Adagrasib shows promise in advanced lung cancer with KRASG12C mutations
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CHICAGO — Adagrasib demonstrated promising efficacy for pretreated patients with advanced or metastatic non-small cell lung cancer who harbor KRASG12C mutations, according to study results presented at ASCO Annual Meeting.
The agent also appeared well-tolerated, results of the phase 1/phase 2 KRYSTAL-1 study showed.
“The results from the KRYSTAL1 study confirmed that KRASG12C is a druggable target. Our patients on study benefited clinically from this agent and it appears to have improved overall survival [compared with] historical outcomes of docetaxel, a standard-of-care chemotherapy in the second-line setting,” researcher Joshua K. Sabari, MD, assistant professor in the department of medicine, division of hematology and medical oncology at NYU Langone Perlmutter Cancer Center, told Healio.
“There are ongoing phase 3 studies comparing KRASG12C inhibitors to docetaxel in the second-line setting and we await that confirmatory data,” Sabari added. “In clinic, when patients are faced with the option of a targeted therapeutic with minimal off-target toxicity versus a nontargeted chemotherapeutic with a board toxicity profile, the choice is easy.”
Background and methods
KRAS — a key mediator of the RAS/MAPK signaling cascade — promotes cellular growth and proliferation. An estimated 14% of patients with NSCLC have KRASG12C mutations, according to study background.
“[These mutations] remain difficult to target, and outcomes for this patient population have remained poor,” Sabari said.
Last year, the FDA approved sotorasib (Lumakras, Amgen) for use in adults with KRAS G12C-mutated locally advanced or metastatic NSCLC who received at least one prior systemic therapy.
Adagrasib (MRTX849, Mirati Therapeutics) is an investigational KRASG12C inhibitor that irreversibly locks the mutant protein in its inactive state.
The agent has a long half-life — approximately 24 hours — with dose-dependent pharmacokinetics and central nervous system penetration. These factors differentiate the agent from other KRASG12C inhibitors, Sabari said.
A prior phase 1/1B study showed the agent induced objective response and exhibited favorable tolerability.
Researchers conducted the multicohort KRYSTAL-1 study to evaluate adagrasib alone or as part of combination therapy for patients with advanced solid tumors with KRASG12C mutations.
At ASCO, Alexander I. Spira, MD, director of Virginia Cancer Specialists Research Institute, presented initial findings from the phase 2 Cohort A.
The cohort included 116 patients (median age, 64 years; 65% women; 84% white) with KRASG12C -mutated, unresectable or metastatic NSCLC.
Patients had received prior treatment with a PD-1/PD-L1 inhibitor in combination with or in sequence with chemotherapy.
All patients had ECOG performance status of 0 (15.5%) or 1 (83.6%), and those with treated, stable central nervous system metastases could participate.
Patients received 600 mg oral adagrasib twice daily.
Objective response rate assessed by blinded independent central review served as the primary endpoint. Secondary endpoints included duration of response, PFS, OS and safety.
Results
Median follow-up was 12.9 months, at which time 31 patients remained on treatment.
Among 112 patients who had measurable disease at baseline, researchers reported a 43% ORR, a 79.5% disease control rate and an 8.5-month (95% CI, 6.2-13.8) median duration of response. One patient (1%) achieved complete response, 47 (42%) achieved partial response and 41 (37%) exhibited stable disease.
Seventeen patients were not evaluable due to study withdrawal prior to their first scheduled assessment (n = 14) or having received post-baseline scans too early (n = 3). Excluding these patients from the analysis yielded an ORR of 51%.
Most responders (75%) achieved greater than 50% tumor reduction. At the time of data cutoff, 50% of patients who achieved response remained on treatment and 33% remained in response.
Median PFS of 6.5 months (95% CI, 4.7-8.4) and median OS of 12.6 months (95% CI, 9.2-19.2), and 51% (95% CI, 40.9-60) of patients remained alive at 1 year.
Thirty-three patients had previously treated but stable central nervous system metastases. In this group, researchers reported a confirmed intracranial objective response rate of 33.3% (95% CI, 18-51.8), with five (15%) achieving complete response, six (18%) achieving partial response and 17 (52%) exhibiting stable disease.
Researchers reported an 85% intracranial disease control rate.
“The safety profile of adagrasib was consistent with what has been previously reported, with the majority of treatment-related adverse events being low grade,” Sabari said. “[They] started early in treatment and quickly resolved after occurrence.”
The majority (97%) of patients experienced any-grade treatment-related adverse events, the most common of which were diarrhea (63%), nausea (62%), vomiting (47%), fatigue (41%), increased alanine aminotransferase (28%), increased blood creatinine (26%), increased aspartate transferase (25%) and decreased appetite (24%).
Forty-three percent of patients experienced grade 3 or higher treatment-related adverse events. The most common grade 3/grade 4 events included increased lipase (6%) and anemia (5.2%).
Researchers reported two grade 5 events — one cardiac failure and one hemorrhage. Adverse events led to dose reductions for 52% of patients, dose interruptions for 61% and discontinuation for 7%.
Next steps
The FDA is reviewing adagrasib for accelerated approval in the second-line setting.
A confirmatory phase 3 study is underway to evaluate adagrasib vs. docetaxel for previously treated KRASG12C-NSCLC.
“Adagrasib would be the second FDA-approved KRAS G12C inhibitor and, therefore, would give patients and physicians a choice in selecting an agent for their treatment,” Sabari told Healio. “Further studies are needed to better understand resistance mechanisms to guide effective combination strategies, as well as opportunities for our patients in the front-line setting.”
Perspective
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Khaled Hassan, MD
The role of KRAS as an oncogene in multiple cancers has been established since the 1980s. Success in inhibiting this pathway remained elusive and KRAS was thought to be “undruggable.”
A major breakthrough occurred with sotorasib, an irreversible small-molecule inhibitor that targets the switch II pocket rather than GDP/GTP binding site in KRASG12C mutations. This led to last year’s FDA approval of sotorasib for treatment of advanced NSCLC with a KRASG12C mutation.
Results of KRYSTAL-1 — presented at ASCO and published simultaneously in The New England Journal of Medicine — showed the efficacy of adagarsib as a potent inhibitor of KRASG12C mutations among patients with NSCLC.
The FDA is reviewing adagrasib for accelerated approval, so we soon may have two drugs that can be used in the second-line treatment algorithm for patients with NSCLC and KRASG12C mutations.
Although adagrasib appears to have some edge over sotorasib in brain metastasis control, post-hoc analysis of the CodeBreaK 100 trial presented at last year’s IASLC World Conference on Lung Cancer showed a comparable brain metastasis control rate with sotorasib. Moreover, concurrent KEAP1 gene mutation had a negative impact on the response rate of adagrasib, similar to that seen with sotorasib.
At this point, showing the role of these drugs in the first-line setting and for patients with active brain metastases is the next objective and would be a game changer. Further, efforts to understand mechanisms of resistance to KRAS targeted therapy and developing potent inhibitors to other yet “undruggable” KRAS mutations are desperately needed.
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Spira AI, et al. Abstract 9002. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
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