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Clinical Trial
. 2025 Jan:199:108003.
doi: 10.1016/j.lungcan.2024.108003. Epub 2024 Nov 1.

Alectinib combined with cobimetinib in ALK-Rearranged lung Cancer: A phase IB study

Ibiayi Dagogo-Jack  1 , Alissa J Cooper  2 , Bruce E Johnson  3 , Justin F Gainor  2 , Jessica J Lin  2 , Lecia V Sequist  2 , Zofia Piotrowska  2 , Subba R Digumarthy  4 , Mari Mino-Kenudson  5 , Alona Muzikansky  2 , Alice T Shaw  6
Affiliations
Clinical Trial

Alectinib combined with cobimetinib in ALK-Rearranged lung Cancer: A phase IB study

Ibiayi Dagogo-Jack et al. Lung Cancer. 2025 Jan.

Abstract

Introduction: Anaplastic lymphoma kinase rearranged (ALK + ) lung cancers often develop ALK-independent resistance mechanisms that reactivate the mitogen-activated protein kinase pathway signaling pathway. We therefore evaluated alectinib combined with the MEK inhibitor cobimetinib in metastatic ALK + lung cancer.

Materials and methods: This phase Ib study employed a 3 + 3 design. Cohort 1 enrolled patients irrespective of prior alectinib exposure. Cohort 2 only enrolled treatment-naive patients. Patients received alectinib 600 mg twice daily (BID) continuously and cobimetinib at either 20 or 40 mg daily on days 1-21 every 28 days. A 2-week alectinib lead-in was incorporated into cohort 2. The primary objective was to determine the maximum tolerated dose (MTD) for cohort 1.

Results: Sixteen patients were enrolled between 9/2017 and 8/2021, ten of whom were in cohort 1. No dose-limiting toxicities (DLTs) were observed with alectinib + cobimetinib 20 mg in cohort 1. On alectinib + cobimetinib 40 mg, DLTs of grade 3-4 creatine phosphokinase elevation and grade 3 rash were observed in 2 of 6 patients, both of whom were alectinib-naïve and required dose reduction. The MTD for cohort 1 was declared as 600 mg alectinib BID + cobimetinib 40 mg. Six alectinib-naïve patients were treated with alectinib + cobimetinib 20 mg in cohort 2. With the lead-in, no patients experienced DLTs. One patient in cohort 2 discontinued cobimetinib for grade 2 pneumonitis. Median progression-free survival was 2.2 months and 49.2 months for alectinib-resistant and alectinib-naïve patients, respectively.

Discussion: Alectinib combined with cobimetinib demonstrated limited activity in alectinib-resistant tumors. Despite dose-limiting dermatologic and muscle enzyme toxicities, durable responses were observed in alectinib-naïve patients.

Keywords: ALK; Alectinib; Cobimetinib; Lung Cancer; MEK.

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Conflict of interest statement

Declaration of competing interest IDJ has received honoraria from Foundation Medicine, Creative Education Concepts, OncLive, ASCO Post, DAVA Oncology, Medscape, Research to Practice, Total Health, Aptitude Health, American Lung Association, Curio, PeerView; consulting fees from AstraZeneca, Boehringer Ingelheim, Bayer, BostonGene, Bristol Myers Squibb, Catalyst, Genentech, Gilead, Janssen, Merus, Novocure, Pfizer, Roche, Sanofi-Genzyme, Syros, ThermoFisher Scientific, and Xcovery, research support from Array, Genentech, Novartis, Pfizer, and Guardant Health; and travel support from Array and Pfizer. AJC has received honoraria from MJH Life Sciences and consulting fees from Gilead. BEJ reports post-marketing royalties for EGFR mutation testing from DFCI and has served as a compensated consultant for Novartis, Checkpoint Therapeutics, Astra Zeneca, Daichi Sankyo, Hummingbird Diagnostics, Genentech, Bluedot Bio, G1 Therapeutics, Jazz Pharmaceuticals, Merus, Abdera, and Simcere Pharmaceutical; is an unpaid member of a steering committee for Pfizer and has received research support from Cannon Medical Imaging. JFG has served as a compensated consultant for Amgen, AstraZeneca, Mariana Therapeutics, Mirati Therapeutics, Merus Pharmaceuticals, Nuvalent, Pfizer, Novocure, AI Proteins, Novartis, Silverback Therapeutics, Sanofi, Blueprint Medicines, Bristol Myers Squibb, Genentech, Gilead Sciences, ITeos Therapeutics, Jounce Therapeutics, Karyopharm Therapeutics, Lilly/Loxo, Merck, Moderna Therapeutics, Takeda; has received honorarium from Novartis, Merck, Novartis, Pfizer, Takeda; has received institutional research funding from Adaptimmune, Alexo Therapeutics, AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, Genentech, Jounce Therapeutics, Merck, Moderna Therapeutics, Novartis, NextPoint Therapeutics, Palleon Pharmaceuticals; research support from Novartis, Genentech and Takeda, and has equity in AI Proteins; and has an immediate family member who has equity in and is employed by Ironwood Pharmaceuticals. JJL has served as a compensated consultant for Genentech, C4 Therapeutics, Blueprint Medicines, Nuvalent, Bayer, Elevation Oncology, Novartis, Mirati Therapeutics, Ellipses Pharma, Hyku Biosciences, Daiichi Sankyo, AnHeart Therapeutics, Takeda, CLaiM Therapeutics, Pfizer, Regeneron, AstraZeneca, and Turning Point Therapeutics; received institutional research funds from Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation Oncology, Roche, Linnaeus, Nuvalent, and Novartis; received CME funding from OncLive, MedStar Health, and Northwell Health. LVS has received research support from Novartis, AstraZeneca and Delfi Diagnostics and received honoraria for DSMB participation from Genentech. ZP has served as a compensated consultant or received honoraria from Boehringer Ingelheim, Daiichi Sankyo, Merck, Bayer, AstraZeneca, Janssen, Takeda, Blueprint Medicines, Cullinan Oncology, Taiho, Genentech, Eli Lilly, C4 Therapeutics, Plexus, PeerView, Research to Practice, Clinical Care Options, Ology, Creative Education Concepts, PER, Haymarket Medical Education, MedStar Health/Georgetown, Philips Gilmore Oncology, DAVA Oncology, Aptitude Health, University of Arkansas, Curio Science, Taiwan Society of Thoracic Surgeons, Medscape/WebMD, OncLive, Targeted Oncology, institutional research support from Novartis, Takeda, Spectrum, AstraZeneca, Tesaro/GSK, Cullinan Oncology, Daiichi Sankyo, AbbVie, Janssen, Blueprint Medicines, and travel support from Janssen and AstraZeneca. MM-K has served as a compensated consultant or advisory board member for AstraZeneca, Pfizer, Boehringer Ingelheim, Sanofi, Repare, AbbVie and Daiichi-Sankyo, and received honoraria from MSD and royalties from Elsevier. ATS is employed by Novartis and has equity in Novartis.

Figures

Figure 1.
Figure 1.. Study Schema.
The study schema is presented, including eligibility criteria and dose levels explored in dose escalation cohorts 1 and 2.
Figure 2.
Figure 2.. Efficacy of Alectinib + Cobimetinib.
(A) Waterfall plot depicts best tumor response in the overall patient population, including cohorts 1 and 2, as assessed by RECIST version 1.1. Kaplan-Meier curves depict progression-free survival in 9 alectinib-naïve patients receiving the combination (B) and progression-free survival in 7 patients with alectinib-resistant disease receiving the combination (C).
Figure 3.
Figure 3.. ALK-Independent Resistance Mechanisms Identified in Post-Progression Biopsies.
(A) The figure demonstrates treatment course of a patient who developed early onset progression during first-line treatment with alectinib + cobimetinib due to emergence of MET amplification. (B) The figure summarizes the treatment course of a patient who experienced small cell transformation (as indicated by synaptophysin expression and tumor morphology on H&E) of cancer after 27 months on first-line treatment with the combination. Cobi: cobimetinib; RT: radiation therapy; H&E: hematoxylin and eosin stain.
Figure 3.
Figure 3.. ALK-Independent Resistance Mechanisms Identified in Post-Progression Biopsies.
(A) The figure demonstrates treatment course of a patient who developed early onset progression during first-line treatment with alectinib + cobimetinib due to emergence of MET amplification. (B) The figure summarizes the treatment course of a patient who experienced small cell transformation (as indicated by synaptophysin expression and tumor morphology on H&E) of cancer after 27 months on first-line treatment with the combination. Cobi: cobimetinib; RT: radiation therapy; H&E: hematoxylin and eosin stain.
Figure 4
Figure 4
A. MET Amplification in a Patient Receiving Alectinib + Cobimetinib in the 1st Line B. Small Cell Transformation After 27 Months on 1st Line Alectinib + Cobimetinib
Figure 4
Figure 4
A. MET Amplification in a Patient Receiving Alectinib + Cobimetinib in the 1st Line B. Small Cell Transformation After 27 Months on 1st Line Alectinib + Cobimetinib
See this image and copyright information in PMC

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