Expert Point of View: Jason J. Luke, MD

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Jason J. Luke, MD

Jason J. Luke, MD

The invited discussant of LEAP-004, Jason J. Luke, MD, Associate Professor of Medicine and Director of the Cancer Immunotherapeutics Center, University of Pittsburgh Hillman Cancer Center, said the investigators of LEAP-0041 deserve credit for designing a study with a clearly defined PD-1–refractory population, one-third of whom had at least three prior lines of therapy and half of whom had elevated levels of lactate dehydrogenase. Although this population is clearly in need of regimens that will improve outcomes, he added, whether lenvatinib and pembrolizumab will qualify for the job is still a question.

Dr. Luke commented: “It’s unclear to me whether this efficacy really differentiates from what we have seen with previous combinations…. Are these regimens good enough to register this sort of approach in the setting of refractory disease?”

Results With VEGFR Inhibitors Alone and in Combination

As single agents, the vascular endothelial growth factor receptor (VEGFR) inhibitors lenvatinib, axitinib, aflibercept, and bevacizumab have yielded response rates in this setting of 13%, a median duration of response of 7.4 months, and a median progression-free survival of 4.8 months. When combined with chemotherapy or immunotherapy, these numbers are 24%, 7.6 months, and 6.5 months, he noted.

In LEAP-004, the 21.4% response rate to lenvatinib/pembrolizumab was similar to that with previous combinations. The regimen “appears to be useful” in the PD-1–refractory setting; however, the duration of response (8.3 months), although improved from the previous analysis (6 months),2 is still “less than one might expect with checkpoint blockade,” pointed out Dr. Luke. “This calls into question the mechanism by which we are pursuing this anticancer effect.”

The same question arises from a study of axitinib plus the anti–PD-1 agent toripalimab in treatment-naive metastatic mucosal melanoma, noted Dr. Luke. In a 2019 study by Sheng et al,3 this combination yielded a response rate of 48% “in this notoriously difficult-to-treat population,” though, again, the duration of response was less than with checkpoint blockade. Translational studies revealed high levels of an angiogenesis signature score among responders. “That’s something we might keep in mind when we think about other VEGFR approaches,” Dr. Luke suggested.

One of the obvious concerns with VEGFR tyrosine kinase inhibitors, he added, is “they are difficult drugs to take.” Evidence of this is the 46% rate of grade 3 to 5 adverse events in LEAP-004 and the requirement for dose reductions in more than half the patients.

This makes it important to know which patients are most likely to benefit from anti-VEGFR/anti–PD-1/L1 combinations. Previous studies in melanoma and other malignancies have hinted at a few biomarkers: low baseline serum angiopoietin 2; early induction of hypertension; angiogenesis gene signatures; and a constellation of angiogenesis-low, T effector cell–high, and myeloid cell–high populations.

The hope is more will be learned from upcoming neoadjuvant studies and front-line randomized trials comparing VEGFR/anti–PD-1 regimens with pembrolizumab alone, Dr. Luke added. 

DISCLOSURE: Dr. Luke holds stock or other ownership interests in Actym Therapeutics, Alphamab Oncology, Arch Oncology, Kanaph Therapeutics, Mavu Pharmaceutical, Onc.AI, Pyxis, and Tempest Therapeutics; has served as a consultant or advisor to 7 Hills Pharma, AbbVie, Alnylam, Alphamab Oncology, Astellas Pharma, Bayer, Bristol Myers Squibb, C-Stone Pharmaceuticals, Checkmate Pharmaceuticals, Crown Bioscience, Eisai, EMD Serono, Flame Biosciences, Genentech, Immunocore, Incyte, Inzen, Janssen, Kadmon, KSQ Therapeutics, Merck, Mersana, Nektar, Novartis, Partner Therapeutics, Pfizer, Reflexion Medical, Regeneron, Ribon Therapeutics, Rubius, Silicon Therapeutics, Spring Bank, Synlogic, Tempest Therapeutics, Tesaro, TRex Bio, Werewolf, Xencor, and Xilio; has received research funding from Agios, Array BioPharma, Astellas Pharma, BioNTech AG, EMD Serono, FStar, Genmab, Ikena Oncology, Immatics, Kadmon, KAHR Medical, Moderna Therapeutics, Nektar, Numab, Replimmune, Rubius Therapeutics, Scholar Rock, Spring Bank, Synlogic, Takeda, Tizona Therapeutics, and Trishula Therapeutics; has received institutional research funding from AbbVie, Bristol Myers Squibb, Corvus Pharmaceuticals, Incyte, MacroGenics, Merck, and Xencor; holds intellectual property in “Serial #15/612,657 (cancer immunotherapy)” and “Serial #PCT/US18/36052 (microbiome biomarkers for anti–PD-1/PD-L1 responsiveness: diagnostics, prognostic and therapeutic uses thereof); and has been reimbursed for travel, accommodations, or other expenses by Array BioPharma, Bristol Myers Squibb, EMD Serono, Janssen, Merck, Mersana, Novartis, Pyxis, Reflexion Medical, and Xilio.


1. 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. 2021 ASCO Annual Meeting. Abstract 9504. Presented June 6, 2021.

2. Arance Fernandez 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. ESMO Virtual Congress 2020. Abstract LBA44. Presented September 19, 2020.

3. Sheng X, Yan X, Chi Z, et al: Axitinib in combination with toripalimab, a humanized immunoglobulin G4 monoclonal antibody against programmed cell death-1, in patients with metastatic mucosal melanoma: An open-label phase IB trial. J Clin Oncol 37:2987-2999, 2019.

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LEAP-004 Trial Update on Lenvatinib Plus Pembrolizumab After Disease Progression in Metastatic Melanoma

Longer follow-up of the LEAP-004 trial in metastatic melanoma upheld the benefit seen with the VEGF kinase inhibitor lenvatinib plus the PD-1 inhibitor pembrolizumab for patients experiencing disease progression on prior checkpoint blockade, investigators reported at the 2021 ASCO Annual Meeting.1