'Major Advance': Sotorasib Benefit Persists in KRAS+ NSCLC

One third of patients with non-small cell lung cancers (NSCLC) bearing the KRAS^G12C 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 KRAS^G12C -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, New York.

"We expect about half of that [survival rate] in patients who are treated with docetaxel," she said in a plenary session here at the American Association for Cancer Research (AACR) Annual Meeting 2022.

Sotorasib was approved by the US 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 (PFS) of at least 12 months, and this long-term benefit was seen across variant allele frequencies of KRAS^G12C, programmed death protein 1-ligand 1 (PD-L1) tumor proportion score, and other comutations, she noted.

"KRAS^G12C 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 the Dana-Farber Cancer Center, Boston, Massachusetts.

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 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 in 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 KRAS^G12C inhibitors, including CDK4/6, including P13K-Akt pathways," he said in a reply to a question from Medscape Medical News.

"The solution there really is, number one, we need to identify proactively the resistance mechanisms involved and driving each cancer's resistance, and number two, 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 Awad reported last year at the 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.

Awad reported that among 30 patients with NSCLC or colorectal cancer bearing the KRAS^G12C 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 KRAS^G12C inhibitors, including secondary KRAS mutations, MAP [mitogen-activated protein] kinase pathway alterations, acquired genomic rearrangements, and histologic transformation," he said.

Long Follow-Up

The long-term data reported at this year's meeting by Dy and colleagues included data on 48 patients enrolled in phase 1 of the trial, which had a primary endpoint of safety and tolerability, and 126 patients enrolled in phase 2, with a primary endpoint of objective response rate by blinded independent review.

The trial was conducted in centers in the United States, Europe, Australia, Japan, and South Korea.

Nearly all patients were pretreated: 92.5% of patients had received prior platinum-based chemotherapy and 90.2% had received anti-PD-1/PD-L1 immunotherapy.

Patients received oral sotorasib 960 mg once daily and were followed with radiographic scans every 6 weeks for the first year and once every 12 weeks thereafter.

Of the 174 patients enrolled, two were not evaluable for response at 2 years due to a lack of measurable lesions at baseline.

At a median follow-up of 24.9 months, five patients (2.9%) had a complete response and 65 (37.8%) had a partial response, for an objective response rate of 40.7%. An additional 74 patients (43%) had stable disease, for a disease control rate of 83.7%. Of the remaining patients, 23 (13.4%) had disease progression, and five were either not evaluable or had missing scan data.

Median progression-free survival was 6.3 months. Median time to response was 6 weeks, and median duration of response was 12.3 months. Half of patients who had a response retained that response for at least 12 months.

Median OS was 12.5 months. The 1-year and 2-year OS rates were 50.8% and 32.5%, respectively.

Grade 3 or 4 treatment-related adverse events occurred in 21% of patients, and one patient had new-onset grade 3 hemolytic anemia 1 year after starting therapy. There were no treatment-related deaths and no treatment-related adverse events leading to discontinuation after the first year.

In exploratory analyses, the benefit of the drug was seen across tumors with varying levels of PD-L1 expression and the oncogenic STK11 comutation, and across KRAS^G12C variant allele frequency.

The investigators also reported that baseline circulating tumor DNA (ctDNA) levels correlated with tumor burden, and that patients who had long-term benefits had lower baseline ctDNA. This finding is consistent with the documented role of ctDNA as a marker for poor prognosis regardless of therapy.

Dy has reported receiving consulting fees from AstraZeneca, Eli Lilly, Mirati Therapeutics, and Takeda in the past 2 years. Yap has disclosed receiving consulting fees from multiple companies. Awad has disclosed consulting for multiple companies.

AACR 2022 Annual Meeting. Abstract CT008. Presented April 10, 2022.

Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.

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