On September 10, 2023 Amgen (NASDAQ:AMGN) reported exciting data from a study arm of the CodeBreaK 101 clinical trial, a Phase 1b study evaluating LUMAKRAS (sotorasib) with carboplatin and pemetrexed in adult patients with KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC) (Press release, Amgen, SEP 10, 2023, View Source [SID1234635041]). These results were featured in an oral presentation at the International Association for the Study of Lung Cancer (IASLC) 2023 World Conference on Lung Cancer (WCLC) in Singapore on Sunday, September 10.
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In patients treated in the first-line setting (n=20), the confirmed objective response rate (ORR) was 65%, with a 100% disease control rate (DCR) (95% CI: 83.2, 100). In assessable patients in the second-line setting (n=13), the ORR was 54%, with a DCR of 85% (95% CI: 54.6, 98.1). Among patients with protein ligand-1 (PD-L1) expression less than 1%, the ORR was 62% in the first-line setting and 50% in the second-line setting. With a median follow-up of 3.0 months, preliminary rapid and durable responses were observed. Progression-free survival (PFS) and overall survival (OS) were immature.
"We are delighted to see the positive data from the global CodeBreaK 101 trial further validate our approach to move LUMAKRAS earlier within the treatment paradigm through novel therapeutic combinations," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "Notably, these results follow and further expand upon the Phase 2 investigator-led data demonstrating favorable efficacy and safety of LUMAKRAS plus carboplatin and pemetrexed in the first-line treatment of patients with KRAS G12C-mutated NSCLC."
The LUMAKRAS plus chemotherapy combination reported treatment-related adverse events (TRAEs) consistent with LUMAKRAS and other platinum doublet-based approaches. The most common TRAEs were neutropenia/neutrophil count decrease (53%), anemia (39%) and thrombocytopenia/platelet count decrease (37%). No fatal adverse events occurred.
"Combination treatment is an important approach to prevent or delay the onset of drug resistance and improve the depth and durability of targeted response in KRAS G12C-mutated NSCLC," said Jeffrey M. Clarke, M.D., oncologist and associate professor of medicine, Duke Cancer Institute at Duke University. "The CodeBreaK 101 results show exciting efficacy with sotorasib plus chemotherapy and, importantly for a combination treatment, a safety profile consistent with the individual therapies. These data warrant continued investigation in larger trials."
Based on these results, Amgen has initiated a Phase 3 study of LUMAKRAS plus carboplatin and pemetrexed in first-line KRAS G12C-mutant and negative for programmed cell death PD-L1 advanced NSCLC (CodeBreaK 202; NCT05920356), with enrollment expected to start before the end of 2023.
About CodeBreaK 101
CodeBreaK 101 (NCT04185883) is a global Phase 1b/2 clinical trial evaluating the safety, tolerability, pharmacokinetics, and efficacy of sotorasib in combination with other anticancer therapies in patients with advanced solid tumors and the KRAS G12C mutation. Subprotocol F of the Phase 1b trial is assessing the safety, tolerability, pharmacokinetics, and efficacy of sotorasib in combination with carboplatin and pemetrexed with or without pembrolizumab maintenance, with docetaxel, or with carboplatin and paclitaxel in patients with KRAS G12C-mutated NSCLC.1
About LUMAKRAS/LUMYKRAS (sotorasib)
Amgen took on one of the toughest challenges of the last 40 years in cancer research by developing LUMAKRAS/LUMYKRAS, a KRASG12C inhibitor.2 LUMAKRAS/LUMYKRAS has demonstrated a positive benefit-risk profile with rapid, deep, and durable anticancer activity in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring the KRAS G12C mutation with a once daily oral formulation.3
Amgen is progressing the largest and broadest global KRASG12C inhibitor development program with unparalleled speed and exploring more than 10 sotorasib combination regimens, with clinical trial sites spanning five continents. To date, over 6,500 patients around the world have received LUMAKRAS/LUMYKRAS through the clinical development program and commercial use.
In May 2021, LUMAKRAS was the first KRASG12C inhibitor to receive regulatory approval with its approval in the U.S., under accelerated approval. LUMAKRAS/LUMYKRAS is also approved in the European Union, Japan, United Arab Emirates, South Korea, Hong Kong, Switzerland, Taiwan, Turkey, Thailand, Qatar, Australia, Argentina, Brazil, Canada, Great Britain, Kuwait, Macao, Singapore, Mexico, Israel, Bulgaria, Hungary, Romania, and Russia. Additionally, Amgen has submitted MAAs in Colombia, Malaysia and Saudi Arabia.
LUMAKRAS/LUMYKRAS is also being studied in multiple other solid tumors.4
About Advanced Non-Small Cell Lung Cancer and the KRAS G12C Mutation
Lung cancer is the leading cause of cancer-related deaths worldwide, and it accounts for more deaths worldwide than colon cancer, breast cancer and prostate cancer combined.5 Overall survival rates for NSCLC are improving but remain poor for patients with advanced disease, and 5-year survival is only 9% for those with metastatic disease.6
KRAS G12C is the most common KRAS mutation in NSCLC.7 About 13% of patients with non-squamous NSCLC harbor the KRAS G12C mutation.8 Unmet medical need remains high and treatment options are limited for NSCLC patients with the KRAS G12C mutation whose first-line treatment has failed to work or has stopped working. The outcomes with other approved therapies are suboptimal, with a median progression-free survival of approximately four months following second-line treatment of KRAS G12C-mutated NSCLC.9
LUMAKRAS (sotorasib) U.S. Indication
LUMAKRAS is indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy.
This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
LUMAKRAS (sotorasib) Important U.S. Safety Information
Hepatotoxicity
LUMAKRAS can cause hepatotoxicity, which may lead to drug-induced liver injury and hepatitis.
Among 357 patients who received LUMAKRAS in CodeBreaK 100, hepatotoxicity occurred in 1.7% (all grades) and 1.4% (Grade 3). A total of 18% of patients who received LUMAKRAS had increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST); 6% were Grade 3 and 0.6% were Grade 4. In addition to dose interruption or reduction, 5% of patients received corticosteroids for the treatment of hepatotoxicity.
Monitor liver function tests (ALT, AST and total bilirubin) prior to the start of LUMAKRAS every 3 weeks for the first 3 months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop transaminase and/or bilirubin elevations.
Withhold, dose reduce or permanently discontinue LUMAKRAS based on severity of adverse reaction.
Interstitial Lung Disease (ILD)/Pneumonitis
LUMAKRAS can cause ILD/pneumonitis that can be fatal. Among 357 patients who received LUMAKRAS in CodeBreaK 100, ILD/pneumonitis occurred in 0.8% of patients, all cases were Grade 3 or 4 at onset, and 1 case was fatal. LUMAKRAS was discontinued due to ILD/pneumonitis in 0.6% of patients.
Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold LUMAKRAS in patients with suspected ILD/pneumonitis and permanently discontinue LUMAKRAS if no other potential causes of ILD/pneumonitis are identified.
Most Common Adverse Reactions
The most common adverse reactions occurring in ≥ 20% were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity and cough.
Drug Interactions
Advise patients to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, dietary and herbal products.
Inform patients to avoid proton pump inhibitors and H2 receptor antagonists while taking LUMAKRAS.
If coadministration with an acid-reducing agent cannot be avoided, inform patients to take LUMAKRAS 4 hours before or 10 hours after a locally acting antacid.
Please see LUMAKRAS full Prescribing Information.