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Expert Point of View: Pasi A. Jänne, MD, PhD, and Charu Aggarwal, MD, MPH


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Pasi A. Jänne, MD, PhD

Pasi A. Jänne, MD, PhD

Charu Aggarwal, MD, MPH

Charu Aggarwal, MD, MPH

The invited discussant of CodeBreak 100 was Pasi A. Jänne, MD, PhD, Professor of Medicine at Harvard Medical School and a thoracic oncologist at Dana-Farber Cancer Institute, Boston.1Charu Aggarwal, MD, MPH, Leslye M. Heisler Associate Professor for Lung Cancer Excellence at the University of Pennsylvania, also commented on CodeBreak 100 for The ASCO Post.

Dr. Jänne described how after “struggling” with targeting KRAS for many years, “drugging” it has now become a fruitful endeavor. A breakthrough came in 2013 with the discovery of a unique binding pocket that could link a KRAS inhibitor to the cysteine found in the G12C mutation, providing these drugs with both selectivity and potency. The drugs bind to G12C in its inactive state, blocking its oncogenic signaling and preventing tumorigenesis.

Since then, many compounds have entered preclinical and clinical development, and two are in phase III clinical trials: sotorasib and adagrasib (MRTX849). With sotorasib and adagrasib, response rates of 32% to 45% have been observed.1,2 However, both Dr. Jänne and Dr. Aggarwal questioned why the activity is less than that seen with other targeted agents in non–small cell lung cancer (NSCLC).

“The response rates with sotorasib are not as high as those seen with tyrosine kinase inhibitors in other oncogene-addicted tumors, such as those with mutations in EGFR, ALK, and ROS1,” Dr. Aggarwal noted. “This is likely related to the heterogeneity of the mutational landscape of KRAS G12C cancers.” Dr. Jänne added other possibilities—including the heavy pretreatment of the trial populations; patients’ heavy smoking history; and that by binding to GDP, the drugs leave tumors vulnerable to upstream stimuli that could facilitate resistance.

“However, these response rates coupled with other outcomes, such as the duration of response and favorable adverse-event profile, represent a meaningful advance…and a new treatment option for patients with previously treated metastatic NSCLC,” Dr. Aggarwal commented.

Next Steps

According to Dr. Jänne and Dr. Aggarwal, the next step will be to look for differential benefits in subsets, such as patients with concomitant STK11 mutations, who had a robust response to adagrasib (64%) in the KRYSTAL-1 trial.2 “This is important because this population tends to respond poorly to single-agent checkpoint inhibitors.” Dr. Jänne pointed out. Along these lines, Dr. Aggarwal said it will be important to refine first-line treatment strategies for particular subsets of NSCLC, such as patients with TP53/STK11/KEAP1-mutant subtypes.

There are now at least five KRAS G12C inhibitors in clinical trials, with sotorasib and adagrasib in phase III trials vs docetaxel in the second-line setting. Other compounds are in preclinical development. Based on preclinical synergistic activity, KRAS G12C inhibitors are also now being studied in combination with other agents, including afatinib, palbociclib, cetuximab, trametinib, pembrolizumab, and other experimental compounds. 

DISCLOSURE: Dr. Jänne holds stock or other ownership interests in Gatekeeper Pharmaceuticals; has served as a consultant or advisor to Araxes Pharma, AstraZeneca, Biocartis, Boehringer Ingelheim, Chugai Pharma, Daiichi Sankyo, Ignyta, Lilly, Loxo, Merrimack, Mirati Therapeutics, Novartis, Pfizer, Roche/Genentech, Sanofi, SFJ Pharmaceuticals Group, Silicon Therapeutics, Takeda, and Voronoi; has received research funding from Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Lilly, Puma Biotechnology, Revolution Medicines, and Takeda; and is an inventor on -DFCI-owned intellectual property on “EGFR mutations licensed to Lab Corp.” Dr. Aggarwal has served as a consultant or advisor to AstraZeneca, Celgene, Genentech, Lilly, and Merck; has an immediate family member who has served on a speakers bureau for AstraZeneca and Roche/Genentech; and has received institutional research funding from AstraZeneca/MedImmune, Genentech/Roche, Incyte, MacroGenics, and Merck Sharp & Dohme.

REFERENCES

1. Li BT, Skoulidis F, Falchook G, et al: CodeBreak 100: Registrational phase 2 trial of sotorasib in KRAS p.G12C mutated non-small cell lung cancer. 2020 World Conference on Lung Cancer. Abstract PS01.07. Presented January 30, 2021.

2. Jänne PA, Rybkin II, Spira AI, et al: KRYSTAL-1: Activity and safety of adagrasib (MRTX849) in advanced/metastatic non–small-cell lung cancer harboring KRAS G12C mutation. 2020 EORTC-NCI-AACR Symposium. Abstract LBA-03. Presented October 25, 2020.


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