in the Journal for ImmunoTherapy of Cancer demonstrated that patients who received lifileucel who underwent at least 4 prior lines of therapy (n = 54) achieved an ORR of 29.6% (95% CI, 18.0%-43.6%). Patients who were treated with a previous anti–CTLA-4 agent (n = 125), those who received prior anti–PD-1 plus anti–CTLA-4 combination therapy (n = 82), and those who were primary refractory to anti–PD-(L)1 treatment (n = 83) achieved ORRs of 32.8% (95% CI, 24.7%- 41.8%), 26.8% (95% CI, 17.6%-37.8%), and 31.3% (95% CI, 21.6%-42.4%), respectively.3

NOVEL THERAPIES AND COMBINATIONS MOVE THROUGH THE DEVELOPMENT PIPELINE IN MELANOMA

In light of the success of lifileucel monotherapy in patients with heavily pretreated melanoma, investigators are evaluating the agent in combination with pembrolizumab (Keytruda) for the frontline treatment of patients with advanced melanoma in the phase 2 IOV-COM-202 study (NCT03645928).4

During the 2024 American Society of Clinical Oncology Annual Meeting, investigators presented findings from cohort 1A (n = 23) of IOV-COM-202, which enrolled patients with immune checkpoint inhibitor–naive melanoma; prior treatment with a BRAF/MEK inhibitor was permitted if a patient had BRAF-mutated disease. Response-evaluable patients achieved an ORR of 65.2% (95% CI, 42.7%-83.6%), with a CR rate of 30.4%. At a median follow-up of 21.7 months, the median DOR was NR (95% CI, 16.8-NR). The 6- and 12-month DOR rates were 73.3% and 53.3%, respectively. At the data cutoff, 66.7% of responders remained on the study with an ongoing response. These findings led to the initiation of the phase 3 TILVANCE-301 trial (NCT05727904), which is examining lifileucel plus pembrolizumab vs pembrolizumab monotherapy in patients with treatment-naive advanced melanoma. The coprimary end points of the global, randomized study are ORR per RECIST 1.1 by blinded independent review committee (BICR) assessment and BICRassessed PFS per RECIST 1.1. Overall survival is the key secondary end point, with other secondary end points including DOR, event-free survival, and safety.

Other novel agents under investigation in melanoma include IBI363, which is being examined in a phase 1 trial (NCT05460767) study which enrolled patients with melanoma and other solid tumors.5 “IBI363 is a PD-1, IL-2α bispecific antibody. “We’ve always known that being able to utilize combinations of immunotherapy in separate classes may be helpful in [these] patients, and initial signals of efficacy with this drug post PD-1 [inhibitor] failure have shown good disease control rates [DCRs] and ORRs,” Hamid explained.

Findings from the first-in-human trial presented during the 2024 European Society for Medical Oncology Virtual Plenary meeting showed that patients with melanoma who received prior treatment with an immuno-oncology (IO) agent (n = 37) achieved an ORR of 29.7% (95% CI, 15.9%-47.0%), including a 2.7% CR rate. The DCR was 73.0% (95% CI, 55.9%-86.2%). Most patients (73.0%) received at least 2 prior lines of therapy, and the median duration of prior IO treatment was 5.8 months.

These data supported the FDA’s September 2024 decision to grant fast track designation to IBI363 monotherapy for the treatment of patients with unresectable locally advanced or metastatic melanoma, excluding choroidal melanoma, who experienced disease progression following at least 1 prior line of systemic treatment, including a PD-(L)1 inhibitor.6

“There is a huge unmet medical need for these types of drugs which have shown activity in [the] second line,” Hamid said. “Although we have novel options that have been approved in the second line, including TIL therapy, the real issue is that they’re not available for everyone. There are patients who don’t have the [necessary] performance status and would need something available off the shelf.”

Hamid also highlighted the personalized cancer vaccine mRNA-4157 (V940), which is being investigated in combination with pembrolizumab in the phase 2b KEYNOTE-942 trial (NCT03897881). KEYNOTE-942 enrolled patients with completely resected stage IIIB to IV melanoma and randomly assigned them 2:1 to receive mRNA-4157 plus pembrolizumab (n = 107) or pembrolizumab monotherapy (n = 50). The primary end point was recurrence-free survival (RFS); secondary end points included distant metastasis-free survival, safety, and tolerability.7

Data from KEYNOTE-942 published in The Lancet demonstrated that at a median follow-up of 23 months (IQR, 17-30) in the combination group and 24 months (IQR, 21-31) in the monotherapy group, patients achieved an 18-month RFS rate of 79% (95% CI, 69.0%-85.6%) vs 62% (95% CI, 46.9%- 74.3%), respectively. Treatment with V940 plus pembrolizumab led to a 44% reduction in the risk of disease recurrence or death compared with pembrolizumab alone (HR, 0.561; 95% CI, 0.309- 1.017; 2-sided P = .053).

“The major randomized phase 3 [V940-001] trial [NCT05933577] of mRNA-4157 in the adjuvant setting—from stage IIB all the way to stage IV resected [melanoma]—has fully accrued [patients and is examining the agent] plus pembrolizumab vs pembrolizumab,” Hamid said. “The data [with V940] are extremely compelling and hopefully we’ll get some more of that information in the year to come.”

INVESTIGATORS GATHER TO SHARE FURTHER UPDATES ACROSS MELANOMA AND CUTANEOUS MALIGNANCIES

On February 8, 2025, Physicians’ Education Resource, LLC, will host the 21st Annual International Symposium on Melanoma and Other Cutaneous Malignancies®. The virtual conference will be cochaired by Hamid and Sapna Patel, MD, of the University of Colorado Cancer Center in Aurora. During the meeting, Hamid and Patel will present a session titled “Novel Mechanisms in Melanoma and Beyond: Emerging Agents in Nonmelanoma Skin Cancer [NMSC].” They will also be leading multiple panel discussions and question and answer sessions throughout the day engaging leading investigators in the field of melanoma and cutaneous malignancies.8

“[Our presentation] will include up-to-date data on what’s available for NMSCs [as well as] other pathways to explore, and initial data for these patients,” Hamid said. “We’ve made these headways in melanoma itself, [and] we’ve seen that a lot of them translate into NMSCs, [including] squamous, basal, and Merkel cell [cancers]. A lot of these patients are rarely seen and there are questions that ensue. For example, a significant proportion of these cutaneous squamous cell carcinomas are [present] in immune-suppressed patients where immunotherapy may not be the right answer. There are [also] questions about how to move forward with Merkel cell [carcinoma], either initially or post progression on PD-1–[directed] therapies.”

There will also be sessions detailing frontline immunotherapy considerations in melanoma, targeted therapies in melanoma, and TIL therapies, among other exciting topics.8

“This is a didactic-heavy meeting where each topic has 5 to 10 minutes of slides. [There will be] case presentations and experts from around the world discussing how they take care of patients, what they see the future [of treatment] being, and how it could relate to clinical care,” Hamid said.