Sotorasib confers durable benefit in non-small cell lung cancer subset
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Sotorasib exhibited durable efficacy among certain adults with locally advanced or metastatic non-small cell lung cancer, according to study results presented at American Association for Cancer Research Annual Meeting.
The agent also demonstrated a favorable safety profile among those with KRASG12C-mutated disease who progressed on prior therapies, 2-year follow-up of the CodeBreaK 100 trial showed.
The findings show sotorasib (Lumakras, Amgen) is an effective and safe therapy for patients with KRASG12C-mutated NSCLC, according to study author Grace K. Dy, MD, chief of thoracic oncology and professor of oncology at Roswell Park Comprehensive Cancer Center.
“The activity of sotorasib — particularly in the patients who are less likely to respond to immunotherapy — provides rationale for clinical trials testing its use in the earlier treatment setting for certain patients,” Dy told Healio. “[Although] this is not a subject of this particular presentation, our data highlights the importance of comprehensive mutation profiling in the management of NSCLC.
“We will not be able to prescribe sotorasib if we do not adequately test to see if KRASG12C mutation is present,” Dy added. “There are still challenges to date in ensuring that patients with metastatic NSCLC have their tumors sequenced in a timely manner using an assay that will capture all the relevant gene mutations with therapeutic indications.”
Background
KRAS is the most common oncogenic driver in lung adenocarcinoma. Approximately 13% of patients harbor the KRAS p.G12C mutation.
Development of therapies to target this mutation has proven challenging, and patients who fail first-line treatment with immune checkpoint inhibitors — either alone or with chemotherapy — generally have a poor prognosis.
Sotorasib is a first-in-class KRASG12C inhibitor.
The FDA granted accelerated approval to the agent in May 2021 for treatment of adults with KRAS p.G12C-mutated locally advanced or metastatic NSCLC who received prior systemic therapies.
The agency based its approval on previously released results of the global, single-arm phase 1/phase 2 CodeBreaK100 trial, which included patients with KRASG12C-mutated locally advanced or metastatic NSCLC who progressed on prior therapies.
As Healio previously reported, those findings — based on median follow-up of 15.3 months — showed a 37.3% objective response rate and an 80.6% disease control rate, with 37.5% of patients remaining progression free at 9 months.
At AACR, Dy presented 2-year survival and safety, representing the longest follow-up for a KRASG12C inhibitor.
Methodology
The analysis included 174 patients (median prior therapies, 2; range, 1-4+). Nearly all patients (90.2%) received prior anti-PD-1 or anti-PD-L1 treatment, and 82.8% received both prior platinum-based chemotherapy and anti-PD-1/anti-PD-L1 therapy.
Patients received 960 mg sotorasib once daily.
ORR by central review served as the primary endpoint. Key secondary endpoints included duration of response, PFS, OS and safety.
Key findings
Results showed ORR by central review of 40.7% (95% CI, 33.2-48.4), with median response duration of 12.3 months (95% CI, 7.1-14.6).
Researchers reported median PFS of 6.3 months (95% CI, 5.3-8.2) and median OS of 12.5 months (95% CI, 10-17.8). About half (50.8%) of patients remained alive at 1 year, and nearly one-third (32.5%) remained alive at 2 years.
“I take a glass-half-empty/half-full perspective,” Dy told Healio. “I was happy to see a good proportion of patients deriving long-term clinical benefit. We still have more work to do for patients in whom the therapeutic efficacy is not achieved and/or sustained.”
The 2-year survival rate is “very favorable” compared with historical control treatment, Dy said. For context, the 2-year OS for patients with nonsquamous NSCLC who underwent second-line treatment with docetaxel with or without the anti-VEGFR antibody ramucirumab (Cyramza, Eli Lilly) typically ranges from 15% to 22%, Dy said.
Researchers also performed an exploratory analysis in which they analyzed baseline tumor tissue or plasma samples for genomic alterations, and then evaluated correlation between PD-L1 levels and tumor response.
Researchers observed prolonged clinical benefit among patients regardless of tumor mutation burden, PD-L1 expression and STK11 co-mutation status.
Sotorasib appeared well-tolerated. Most toxicities appeared mild and manageable, according to investigators, and no new safety signals emerged among patients who continued sotorasib beyond 1 year.
“Sotorasib ... has a significantly favorable tolerability profile compared [with] many other targeted therapies due to its selectivity toward the KRAS G12C mutation,” Dy told Healio. “A small proportion of patients have [gastrointestinal]/hepatobiliary side effects that merit close monitoring early in the course of therapy, but we observed no late surprises.”
Implications and next steps
The results continue to support long-term clinical benefit of sotorasib across subgroups of patients with KRAS p.G12C-mutated NSCLC, researchers concluded.
The findings also provide rationale for studies that investigate the incorporation of sotorasib earlier in the treatment course to improve the outcomes for patients with NSCLC who are less likely to benefit from immunotherapy, Dy said.
Researchers acknowledged study limitations, including the single-arm nonrandomized design.
A randomized phase 3 trial — CodeBreaK 200 — is underway to compare sotorasib with docetaxel. Results likely will be available later this year.
“I’m very optimistic that the phase 3 trial will confirm what we observed in the CodeBreaK 100-patient population,” Dy said.
Perspective
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Fred R. Hirsch, MD, PhD, FASCO
These are very encouraging data in a population of patients with NSCLC who have received prior therapy. A 1-year survival rate of 50.8% and 2-year survival rate of almost 33% are extremely promising in this setting. In addition, the safety data show it is a well-tolerated drug.
Even though this is a single-arm study, the results should give hope to a subgroup of patients with this abnormality, which was not treatable a few years ago with specific therapy. The KRAS p.G12C mutation occurs in about 13% of patients with nonsquamous NSCLC. This represents a large number of patients.
We await results of the larger randomized phase 3 study that compared sotorasib with standard of care for this population. The results of this study should lead to use of the drug for patients with KRASG12C-positive advanced NSCLC where first-line therapy has failed.
Among the unanswered questions are how is this drug doing in the first-line therapy setting for patients with the KRASG12C mutation, and what are the characteristics of patients who do not benefit from this drug? Do they have co-mutations that restrict or limit the effect?
The next step is to see the efficacy of this drug in the first-line setting and how it performs in combination with other drugs, particularly immunotherapy.
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Dy GK, et al. Abstract CT008. Presented at: American Association for Cancer Research Annual Meeting; April 8-13, 2022; New Orleans.
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