On September 11, 2022 Amgen (NASDAQ: AMGN) reported detailed results from the global Phase 3 CodeBreaK 200 trial, which showed once-daily oral LUMAKRAS/LUMYKRAS (sotorasib) led to significantly superior progression-free survival (PFS; primary endpoint) and a significantly higher objective response rate (ORR; a key secondary endpoint) in patients with KRAS G12C-mutated non small cell lung cancer (NSCLC), compared with intravenous chemotherapy, docetaxel (Press release, Amgen, SEP 11, 2022, View Source [SID1234619382]). These data will be presented Monday, Sept. 12 at 5:20 p.m. CEST at the Presidential Symposium III session as a late-breaker oral presentation (#LBA5812) during the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022 in Paris.

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"The totality of evidence from this study supports LUMAKRAS as an important targeted treatment option for patients with non-small cell lung cancer who harbor the KRAS G12C mutation, and reinforces the critical need for comprehensive biomarker testing for all patients with advanced disease," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "We plan to submit this data to health authorities around the world where LUMAKRAS/LUMYKRAS is conditionally approved, and we look forward to our discussions with regulators."

LUMAKRAS significantly improved PFS as determined by Blinded Independent Central Review (BICR) compared to docetaxel in heavily pre-treated patients (HR, 0.66 [95% CI: 0.51, 0.86]; P = 0.002), and PFS favored LUMAKRAS across all clinically relevant subgroups. The proportion of patients with PFS at one year was 25% for LUMAKRAS versus 10% for docetaxel. LUMAKRAS demonstrated a significantly higher ORR than docetaxel with double the response rates in the LUMAKRAS arm (28% versus 13%, respectively; P < 0.001) and showed consistent benefit across other efficacy secondary endpoints, including improved disease control rate (DCR; 83% versus 60%, respectively). Overall survival (OS; a key secondary endpoint) was not significantly different between treatment arms. The study was not powered to detect a statistical difference in OS, and cross-over from docetaxel to LUMAKRAS was permitted after disease progression.

There were fewer treatment-related adverse events (TRAEs) for LUMAKRAS versus docetaxel. Grade ≥ 3 TRAEs (33% LUMAKRAS; 40% docetaxel) and serious TRAEs (11% LUMAKRAS; 23% docetaxel) were lower with LUMAKRAS compared to docetaxel. The most common TRAEs reported by at least 15% of patients in either treatment group were diarrhea (34% LUMKRAS; 19% docetaxel), fatigue (7% LUMAKRAS; 25% docetaxel), alopecia (1% LUMKARAS; 21% docetaxel), nausea (14% LUMAKRAS; 20% docetaxel) and anemia (3% LUMAKRAS; 18% docetaxel).

"This is the first Phase 3 randomized clinical trial for a KRASG12C inhibitor to show benefit in heavily pre-treated patients who have limited treatment options," said Melissa L. Johnson, M.D., director of Lung Cancer Research, Sarah Cannon Research Institute at Tennessee Oncology and presenting author. "It is encouraging that progression-free survival benefits were consistent across all clinically relevant subgroups, and that sotorasib response rates were more than double compared to docetaxel response rates. This data represents a major advance for the treatment of patients with KRAS G12C-mutated non-small cell lung cancer."

Data from CodeBreaK 200 will be submitted to global regulatory authorities where LUMAKRAS/LUMYKRAS has accelerated approval or conditional marketing authorization. LUMAKRAS is the only KRASG12C inhibitor approved anywhere in the world with approval in 44 markets, including the United States, the European Union, the United Kingdrom and Japan. CodeBreaK 200 is the first randomized, controlled clinical trial for a KRASG12C inhibitor.

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.1 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.2

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, Qatar, and in Australia, Brazil, Canada, Great Britain, Singapore, and Israel under the FDA’s Project Orbis. Additionally, Amgen has submitted MAAs in Argentina, Colombia, Kuwait, Macao, Malaysia, Mexico, Russia, Saudi Arabia, Thailand and Turkey.

LUMAKRAS/LUMYKRAS is also being studied in multiple other solid tumors.3

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.4 Overall survival rates for NSCLC are improving but remain poor for patients with advanced disease, and 5-year survival is only 8% for those with metastatic disease.5

KRAS G12C is the most common KRAS mutation in NSCLC.6 About 13% of patients with NSCLC harbor the KRAS G12C mutation.7 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.8

About CodeBreaK
The CodeBreaK clinical development program for Amgen’s drug sotorasib is designed to study 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.9 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 baseline.2 The Phase 2 trial in colorectal cancer (CRC) enrolled 62 patients and results have been published.10

CodeBreaK 200, the global Phase 3 randomized active-controlled study comparing sotorasib to docetaxel in KRAS G12C-mutated NSCLC completed enrollment of 345 patients. Eligible patients had previously treated, locally advanced and unresectable or metastatic KRAS G12C-mutated NSCLC. The primary endpoint is progression-free survival and key secondary endpoints include overall survival, objective response rate, and patient-reported outcomes.11

Amgen also has several Phase 1b studies investigating sotorasib monotherapy and sotorasib combination therapy across various advanced solid tumors (CodeBreaK 101) open for enrollment.12 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).13

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.
Please see LUMAKRAS full Prescribing Information.

About Amgen Oncology
At Amgen Oncology, our mission to serve patients drives all that we do. That’s why we’re relentlessly focused on accelerating the delivery of medicines that have the potential to empower all angles of care and transform lives of people with cancer.

For the last four decades, we have been dedicated to discovering the firsts that matter in oncology and to finding ways to reduce the burden of cancer. Building on our heritage, Amgen continues to advance the largest pipeline in the Company’s history, moving with great speed to advance those innovations for the patients who need them.