Conference Coverage

‘Major advance’: Sotorasib benefit persists in KRAS+ NSCLC


AT AACR 2022

One third of patients with non–small cell lung cancers (NSCLC) bearing the KRASG12C mutation were alive 2 years after starting therapy with the first-in-class KRAS inhibitor sotorasib (Lumakras, Amgen).

The finding comes from an analysis of long-term follow-up data from the CodeBreaK100 trial, which showed a 2-year overall survival (OS) rate of 32.5% in pretreated patients with KRASG12C-mutant disease.

That rate compares favorably with historical data on NSCLC therapies, said Grace K. Dy, MD, from Roswell Park Comprehensive Cancer Center in Buffalo, N.Y.

“We expect about half of that [survival rate] in patients who are treated with docetaxel,” she said in a plenary session at the annual meeting of the American Association for Cancer Research.

Sotorasib was approved by the Food and Drug Administration in May 2021 as the first drug for patients with NSCLC and KRAS mutations and was described as a “historic milestone.”

In this most recent analysis, which combined data from patients enrolled in phases 1 and 2 of the trial, the “objective response rate of 41% of patients was achieved with sotorasib, with a durable [disease] control rate of 84% and a median duration of response of 12.3 months, with no new safety signals emerging,” she said.

Nearly one-fourth of patients saw long-term benefit, as defined by progression-free survival of at least 12 months, and this long-term benefit was seen across variant allele frequencies of KRASG12C, programmed death–ligand 1 (PD-L1) tumor proportion score, and other comutations, she noted.

“KRASG12C inhibitors represent a major advance in the treatment of KRAS-mutant lung cancers and other types as well,” said invited discussant Mark M. Awad, MD, PhD, director of clinical research at the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Center, Boston.

He cautioned, however, that “the therapeutic efficacy of these G12C inhibitors is currently limited by several things, including patient factors, intrinsic biology, and the emergence of complex resistance mechanisms.”

New approaches will be needed, he said, “to delay and overcome drug resistance to hopefully keep kicking cancer’s KRAS.”

At a media briefing where Dr. Dy presented the data prior to the oral abstract session, moderator Timothy A. Yap, MBBS, PhD, from the University of Texas MD Anderson Cancer Center, Houston, commented that the development of drug resistance is common in oncology.

“That is exactly why we’re now actively working on multiple different combinatorial approaches in the clinic. There have been pretty compelling data published from Mirati [Therapeutics] and from other companies, from Amgen, that really show the resistance mechanisms that actually come about upon monotherapy with KRASG12C inhibitors, including CDK4/6, including P13K-Akt pathways,” he said.

“The solution there really is, No. 1, we need to identify proactively the resistance mechanisms involved and driving each cancer’s resistance, and No. 2, then apply the combinatorial agent, to bring in a combination that’s a rational approach to match a patient’s molecular profile upon resistance,” he said.

Tarnished triumph

As previously reported, sotorasib was hailed as “a triumph of drug discovery” when early results of the trial were reported at the European Society of Medical Oncology annual meeting in 2020.

Sotorasib is a small-molecule, specific, and irreversible inhibitor of KRAS that interacts with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drug inhibits oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.

But as Dr. Awad reported at the 2021 AACR annual meeting, the efficacy of sotorasib and other KRAS inhibitors in development has been threatened by the development of resistance caused by a wide range of genomic and histologic mechanisms.

Dr. Awad reported that among 30 patients with NSCLC or colorectal cancer bearing the KRASG12C mutation who had disease progression while being treated with the investigational inhibitor adagrasib in clinical trials, investigators found multiple on-target KRAS alterations and off-target bypass mechanisms of acquired resistance to the drug.

“Diverse mechanisms confer resistance to the KRASG12C inhibitors, including secondary KRAS mutations, MAP [mitogen-activated protein] kinase pathway alterations, acquired genomic rearrangements, and histologic transformation,” he said.


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