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First-in-Human Study of RAF Family Kinase Inhibitor Lifirafenib in Solid Tumors


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In a first-in-human phase I trial reported in the Journal of Clinical Oncology, Desai et al found that the RAF family kinase inhibitor lifirafenib produced responses in several solid tumor types in patients with BRAF or KRAS/NRAS mutations.

Study Details

The study, conducted in Australia and New Zealand, enrolled 35 patients in a dose-escalation phase and 96 in a dose-expansion phase. In the dose-escalation phase, patients received lifirafenib once daily at either 5, 10, 20, 30, 40, 50, or 60 mg. Cancer types included stage III or IV colorectal cancer, non–small cell lung cancer (NSCLC), melanoma, cholangiocarcinoma, thyroid cancer, endometrial/ovarian cancer, and pancreatic cancer.  

Toxicities

During the dose-escalation phase, dose-limiting toxicities occurred in six patients, with five occurring at doses ≥ 40 mg/day. Dose-limiting toxicities consisted of grade 3 increased alanine transaminase in one patient and grade 4 thrombocytopenia in five patients. The maximum tolerated dose was established as 40 mg/day. In the entire study, the most common grade ≥ 3 adverse events were hypertension (17.6%) and fatigue (9.9%).

Responses

KEY POINTS

  • Among patients with BRAF mutations, responses were observed in melanoma, thyroid cancer, and ovarian cancer.
  • Among patients with KRAS/NRAS mutations, responses were observed in endometrial cancer and NSCLC.

Among all evaluable patients, objective response was observed in 9 (17.0%) of 53 with BRAF mutations, with complete response observed in 1 patient with melanoma. Partial responses were observed in five patients with melanoma, two with thyroid cancer/papillary thyroid cancer, and one with low-grade serous ovarian cancer (LGSOC). An unconfirmed partial response was observed in 1 patient with NSCLC. An additional 27 patients (50.9%) had stable disease. 

Among 66 patients with KRAS/NRAS mutations, objective response was observed in two (3.0%), with partial response observed in one patient with endometrial cancer and one with NSCLC. Stable disease was observed in 33 patients (50.0%). No responses were observed in 20 patients with colorectal cancer.

The investigators concluded, “Lifirafenib is a novel inhibitor of key RAF family kinases and EGFR, with an acceptable risk-benefit profile and antitumor activity in patients with BRAF V600–mutated solid tumors, including melanoma, papillary thyroid cancer, and [ovarian cancer], as well as KRAS–mutated NSCLC and endometrial carcinoma. Future comparisons with first-generation BRAF inhibitors and exploration of lifirafenib alone or as combination therapy in patients with selected RAS mutations who are resistant/refractory to first-generation BRAF inhibitors are warranted.”

Jayesh Desai, MBBS, of Peter MacCallum Cancer Centre, Melbourne, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by BeiGene. For full disclosures of the study authors, visit ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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