Lenvatinib/Pembrolizumab as second line treatment for advanced melanoma patients refractory to programmed death 1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors

LEAP-004 is an open-label, single-arm, phase II (NCT03776136) study of Lenvatinib/Pembrolizumab combination in second line advanced melanoma, recently published on the Journal of Clinical Oncology (1). The study enrolled 103 patients with unresectable stage III or IV melanoma who progressed while on treatment or within 3 months of their last dose of a programmed death 1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitor given alone or in combination. In these cases, usual second line treatment is Ipilimumab or chemotherapy (when Ipilimumab has already been used) or, better, inclusion in a clinical trial. Here, patients received 20 mg of Lenvatinib daily together with Pembrolizumab 200 mg every 3 weeks for a maximum of 35 doses. The primary endpoint of the study was objective response rate (ORR) assessed by RECIST1.1 on blinded independent review.

Initial results presented at virtual ESMO 2020 (2), showed that the combination Lenvatinib/Pembrolizumab had promising efficacy and manageable safety in that setting: ORR was 21.4% (31% in patients progressing to prior anti-PD-1/anti-CTLA-4 combo), with a 6.3 months median duration of Response (DOR). Grade 3–5 treatment-related adverse events (TRAE) occurred in 47 patients (45.6%), most commonly hypertension (21.4%), and one patient died from a treatment-related event (decreased platelet count). Although TRAE rates must be taken into great consideration, less than 10% led to discontinuation, but to dose reductions (2).

At ASCO 2021, longer follow-up data with a median of 15.3 months were presented and upheld the benefit: ORR remained essentially stable (21.4%) over time in comparison with previous analysis, and median DOR increased from 6.3 to 8.2 months (3). More than one third (37.2%) of the responses were ongoing at 9 months, when 17.5% of patients were still on study treatment. Interestingly, ORR increased from 31% to 33.3% in the 30 patients with progressive disease on prior anti-PD-1/anti-CTLA-4 immunotherapy. Median progression-free survival (PFS) and overall survival (OS) remained unchanged at 4.2 and 14 months, respectively, while 17.8% of patients were progression-free, and 54.5% were alive at 12 months (3).

The final manuscript (1) confirmed those results concluding that “Lenvatinib plus Pembrolizumab provides clinically meaningful, durable responses in patients with advanced melanoma with confirmed progressive disease on prior PD-1/L1 inhibitor-based therapy, including those progressing on anti-PD-1 plus anti-CTLA-4 therapy. The safety profile was as expected. These data support Lenvatinib plus Pembrolizumab as a potential regimen for this population of high unmet need”.

Given the strict definition of progressive disease and the high unmet need for effective treatments in anti-PD-L1 resistant melanoma patients, reported 21.4% ORR and 54.5% 12-month OS rate are promising and went on consolidating over time. Moreover, the study enrolled substantial proportion of patients with poor prognostic factors, such as 55.3% with elevated lactate dehydrogenase (LDH) or 58.3% with heavily pretreated disease (more than 2 prior lines of treatment). So, final results are consistent in confirming antitumor activity and tolerability of the combination in patients with advanced melanoma resistant to prior anti-PD-L1-based treatment, irrespective of baseline clinical characteristics (BRAF mutation, elevated LDH), the number of previous lines of therapy or intercurrent systemic treatments.

However, those data are not better looking in respect of previous ones published in similar settings. In particular, three other studies focused on second line options in advanced melanoma patients, exploring the possible role of ipilimumab and anti-PD-1 (either nivolumab or pembrolizumab) combinations with different schedules and doses in anti-PD-1 refractory patients.

Olson and colleagues (4), showed in a phase II prospective trial, that Pembrolizumab 200 mg combined with low dose ipilimumab 1 mg/kg once every 3 weeks for 4 doses, followed by Pembrolizumab monotherapy was able to induce 5 complete and 15 partial responses, making the irRECIST ORR 29% among the entire trial population. Median PFS was 5 months, and the median OS was 24.7 months, with a median DOR of 16.6 months (4).

Silva and colleagues (5) published a multicentric, retrospective study including 355 patients resistant to anti-PD-1/L1s. At a median follow-up of 22.1 months, results showed ORR to be higher with Ipilimumab plus anti-PD-1 (31%), than with ipilimumab monotherapy (13%, P<0.0001). Median OS was longer in the combo group (20.4 months), than with ipilimumab monotherapy (8.8 months) with a hazard ratio of 0.50 and P<0.0001. Median PFS was 3.0 versus 2.6 months, respectively (5).

Similarly, Vanderwalde and colleagues in the S-1616 trial conducted by the SWOG group (6), compared prospectively the classic Ipilimumab/Nivolumab schedule to Ipilimumab monotherapy in 93 primarily refractory advanced melanoma patients with a 3:1 randomization. With a median follow-up of 25.3 months, PFS hazard ratio was 0.63, with a 0.04 P value favoring Ipilimumab/Nivolumab. The 6-month PFS estimates were 34% and 13% for the combination and monotherapy, while ORR was 28% and 9%, respectively. Twelve-month OS was 63% in the experimental arm and 57% in the Ipilimumab arm, concluding that “Ipi/Nivo is an appropriate standard in patients with metastatic melanoma who do not respond to single-agent PD-1 therapy” (6).

What does this mean? It means that, although this target population is clearly in need of regimens that will improve outcomes, whether Lenvatinib and Pembrolizumab will qualify for the job is still a question. The regimen could be useful in the setting of refractory disease, but, even though it is not possible to make indirect comparisons, it appears that effectiveness is not superior or even equal, to what we have seen with previous combinations using anti-PD-1/anti-CTLA-4 combo. In particular, DOR is less than expected and showed with checkpoint blockade.

Furthermore, although Lenvatinib/Pembrolizumab provides a similar likelihood of responses across clinical resistance patterns, the LEAP-004 study was unable to give insights in the definitions of primary or secondary resistances and their phenotypes, mainly because of limited numbers in patient’s subgroups with, subsequently, low statistical power of the data collected. In fact, similar ORRs were observed regardless of whether patients experienced primary resistance in the adjuvant setting (18.2%) or primary (22.6%) or secondary resistance (22.7%) in the metastatic setting. On this regard, the authors wrote, “resistance to immune checkpoint inhibitors is multifaceted and can occur in the absence of benefit (primary resistance) or after a period of response or disease stability (secondary resistance)”.

Probably, we can define two possible clinical scenarios: refractoriness to anti-PD-1s alone and to anti-PD-1/anti-CTLA-4 combinations. In the first case, Ipilimumab/Nivolumab is preferably chosen following the SWOG-1616 trial reported data (the only prospective randomized clinical trial so far), while in the second case, the association Lenvatinib/Pembrolizumab (or Lenvatinib in monotherapy in those patients with preexisting or acquired autoimmune conditions that preclude further immunotherapy) could be offered to patients in order to try to revert resistances. Given the small numbers of 29 patients considered refractory to ipilimumab/nivolumab, we need more data to confirm the efficacy in this population, however, hitting the 21% bar is an excellent result that should consider this combination the standard of care in a difficult to treat cohort.

Obviously, a deeper understanding of the biology underlying resistance phenotypes would have enabled better selection of subgroups and treatments. However, analyses of possible molecular biomarkers of response and resistance are planned.

Evidence suggests that Lenvatinib helps shift the tumor microenvironment to an immune-stimulatory state by inhibiting VEGFR and FGFR. In mouse models, Lenvatinib plus PD-1 inhibition had significantly greater antitumor activity than either agent did alone. Clinically, the combination of Lenvatinib and Pembrolizumab has shown efficacy and a consistent safety profile in several tumor types (ovarian cancer, renal and hepatocarcinoma). Particularly, in metastatic melanoma, previous studies using anti-angiogenesis drugs combined with chemotherapy, like Bevacizumab/Dacarbazine based combo, demonstrated similar efficacy results, although in the different setting of untreated patients: ORR was 18.9% and clinical benefit was 48.6%. Median DOR was 16.9 months and PFS was 5.5 months with a median OS of 11.4 months (7). Translational studies suggested that high levels of an angiogenesis gene signature score at baseline, low baseline serum angiopoietin-2, or early induction of hypertension during treatment, could identify responders, thus helping in better selecting patients for future anti-VEGFR trials.

In conclusion, taken altogether, results are interesting within an area of unmet medical need, in a population that has failed prior therapy, with the majority of patients showing M1c disease. It is also encouraging that authors chose very strict entry criteria for defining progression and refractivity. However, presented data does not appear to be practice changing until confirmed in a randomized phase III trial with an appropriate comparator arm, to be chosen depending on previously received treatment. For example, those patients refractory to anti-PD-1s monotherapy ought to be randomized to receive Lenvatinib/Pembrolizumab versus Ipilimumab/anti-PD-1, while those who had already received the Ipilimumab/anti-PD-1 combination, could be randomized versus Lenvatinib/Placebo. Single arm trials utilizing the surrogate endpoint for clinical benefit ORR are important contributions to field, but are not often influencing clinical decisions.

Treatment options for patients with melanoma that recurred after or progressed on anti-PD-1-based treatment, particularly on anti-PD-1 plus anti-CTLA-4 combinations, are indeed needed, and any combination that proves to improve ORR, DOR and/or OS with less toxicity than Ipilimumab/Nivolumab is to be considered the new de facto standard of care in this setting. Unfortunately, no such combination currently exists.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Translational Medicine. The article did not undergo external peer review.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-23-341/coif) and has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Arance A, de la Cruz-Merino L, Petrella TM, et al. Phase II LEAP-004 Study of Lenvatinib Plus Pembrolizumab for Melanoma With Confirmed Progression on a Programmed Cell Death Protein-1 or Programmed Death Ligand 1 Inhibitor Given as Monotherapy or in Combination. J Clin Oncol 2023;41:75-85. [Crossref] [PubMed]
2. Arance AM, O’Day SJ, de la Cruz-Merino L, et al. Lenvatinib plus pembrolizumab for advanced melanoma that progressed on a PD-1 or PD-L1 inhibitor: Initial results of LEAP-004. Ann Oncol 2020;31:S1142-215.
3. Arance AM, de la Cruz-Merino L, Petrella TM, et al. Lenvatinib plus pembrolizumab for patients with advanced melanoma and confirmed progression on a PD-1 or PD-L1 inhibitor: Updated findings of LEAP-004. J Clin Oncol 2021;39:abstr 9504.
4. Olson DJ, Eroglu Z, Brockstein B, et al. Pembrolizumab Plus Ipilimumab Following Anti-PD-1/L1 Failure in Melanoma. J Clin Oncol 2021;39:2647-55. [Crossref] [PubMed]
5. Pires da Silva I, Ahmed T, Reijers ILM, et al. Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study. Lancet Oncol 2021;22:836-47. [Crossref] [PubMed]
6. Vanderwalde AM, Moon J, Kendra K, et al. CT013 - S1616: Ipilimumab plus nivolumab versus ipilimumab alone in patients with metastatic or unresectable melanoma that did not respond to anti-PD-1 therapy. Session CTPL04 – Combination Immunotherapy Clinical Trial. AACR, Abstract presented April 12, 2022. Cancer Res 2022;82:abstr CT013.
7. Ferrucci PF, Minchella I, Mosconi M, et al. Dacarbazine in combination with bevacizumab for the treatment of unresectable/metastatic melanoma: a phase II study. Melanoma Res 2015;25:239-45. [Crossref] [PubMed]