Phase II, Open-Label Study of Encorafenib Plus Binimetinib in Patients With BRAFV600-Mutant Metastatic Non–Small-Cell Lung Cancer

Author(s): Gregory J. Riely, MD, PhD¹; Egbert F. Smit, MD, PhD²; Myung-Ju Ahn, MD, PhD³; Enriqueta Felip, MD, PhD⁴; Suresh S. Ramalingam, MD⁵; Anne Tsao, MD⁶; Melissa Johnson, MD⁷; Francesco Gelsomino, MD⁸; Raymond Esper, MD, PhD⁹; Ernest Nadal, MD, PhD10; Michael Offin, MD¹; Mariano Provencio, MD, PhD¹¹; Jeffrey Clarke, MD¹²; Maen Hussain, MD⁹; Gregory A. Otterson, MD¹³; Ibiayi Dagogo-Jack, MD¹⁴; Jonathan W. Goldman, MD¹⁵; Daniel Morgensztern, MD¹⁶; Ann Alcasid, BA¹⁷; Tiziana Usari, BSc¹⁸; Paul Wissel, MD¹⁹; Keith Wilner, PhD²⁰; Nuzhat Pathan, PhD²⁰; Svitlana Tonkovyd, MD²¹; and Bruce E. Johnson, MD²²

Source: DOI: 10.1200/JCO.23.00774 Journal of Clinical Oncology 41, no. 21 (July 20, 2023) 3700-3711.

Dr. Maen Hussein's Thoughts

Targeted therapy in NSCLC, FCS was part of this trial.

PURPOSE

The combination of encorafenib (BRAF inhibitor) plus binimetinib (MEK inhibitor) has demonstrated clinical efficacy with an acceptable safety profile in patients with BRAFV600E/K-mutant metastatic melanoma. We evaluated the efficacy and safety of encorafenib plus binimetinib in patients with BRAFV600E-mutant metastatic non–small-cell lung cancer (NSCLC).

METHODS

In this ongoing, open-label, single-arm, phase II study, patients with BRAFV600E-mutant metastatic NSCLC received oral encorafenib 450 mg once daily plus binimetinib 45 mg twice daily in 28-day cycles. The primary end point was confirmed objective response rate (ORR) by independent radiology review (IRR). Secondary end points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival, time to response, and safety.

RESULTS

At data cutoff, 98 patients (59 treatment-naïve and 39 previously treated) with BRAFV600E-mutant metastatic NSCLC received encorafenib plus binimetinib. Median duration of treatment was 9.2 months with encorafenib and 8.4 months with binimetinib. ORR by IRR was 75% (95% CI, 62 to 85) in treatment-naïve and 46% (95% CI, 30 to 63) in previously treated patients; median DOR was not estimable (NE; 95% CI, 23.1 to NE) and 16.7 months (95% CI, 7.4 to NE), respectively. DCR after 24 weeks was 64% in treatment-naïve and 41% in previously treated patients. Median PFS was NE (95% CI, 15.7 to NE) in treatment-naïve and 9.3 months (95% CI, 6.2 to NE) in previously treated patients. The most frequent treatment-related adverse events (TRAEs) were nausea (50%), diarrhea (43%), and fatigue (32%). TRAEs led to dose reductions in 24 (24%) and permanent discontinuation of encorafenib plus binimetinib in 15 (15%) patients. One grade 5 TRAE of intracranial hemorrhage was reported. Interactive visualization of the data presented in this article is available at the PHAROS dashboard (https://clinical-trials.dimensions.ai/pharos/).

CONCLUSION

For patients with treatment-naïve and previously treated BRAFV600E-mutant metastatic NSCLC, encorafenib plus binimetinib showed a meaningful clinical benefit with a safety profile consistent with that observed in the approved indication in melanoma.

Author Affiliations

¹Memorial Sloan Kettering Cancer Center, New York, NY;²Department of Pulmonary Diseases, Leiden University Medical Center, Leiden, the Netherlands;³Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea;⁴Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, Barcelona, Spain;⁵Winship Cancer Institute of Emory University, Atlanta, GA;⁶MD Anderson Cancer Center, Houston, TX;⁷Tennessee Oncology, Sarah Cannon Research Institute, Nashville, TN;⁸Medical Oncology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy;⁹Florida Cancer Specialists, Fort Myers, FL;¹⁰Medical Oncology, Catalan Institute of Oncology, Barcelona, Spain;¹¹Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain;¹²Duke Cancer Center, Durham, NC;¹³Ohio State University Comprehensive Cancer Center, Columbus, OH;¹⁴Massachusetts General Hospital, Boston, MA;¹⁵David Geffen School of Medicine at UCLA, Los Angeles, CA;¹⁶Washington University School of Medicine, St Louis, MO;¹⁷Pfizer, Collegeville, PA;¹⁸Pfizer, Milan, Italy;¹⁹Pfizer, New York, NY;²⁰Pfizer, La Jolla, CA;²¹Pfizer, Warsaw, Poland;²²Dana-Farber Cancer Institute, Boston, MA

Amivantamab Plus Lazertinib in Atypical EGFR-Mutated Advanced Non–Small Cell Lung Cancer: Results From CHRYSALIS-2

The CHRYSALIS-2, the cohort C analysis of patients with atypical EGFR mutations showed meaningful and durable activity. Atypical mutations can be difficult to deal with as a clinician, and having concrete data on these (S768I, L861Q and G719ZX) mutations gives assurance that this doublet is active. Overall response rate (ORR) was 52% and median progression-free survival (PFS) was 11.1 months in refractory patients and 19.5 months in the treatment-naive population.

Survival with Osimertinib plus Chemotherapy in EGFR-Mutated Advanced NSCLC

The final overall survival (OS) analysis from the FLAURA2 confirms the well-published findings that Osi + chemo improves survival over Osi monotherapy. OS difference was about 10 months at 47 vs 37 months, with a predictable toxicity tradeoff.

Updated Overall Survival Analysis From the Phase II PHAROS Study of Encorafenib Plus Binimetinib in Patients With BRAF V600E-Mutant Metastatic Non–Small Cell Lung Cancer

This update demonstrated that encorafenib plus binimetinib was associated with the longest median overall survival (mOS) reported to date among targeted therapies in patients with treatment-naïve BRAF V600E–mutant metastatic NSCLC (mNSCLC). Median OS was 47.6 months in treatment-naïve patients. By the way check the authors there 😊.

Simultaneous Durvalumab and Platinum-Based Chemoradiotherapy in Unresectable Stage III Non–Small Cell Lung Cancer: The Phase III PACIFIC-2 Study

PACIFIC-2 was a phase III trial testing durva given concurrently with cCRT (and continued as consolidation) versus placebo + cCRT in unresectable stage III NSCLC, and it did not meet its primary endpoint. The overall response rate (ORR) was essentially identical (60.7% vs 60.6%), and pneumonitis rates were similar (any grade 28.8% vs 28.7%; grade ≥3: 4.6% vs 5.6%), but adverse events (AEs) leading to discontinuation and fatal AEs were higher with durva (25.6% vs 12.0%; 13.7% vs 10.2%), especially early on. Starting IO up front with cCRT didn’t improve outcomes and added early toxicity—consolidation durva after cCRT is still the way to go.

Sevabertinib in Advanced HER2-Mutant Non–Small-Cell Lung Cancer

Sevabertinib shows strong efficacy in HER2-mutant NSCLC, with an overall response rate (ORR) of 64% and median progression-free survival (PFS) of 8.3 months in previously treated, HER2-TKI–naive patients, and an overall response rate (ORR) of 71% with a duration of response (DOR) of 11.0 months in first-line therapy. Activity is highest in TKD mutations, especially Y772_A775dupYVMA, and intracranial responses are seen. Safety is manageable: diarrhea is common but mostly low grade, with grade ≥3 in 5–23% and rare discontinuations. Notably, interstitial lung disease (ILD) was not observed. These data position sevabertinib as a viable oral TKI alongside ADCs for HER2-mutant NSCLC, particularly for TKD/YVMA disease.