On November 12, 2021 Amgen (NASDAQ: AMGN) reported the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion recommending conditional marketing authorization of LUMYKRAS (sotorasib), known as LUMAKRAS in the U.S., for the treatment of adults with advanced non-small-cell lung cancer (NSCLC) with KRAS G12C mutation and who have progressed after at least one prior line of systemic therapy (Press release, Amgen, NOV 12, 2021, View Source [SID1234595324]). If the European Commission follows the recommendation for approval, LUMYKRAS will be the first targeted therapy available in the European Union (EU) for the KRAS G12C mutation, one of the most prevalent biomarkers in NSCLC.
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"After 40 years of cancer research to target the KRAS mutation, many in the scientific community believed that KRAS was ‘undruggable’ leaving patients with this mutation with limited treatment options," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "The LUMYKRAS development program was designed to bring this targeted therapy to patients with KRAS G12C-mutated non-small cell lung cancer as quickly as possible. The EMA CHMP positive opinion brings patients in the EU closer to this transformative therapy and highlights our commitment to improving patient outcomes in difficult-to-treat cancers."
The CHMP based its positive opinion on results from the Phase 2 CodeBreaK 100 clinical trial, the largest trial conducted to date exclusively for patients with the KRAS G12C mutation. CodeBreaK 100 enrolled 126 patients, 124 of whom had centrally evaluable lesions at baseline. In the trial, LUMYKRAS demonstrated favorable efficacy and tolerability in these 124 patients with KRAS G12C mutation-positive NSCLC who had disease progression after receiving an immunotherapy and/or chemotherapy. LUMYKRAS 960 mg, administered orally once-daily, demonstrated an objective response rate (a proportion of patients with ≥ 30% decrease in the sum of the longest diameter of the target lesions compared with baseline) of 37.1% (95% CI: 28.6-46.2) a median duration of response (DoR) of 11.1 months, disease control rate (DCR) of 80.6% and median overall survival (OS) of 12.5 months.3
The most common treatment-related adverse reactions were diarrhea (32%), nausea (19%), increase in aminotransferase level (ALT) and increase in the aspartate aminotransferase level (AST) (15% each). The most common severe (grade ≥ 3) treatment-related adverse reactions were increased alanine aminotransferase (ALT; 6%), increased aspartate aminotransferase (AST; 6%), and diarrhea (4%). Only 7% of patients discontinued treatment due to treatment-related adverse events.3
The detailed CodeBreaK 100 Phase 2 data in NSCLC were presented at the 2020 World Conference on Lung Cancer (WCLC) and published in the New England Journal of Medicine (NEJM).
"Patients with KRAS G12C-mutated NSCLC face poor prognosis and usually do not respond to currently available treatments," said Prof. Fabrice Barlesi, general director of Gustave Roussy, Villejuif, France. "The introduction of sotorasib in the EU as a novel treatment option would be a welcome development as a potentially new standard of care for the tens of thousands of patients with NSCLC living with this common mutation."
"The rapid tumor shrinkage and durable responses observed in the large-scale CodeBreaK 100 clinical trial that support this positive opinion are impressive and demonstrate the potential benefit sotorasib can offer our patients who have the KRAS G12C mutation," said Prof. Jürgen Wolf, M.D., medical director, Center for Integrated Oncology, University Hospital of Cologne, Germany. "As we move closer to a potential EMA approval, it is critical that we continue to increase the implementation of biomarker testing so we can match the right patients who may benefit from this first-in-class targeted therapy as quickly as possible."
NSCLC accounts for approximately 84% of the 2.2 million new lung cancer diagnoses each year worldwide, including approximately 400,000 new cases in Europe.4,5 KRAS G12C is one of the most prevalent driver mutations in NSCLC, with about 13-15% of patients with non-squamous NSCLC having the KRASG12C mutation.6,7 LUMYKRAS, which is administered orally in a tablet formulation, binds with the mutated KRAS G12C protein keeping the mutated protein in an inactive state, thus preventing it from switching to its favored active state that supports cancer cell growth. LUMYKRAS has been shown to irreversibly bind to the inactive KRAS G12C protein, permanently locking it in an inactive state, inhibiting oncogenic signaling and tumorigenesis.3,8
The CHMP’s recommendation will now be reviewed by the European Commission, which has the authority to approve medicines for use throughout the European Union. A European Commission decision is expected by mid-January 2022.
In May 2021, LUMAKRAS was the first KRASG12C inhibitor to receive regulatory approval anywhere in the world with its approval in the U.S., under accelerated approval. Regulatory approvals have also been received in the United Arab Emirates (LUMAKRAS), and under Project Orbis in Canada (LUMAKRAS) and Great Britain (LUMYKRAS). In addition to our EMA MAA, there are 16 regulatory applications pending review around the world.
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.8 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.9
Amgen is progressing the largest and broadest global KRASG12C inhibitor development program with unparalleled speed and exploring more than 10 sotorasib combination regimens, including triplets, with clinical trial sites spanning five continents. To date, LUMAKRAS/LUMYKRAS has treated over 3,000 patients around the world through the clinical development program and commercial use.
In the U.S., LUMAKRAS was reviewed by the FDA under its Real-Time Oncology Review (RTOR), a pilot program that aims to explore a more efficient review process that ensures safe and effective treatments are made available to patients as early as possible. Amgen is participating in the FDA’s Project Orbis initiative and through the initiative, has Marketing Authorization Applications (MAAs) for sotorasib in review in Australia and Brazil. Additionally, Amgen has submitted MAAs in the Japan, Switzerland, South Korea, Singapore, Israel, Turkey, Taiwan, Colombia, Thailand, Mexico, Hong Kong, Saudi Arabia, Argentina and Kuwait.
LUMAKRAS/LUMYKRAS is also being studied in multiple other solid tumors.10
About 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.11 Overall survival rates for NSCLC are improving but remain poor for patients with advanced disease and 5-year survival is only 7% for those with metastatic disease.12
KRAS G12C is the most common KRAS mutation in NSCLC.13 About 13% of patients with non-squamous NSCLC harbor the KRAS G12C mutation.1 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 current therapies are suboptimal with a median progression-free survival of approximately 4 months following second-line treatment of KRAS G12C-mutated NSCLC.14
About CodeBreaK
The CodeBreaK clinical development program for Amgen’s drug sotorasib is designed to treat patients with an advanced solid tumor with the KRAS G12C mutation and address the longstanding unmet medical need for these cancers.
CodeBreaK 100, the Phase 1 and 2, first-in-human, open-label multicenter study, enrolled patients with KRAS G12C-mutant solid tumors.11 Eligible patients must have received a prior line of systemic anticancer therapy, consistent with their tumor type and stage of disease. The primary endpoint for the Phase 2 study was centrally assessed objective response rate. The Phase 2 trial in NSCLC enrolled 126 patients, 124 of whom had centrally evaluable lesions by RECIST at baseline3. The Phase 2 trial in colorectal cancer (CRC) is fully enrolled and results have been submitted for publication.
A global Phase 3 randomized active-controlled study comparing sotorasib to docetaxel in patients with KRAS G12C-mutated NSCLC (CodeBreaK 200) has completed enrollment. Amgen also has several Phase 1b studies investigating sotorasib monotherapy and sotorasib combination therapy across various advanced solid tumors (CodeBreaK 101) open for enrollment. A Phase 2 randomized study will evaluate sotorasib in patients with stage IV KRAS G12C-mutated NSCLC in need of first-line treatment (CodeBreaK 201).
For information, please visit www.hcp.codebreaktrials.com.
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 ≥ 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.