乌鸦传媒

Adding the tyrosine kinase inhibitor lenvatinib (Lenvima) to pembrolizumab (Keytruda) led to durable responses in advanced melanoma that had progressed on prior anti-PD-1/L1 therapy, a multicenter study showed.

The combination produced objective responses in 22 of 103 patients, including a third of patients previously treated with a PD-1 inhibitor plus a CTLA-4 inhibitor. The median response duration was 8.3 months.

Grade 3-5 treatment-related adverse events (TRAEs) occurred in 47 patients, including one death associated with low platelet count, reported Ana Arance, MD, PhD, of Hospital Clinic Barcelona, and co-authors in the .

"The findings are encouraging because patients with unresectable stage III/IV melanoma refractory to anti-PD-1/L1 therapy alone, anti-PD-1/L1 plus anti-CTLA-4 therapy, or BRAF/MEK-directed therapies are an expanding population with limited treatment options," the authors concluded. "Importantly, the combination of lenvatinib and pembrolizumab induced responses among patients with primary and secondary resistance to anti-PD-1/L1-based therapy irrespective of baseline tumor characteristics in a population with a high proportion of poor prognostic factors."

The findings reflect the ongoing search for new treatment options for advanced cancers after progression on immune checkpoint inhibitors (ICIs). As recently reported, the combination of the VEGF inhibitor ramucirumab (Cyramza) and pembrolizumab improved overall survival versus ramucirumab and chemotherapy in non-small cell lung cancer (NSCLC) that had progressed on an ICI and chemotherapy. The growing population of patients treated with ICIs will continue to increase the need for effective post-progression therapies, Arance and co-authors noted.

Lenvatinib has demonstrated modest single-agent activity in advanced melanoma. In a phase I/II trial of metastatic melanoma, lenvatinib plus pembrolizumab produced an objective response rate (ORR) of 48%, a median response duration of 12.5 months, and a median progression-free survival of 5.5 months in patients who had received up to two prior systemic regimens.

LEAP-004 involved patients with unresectable/metastatic melanoma that had progressed on single-agent or combination ICI therapy. Investigators in five countries enrolled 103 patients and treated them with lenvatinib and pembrolizumab until disease progression or unacceptable toxicity. The primary endpoint was ORR.

The ORR by independent review was 21.4% versus 28.2% by investigator assessment. Two-thirds of the patients had some degree of tumor shrinkage, including patients with elevated baseline lactate dehydrogenase levels, BRAF-mutant and PD-L1-negative tumors, and prior treatment with combination ICI therapy. Categorized by type of resistance, the ORR was 18.2% for primary resistance in the adjuvant setting, 22.6% for primary resistance in the metastatic setting, and 22.7% for secondary resistance in the metastatic setting.

The 8.3-month median response duration was by independent review, and had not yet been reached by investigator assessment. The independent review committee estimated that 38% of responses lasted at least 9 months as compared with a 70.1% estimate by study investigators.

Beyond objective response, 46 (44.7%) patients had stable disease of any duration, and the median duration was 5.75 months. Stable disease persisted for at least 6 months in an estimated 47.8% of cases.

TRAEs occurred in 99 (96.1%) patients, including grade 3-5 TRAEs in 45.6%. The most common any-grade TRAEs were hypertension, diarrhea, and nausea. The only grade 3-4 TRAEs that occurred in at least five patients were hypertension and diarrhea.

In addition to the patient who died of complications related to low platelet count, one patient died of an arterial thromboembolic event not considered treatment related, but clinically significant for lenvatinib. Two patients died of sepsis, and neither death was considered treatment related.

During a at the 2021 American Society of Clinical Oncology (ASCO) meeting, Arance said the results demonstrated "clinically meaningful durable responses." However, ASCO Jason Luke, MD, of the University of Pittsburgh Hillman Cancer Center, questioned whether the lenvatinib-pembrolizumab combination has a future in the setting of ICI post-progression.

"It's unclear to me whether this efficacy really differentiates from what we have seen with previous combinations," said Luke. "Are these regimens good enough to register this sort of approach in the setting of refractory disease?"

The 8.3-month median duration of response appeared shorter than what might be expected of ICI responses, he added.

In contrast, the ramucirumab-pembrolizumab study in NSCLC demonstrated an overall survival advantage in a randomized trial. Following that presentation at the 2022 ASCO meeting, invited discussant Christine Bestvina, MD, of the University of Chicago Comprehensive Cancer Center, said the study provided evidence of synergistic anticancer activity and called the findings "practice changing today."

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