Expert Talks Progress, What's Next in Melanoma Treatment

Michael A. Postow, MD

Immunotherapy and BRAF plus MEK inhibition are the key players in the treatment of patients with melanoma, Michael A. Postow, MD, chief of Melanoma Service and associate attending physician at Memorial Sloan Kettering Cancer Center, said in a presentation during the 2020 ASCO Direct Highlights webcast, a program developed by Physicians’ Education Resource® (PER®), LLC.

“We have 2 main treatment modalities, both in the adjuvant setting for patients who have resected stage III melanoma that involves a lymph node, as well as in the metastatic setting,” Postow said. “[These strategies] consist of immunotherapy or, if patients have a BRAF mutation, BRAF plus MEK targeted therapy.”

For patients with resected stage III/IV disease, PD-1 inhibitors such as pembrolizumab (Keytruda) and nivolumab (Opdivo) are often utilized in the adjuvant setting, as they are known to result in relapse-free survival (RFS) benefit. For those whose tumors harbor BRAF mutations, the BRAF inhibitor dabrafenib (Tafinlar) combined with the MEK inhibitor trametinib (Mekinist) also yields benefit.

For patients with unresectable stage III/IV disease, options consist of PD-1 monotherapy or the combination of PD-1 inhibitors and ipilimumab (Yervoy). Additionally, for those with mutations, 3 different BRAF plus MEK inhibitor combinations are available. However, the question of what should be done after these approaches remains open, according to Postow.

During his presentation, Postow briefly reviewed the latest updates with immunotherapy and other targeted treatments in melanoma reported during the 2020 ASCO Virtual Scientific Program.

EORTC 1325/KEYNOTE-054 With Adjuvant Pembrolizumab Yields RFS Benefit

In the adjuvant space, 3-year follow-up data from the phase 3 double-blind EORTC 1325/KEYNOTE-054 trial (NCT02362594) evaluating the use of adjuvant pembrolizumab versus placebo in patients with resected high-risk stage III melanoma were presented at this year’s meeting.¹

In the trial, patients were randomized 1:1 to either 200 mg of pembrolizumab delivered intravenously every 3 weeks for 1 year or placebo delivered intravenously every 3 weeks for 1 year. “What was unique about this trial, [is that it] allowed for crossover to pembrolizumab upon disease recurrence,” noted Postow. Following recurrence, patients could be given the same schedule of pembrolizumab until disease progression or recurrence or up to 2 years.

The primary end point of the trial was RFS per investigation in the overall population, as well as in patients who had PD-L1—positive tumors. Secondary end points included distant metastasis-free survival and overall survival (OS) in all patients and patients with PD-L1–positive tumors, as well as safety and health-related quality of life. Investigators are still trying to understand whether PD-L1 inhibitors such as pembrolizumab are best saved for the adjuvant or the metastatic setting, according to Postow.

The updated data from the trial confirmed a sustained RFS benefit with pembrolizumab versus placebo in this patient population, and this improvement proved to be consistent across subgroups. In the overall population, the RFS was 64% versus 44% (HR, 0.56), translating to a 20% improvement. In the PD-L1­—positive population, the RFS rates with pembrolizumab and placebo was 65% versus 46%, respectively.

Notably, patients with BRAF-mutated and wild-type disease also experienced a RFS benefit with the agent, said Postow, who added that more information is needed on how adjuvant pembrolizumab will impact OS.

Checkpoint Blockade in PD-L1 Refractory Melanoma Shows Antitumor Activity

Shifting over to the metastatic setting, a recent study (NCT02743819) examined the effectiveness of the combination of the CTLA-4 inhibitor ipilimumab with the PD-1 inhibitor pembrolizumab immediately following progression on a PD-1 inhibitor in patients with advanced melanoma.²

Patients with unresectable or metastatic disease, confirmed progression on a PD-1 antibody immediately prior or within 6 months of adjuvant therapy, and an ECOG performance status of 0 to 1 were eligible for enrollment. Sixty of the 70 patients enrolled previously received a PD-1 monotherapy and 10 had received prior PD-1—based combinations. Upon starting the trial, patients were given 200 mg of pembrolizumab along with 1 mg/kg of ipilimumab for 3 weeks in 4 doses. Sixty-one of 70 patients were determined to be evaluable for response.

This study yielded “remarkable results” in PD-L1 refractory melanoma, according to Postow. The combination led to an irRECIST response rate of 27% and a median duration of response (DOR) of 18.5 months (95% CI, 10.6-undetermined); this was higher than the 15% response observed in historical controls with ipilimumab monotherapy. Additionally, the median PFS was 5.0 months (95% CI, 2.8-8.3) and the median OS was 24.7 months (95% CI, 15.2-undetermined) with this approach.

With regard to safety, pembrolizumab plus low-dose ipilimumab resulted in a lower high-grade immune-related AE rate, with 26% of patients experiencing grade 3 events and only 1 patient reporting a grade 4 event, noted Postow. Again, these data compared favorably with the grade 3/4 AE rate observed with frontline ipilimumab plus nivolumab (59%).

Ipilimumab Plus Anti—PD-1 Yields High Response Rates in PD-1–Resistant Melanoma

In another multicenter, retrospective study presented during the meeting, investigators set out to answer the question of whether a subset of PD-1—resistant patients can benefit from either ipilimumab monotherapy or ipilimumab in combination with a PD-1 inhibitor.³

Of 355 patients with stage III/IV melanoma enrolled on the study, all had received prior treatment with a PD-1 monotherapy in the adjuvant (n = 44; 12%) or metastatic setting (n = 311; 88%) and experienced either disease progression or recurrence. Seventy-four percent of patients (n = 230) had innate resistance to PD-1 treatment, and 26% (n = 81) had acquired resistance. Following this, patients were given either ipilimumab (n = 162; 46%) or ipilimumab plus a PD-1 inhibitor (n = 193; 54%).

Results showed an objective response rate of 32% with the ipilimumab combination versus just 13% with ipilimumab monotherapy. Notably, the DOR with the combination was 11.6 months (95% CI, 9.4-15.5) versus 9.0 months (95% CI, 4.4-13.7) with the monotherapy. With regard to safety, similar rates of high-grade AEs were observed in the combination and monotherapy arms, at 31% and 33%, respectively (P = .6474).

“If you give combination checkpoint blockade after [a patient becomes] PD-1 refractory, you still see a pretty good response rate, and it may not be that everyone needs combination [treatment] up front,”said Postow. “Understanding which patients need that up-front treatment is still one of the most important questions in our field.”

Atezolizumab Plus Cobimetinib and Vemurafenib Leads to Lower Rates of CNS Metastases

The combination of immunotherapy and targeted therapy has demonstrated intracranial activity in patients with melanoma and central nervous system (CNS) metastases. At the meeting, data from an exploratory analysis of the pivotal phase 3 IMspire150 trial were reported. Here, investigators evaluated whether the combination of the PD-L1 inhibitor atezolizumab (Tecentriq) combined with the BRAF inhibitor vemurafenib (Zelboraf) plus and the MEK inhibitor cobimetinib (Cotellic) delayed the time to diagnosis of CNS metastases versus BRAF and MEK inhibitors along among patients without CNS metastases at baseline.⁴

To be eligible for enrollment, patients needed to have previously untreated, advanced BRAF V600—mutated melanoma, an ECOG performance status of 0 or 1, measurable disease by RECIST v1.1 criteria, and no history of CNS metastases. Patients were randomized 1:1 to receive atezolizumab plus vemurafenib and cobimetinib or vemurafenib and cobimetinib alone.

Results showed that the addition of atezolizumab to vemurafenib and cobimetinib resulted in a higher investigator-assessed PFS, at a median PFS of 15.1 months (95% CI, 11.4-18.4) versus 10.6 months (95% CI, 9.3-12.7) in the vemurafenib/cobimetinib arm (HR, 0.78; 95% CI, 0.63-0.97); log-rank P =.0249). Notably, the addition of atezolizumab to the targeted therapy doublet delayed the time to first CNS metastases (HR, 0.79; 95% CI, 0.55-1.14).

OS data are anticipated to confirm the efficacy of this triplet regimen in this space, said Postow.

TIL Lifileucel Shows Promise in Metastatic Melanoma

No approved agents are available for patients with metastatic disease who have progressed after checkpoint inhibitors and BRAF/MEK therapies. Tumor-infiltrating lymphocytes (TIL) have shown antitumor efficacy with durable long-term responses in heavily pretreated patients. The novel agent lifileucel (LN-144) is under examination in the global, phase 2, multicenter Iovance C-144-01 trial (NCT02360579).⁵

To be eligible for enrollment, patients had to have unresectable or metastatic melanoma and have received at least 1 prior line of systemic therapy, including an anti—PD-1 agent, and if BRAF V600–positive, a BRAF inhibitor or BRAF/MEK combination. Data from the second cohort (n = 66) of the trial were reported at the 2020 ASCO Virtual Scientific Program.

The safety profile of the product proved consistent with the underlying advanced disease, and the safety profile of the lymphodepletion and interleukin-2 regimens. Notably, the number of AEs appeared to decrease in frequency over time; this indicates potential benefit of one-time treatment with the agent, said Postow. Efficacy results showed an ORR of 36.4% at a median follow-up of 18.7 months. At the time of the presentation, the median DOR had not yet been reached.

Although this therapy is not yet FDA approved, the hope is that it soon will be, said Postow. The data with TIL therapy appears to be favorable, but other treatments are needed for the majority of patients with melanoma, Postow concluded.

References

1. Eggermont AM, Blank CU, Mandala M, et al. Pembrolizumab versus placebo after complete resection of high-risk stage III melanoma: New recurrence-free survival results from the EORTC 1325-MG/Keynote 054 double-blinded phase III trial at three-year median follow-up. J Clin Oncol 2020;38(suppl 15):10000. doi:10.1200/JCO.2020.38.15_suppl.10000

2. Olson D, Luke JJ, Poklepovic AS, 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(suppl 15):10004. doi:10.1200/JCO.2020.38.15_suppl.10004

3. Da Silva IP, Ahmed T, Lo S, 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(suppl 15):10005. doi:10.1200/JCO.2020.38.15_suppl.10005

4. Ascierto PA, Robert C, Lewis KD, 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(suppl 15): 10023. doi:10.1200/JCO.2020.38.15_suppl.10023

5. 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