New and Updated Findings Showcase a Shift With Immunotherapy Across Melanoma

Data that emerged from the 2021 ASCO Annual Meeting represent potential paradigm shifts for patients with advanced melanoma, said Daniel Johnson, MD, who added that some of these shifts include a less-toxic frontline regimen to challenge nivolumab (Opdivo) plus ipilimumab (Yervoy), neoadjuvant checkpoint inhibition, and novel strategies for patients with refractory disease who have limited options.

Perioperative Setting

Findings from the phase 3 EORTC1325/KEYNOTE‑054 trial (NCT02362594) served as the basis for the 2019 approval of adjuvant pembrolizumab (Keytruda) for patients with melanoma who have involvement of lymph node(s) following complete resection.¹ Updated results from part 1 of the study demonstrated a 3-year recurrence-free survival rate of 63.7% with pembrolizumab vs 44.1% with placebo in patients with high-risk, resected, stage III melanoma (HR, 0.56; 95% CI, 0.47-0.68; P < .001).

Part 2 of the study evaluated the efficacy and safety of pembrolizumab in the subgroup of patients who had a recurrence and crossed over (n = 155) or were rechallenged (n = 20) with pembrolizumab.²

In the crossover population, the median progression-free survival (PFS) was 8.5 months with pembrolizumab (95% CI, 5.7-15.2). In the rechallenged population, the median PFS was 4.1 months (95% CI, 2.6–not evaluable [NE]).

“This is a very similar [PFS] curve that we see with frontline metastatic treatment with PD-1 monotherapy,” said Johnson, a medical oncologist at Ochsner Health and deputy director of the Ochsner Precision Cancer Therapies Program, in a virtual presentation during the 2021 ASCO Direct Highlights™ webcast in New Orleans, a program developed by Physicians’ Education Resource® LLC.

“[The rechallenged population included a] very small number [of patients] and short follow-up, [but] pembrolizumab does have activity if you rechallenge patients who recur after completing adjuvant treatment,” Johnson added.

Regarding neoadjuvant treatment, findings from an ongoing phase 2 study (NCT02519322) demonstrated that the combination of nivolumab and the anti-LAG3 monoclonal antibody relatlimab led to a pathologic complete response (pCR) rate of 59% and a near pCR rate of 7% in patients with resectable stage III or oligometastatic melanoma.³ Of these responses, major pathologic responses were observed in 66% of patients.

“The theory [for giving checkpoint inhibitors] neoadjuvantly instead of waiting [until] the adjuvant setting is that there may be a more robust immune response when we give immunotherapy to a patient who has an intact tumor because we are altering the tumor immune microenvironment,” Johnson said. “It does seem that combination immunotherapy in the neoadjuvant setting for melanoma is better than monotherapy.”

Frontline Setting

The combination of nivolumab and relatlimab is also an emerging option for the frontline treatment of patients with advanced melanoma. The primary results of the phase 3 RELATIVITY-047 trial (NCT03470922) demonstrated a median PFS of 10.12 months with a fixed-dose combination of nivolumab plus relatlimab compared with 4.63 months with nivolumab alone in this patient population (HR, 0.75; 95% CI, 0.62-0.92; P = .0055).⁴

Moreover, the PFS favored the combination across key prespecified subgroups, and the safety profile was manageable.

“RELATIVITY-047 is the first phase 3 study to validate [dual] LAG-3 and PD-1 inhibition,” said Johnson.

Also in the frontline setting, mature findings from the phase 3 CheckMate 067 trial (NCT01844505) demonstrated that with 6.5 years of follow-up, the median overall survival (OS) was 72.1 months with nivolumab plus ipilimumab compared with 36.9 months with nivolumab alone (HR, 0.84; 95% CI, 0.67-1.04) and 19.9 months with ipilimumab alone (HR, 0.52; 95% CI, 0.43-0.64).⁵ The estimated OS rates at 78 months were 49%, 42%, and 23%, respectively.

Moreover, clinical benefit was observed with the combination across all clinically relevant subtypes, irrespective of BRAF mutation and baseline liver metastasis status.

“The frontline metastatic [setting] is where there is going to be some controversy [about] what to do. [The combination of nivolumab and relatlimab] is going to be a bit of a game changer [because] we see high response rates with improved PFS compared with nivolumab alone, but [the regimen is] not as toxic as [nivolumab plus ipilimumab],” Johnson said.

“We should still use nivolumab plus ipilimumab for [patients with] brain metastases, high [lactate dehydrogenase] or high disease burden, and BRAF mutations. However, in a patient who has time and a shot at second-line therapy, it might make sense to start with the less toxic regimen,” added Johnson.

Relapsed/Refractory Setting

Updated findings from the phase 2 MK-7902-004/E7080-G000-225/LEAP-004 trial (NCT03776136) demonstrated that with 3 additional months of follow-up, the 9-month blinded independent central review–confirmed overall response rate (ORR) by RECIST v1.1 criteria remained 21.4% (95% CI, 13.9%-30.5%) with the combination of lenvatinib (Lenvima) and pembrolizumab in patients with advanced melanoma who had confirmed progression on a PD-1 or PD-L1 inhibitor.⁶ The number of CRs increased from 2 to 3 with additional follow-up.

The median duration of response (DOR) increased from 6.3 months to 8.3 months (95% CI, 3.2-15.9+) and an estimated 38.6% of responses were ongoing for at least 9 months.

“Once [a patient] progresses on PD-1 inhibitors, we can give anti–CTLA-4 combinations, but, in general, if they are BRAF wild-type, they don’t have a lot of treatment options. So, this is an area of need to identify treatments for these patients,” Johnson said.

Finally, Johnson highlighted data evaluating lifileucel (LN-144), the cryopreserved autologous tumor-infiltrating lymphocyte therapy, in patients with advanced melanoma. Findings from the phase 2 C-144-01 study (NCT02360579) demonstrated an ORR of 36.4% with a one-time infusion of lifileucel in patients with heavily pretreated advanced or metastatic melanoma.⁷ At a median follow-up of 33.1 months, the median DOR was not reached (range, 2.2 to 38.5+).

“No treatments are approved for patients with advanced melanoma whose disease progresses after checkpoint inhibitors or BRAF/MEK inhibitors. Patients with advanced melanoma who are either primary refractory or develop resistance can be treated with chemotherapy, but there are poor response rates in melanoma to chemotherapy,” concluded Johnson.

References

1. FDA approves pembrolizumab for adjuvant treatment of melanoma. News release. FDA. February 15, 2019. Accessed August 13, 2021. https://bit.ly/3jTx0c5
2. Eggermont AM, Meshcheryakov A, Atkinson V, et al. Crossover and rechallenge with pembrolizumab in recurrent patients from the EORTC 1325-MG/Keynote-054 phase 3 trial, pembrolizumab versus placebo after complete resection of high-risk stage III melanoma. J Clin Oncol. 2021;39(suppl 15):9500. doi:10.1200/JCO.2021.39.15_suppl.9500
3. Amaria RN, Postow MA, Tetzlaff MT, et al. Neoadjuvant and adjuvant nivolumab (nivo) with anti-LAG3 antibody relatlimab (rela) for patients (pts) with resectable clinical stage III melanoma. J Clin Oncol. 2021;39(suppl 15):9502. doi:10.1200/JCO.2021.39.15_suppl.9502
4. Lipson EJ, Tawbi HAH, Schadendorf D, et al. Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: primary phase III results from RELATIVITY-047 (CA224-047). J Clin Oncol. 2021;39(suppl 15):9503. doi:10.1200/JCO.2021.39.15_suppl.9503
5. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. CheckMate 067: 6.5-year outcomes in patients (pts) with advanced melanoma. J Clin Oncol. 2021;39(suppl 15):9506. doi:10.1200/JCO.2021.39.15_suppl.9506
6. Arance AM, de la Cruz-Merino L, Petrella TM, et al. Lenvatinib (len) plus pembrolizumab (pembro) for patients (pts) with advanced melanoma and confirmed progression on a PD-1 or PD-L1 inhibitor: updated findings of LEAP-004. J Clin Oncol. 2021;39(suppl 15):9504. doi:10.1200/JCO.2021.39.15_suppl.9504
7. Larkin J, Sarnaik A, Chesney JA, et al. Lifileucel (LN-144), a cryopreserved autologous tumor infiltrating lymphocyte (TIL) therapy in patients with advanced melanoma: evaluation of impact of prior anti-PD-1 therapy. J Clin Oncol. 2021;39(suppl 15):9505. doi:10.1200/JCO.2021.39.15_suppl.9505