On September 8, 2021 Amgen (NASDAQ: AMGN) reported results from two analyses of the Phase 2 CodeBreaK 100 clinical trial evaluating LUMAKRAS (sotorasib), the first and only KRASG12C inhibitor approved in the U.S., in the treatment of previously treated patients with advanced or metastatic KRAS G12C-mutated non-small cell lung cancer (NSCLC) (Press release, Amgen, SEP 8, 2021, View Source [SID1234587394]). These new analyses, respectively, provide encouraging evidence of durable systemic anticancer activity in patients with previously treated, stable brain metastases with LUMAKRAS, as well as insights into biomarkers of LUMAKRAS response. Together with a poster describing a recently initiated clinical study of the investigational half-life extended (HLE) bispecific T cell engager (BiTE) molecule acapatamab (formerly AMG 160) in patients with NSCLC, these data are being featured during the virtual 2021 World Conference on Lung Cancer (WCLC21) hosted by the International Association for the Study of Lung Cancer (IASLC).

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"Amgen is expanding the reach, impact and potential of our innovative therapies to personalize care for patients with historically difficult-to-treat cancers like lung cancer," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "We are pleased to present additional analyses for LUMAKRAS, our newly approved KRASG12C inhibitor, as well as a trial-in-progress poster for acapatamab, our investigational BiTE molecule being studied in NSCLC and other solid tumors. Of the data presented at WCLC, we are particularly encouraged by the first evaluation of LUMAKRAS’ ability to maintain stabilization of brain metastases in patients with previously treated, stable brain metastases. We look forward to the results from our CodeBreaK 101 study where we are studying a cohort of KRAS G12C-mutated NSCLC patients with untreated, active brain metastases to better understand the clinical benefit of LUMAKRAS."

New Analyses From the LUMAKRAS Phase 2 CodeBreaK 100 Clinical Trial
In a post-hoc analysis (WCLC21 Poster 52.03) of 40 patients (23% of 174 trial participants) with KRAS G12C-mutated advanced NSCLC who had stable, previously treated brain metastases at their enrollment in the CodeBreaK 100 trial, LUMAKRAS achieved a 77.5% disease control rate (DCR), a median progression-free survival (PFS) of 5.3 months and a median overall survival (OS) of 8.3 months. This DCR was similar to patients without brain metastases. In patients evaluable by Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria, 14 of 16 patients (88%) maintained intracranial disease control of their stable brain lesions during LUMAKRAS therapy with two achieving complete responses of non-target lesions. The safety profile of LUMAKRAS in the brain metastases group was consistent with previous reports. Amgen is enrolling patients with active brain metastases in an arm of the CodeBreaK 101 study (NCT04185883).

"Up to 40% of patients with KRAS G12C-mutated NSCLC may develop brain metastases.1 Given the overall poor prognosis for this patient subset, there is an urgent need for novel treatment options,"2 said lead author Suresh S. Ramalingam, M.D., executive director of Winship Cancer Institute of Emory University in Atlanta. "Our results demonstrate the potential of sotorasib to provide meaningful clinical benefit for KRAS G12C-mutated NSCLC in the brain."

An additional exploratory descriptive analysis of CodeBreaK 100 being presented during a Mini Oral Presentation (MA14.03) examined whether the mutation profile of the tumors, in addition to KRASG12C, is correlated with patients’ responses or resistance to LUMAKRAS. An analysis of baseline tumor samples from 65 patients revealed no single genetic signature that predicted LUMAKRAS responses and ongoing evaluations will be needed to further identify potential targetable mechanisms of resistance. However, the KEAP1 mutation, a known driver of poor clinical outcomes, was observed in 7 of 22 patients with early progression and PFS of less than 3 months.

"The introduction of sotorasib ushered in a new standard of care for patients with KRAS G12C-mutated NSCLC," said lead author Ferdinandos Skoulidis, M.D., Ph.D., assistant professor of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center. "These biomarker data provide direction for continued research into characterizing mutation profiles associated with sotorasib treatment response to help guide clinical practice and inform innovative combination approaches to overcome potential mechanisms of resistance."

Advancing BiTE Molecule Acapatamab in NSCLC
In addition to the LUMAKRAS data, a trial-in-progress abstract outlined the design of an ongoing open-label, Phase 1b study (NCT04822298) evaluating the safety and tolerability of acapatamab, a half-life extended BiTE immuno-oncology therapy that targets prostate specific membrane antigen (PSMA)-expressing cancer cells in adults with relapsed/refractory NSCLC. The encouraging benefit-risk profile of acapatamab in an ongoing trial of patients with metastatic castration-resistant prostate cancer (mCRPC) (NCT03792841) suggested its potential for patients with NSCLC, as up to 49 to 85% of the endothelial cells in a tumor’s newly grown blood supply express PSMA.3,4 Acapatamab engages PSMA on cancer cells and CD3 on T cells, inducing T-cell activation, proliferation and target cell lysis to prompt a cancer-fighting immune response.5

About LUMAKRASTM (sotorasib)
Amgen took on one of the toughest challenges of the last 40 years in cancer research by developing LUMAKRAS, a KRASG12C inhibitor.6 LUMAKRAS 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.7

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. LUMAKRAS is also approved in the United Arab Emirates.

Amgen is progressing the largest and broadest global KRASG12C 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 has treated almost 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 submitted Marketing Authorization Applications (MAAs) for sotorasib in Australia, Brazil, Canada and the United Kingdom. Additionally, Amgen has submitted an MAA in the EU and New Drug Applications in Japan (J-NDA), Switzerland, South Korea, Singapore, Israel, Turkey and Taiwan.

LUMAKRAS is also being studied in multiple other solid tumors.6

LUMAKRASTM (sotorasib) U.S. Indication
LUMAKRASTM 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 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 LUMAKRASTM full Prescribing Information.

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.8 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.9

KRAS G12C is the most common KRAS mutation in NSCLC.10 In the U.S., about 13% of patients with non-squamous NSCLC harbor the KRAS G12C mutation.11 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.12

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. As the most advanced KRAS G12C clinical development program, CodeBreaK has enrolled more than 800 patients across 13 tumor types since its inception.

CodeBreaK 100, the Phase 1 and 2, first-in-human, open-label multicenter study, enrolled patients with KRAS G12C-mutant solid tumors. 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. 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.

About BiTE Technology
BiTE (bispecific T cell engager) technology is a targeted immuno-oncology platform that is designed to engage a patient’s own T cells to any tumor-specific antigen, activating the cytotoxic potential of T cells to eliminate detectable cancer. The BiTE immuno-oncology platform has the potential to treat different tumor types through tumor-specific antigens. The BiTE platform has a goal of leading to off-the-shelf solutions, which have the potential to make innovative T cell treatment available to all providers when their patients need it. Amgen is advancing BiTE molecules across a broad range of hematologic malignancies and solid tumors and further investigating BiTE technology with the goal of enhancing patient experience and therapeutic potential.

About Acapatamab (formerly AMG 160)
Acapatamab is a half-life extended (HLE) BiTE immune-oncology therapy that targets PSMA-expressing cancer cells being investigated in prostate cancer and non-small cell lung cancer (NSCLC).

Simultaneously binding to PSMA on tumor cells and CD3 on T cells, acapatamab is designed to engage patients’ own T cells to fight cancer. In an ongoing Phase I, first-in-human study in patients with metastatic castration-resistant prostate cancer (mCRPC), acapatamab has demonstrated a manageable safety profile and promising efficacy as monotherapy.3

The mCRPC study is also examining acapatamab in combination with pembrolizumab. A Phase 1/2, master protocol study is investigating the safety, tolerability, dosing and efficacy of acapatamab, in combination with enzalutamide, abiraterone, or the PD-1 inhibitor AMG 404 in patients with earlier-line mCRPC. An ongoing open-label, Phase 1b study is evaluating the safety and tolerability of acapatamab in adults with relapsed/refractory NSCLC.