On August 7, 2022 Amgen (NASDAQ: AMGN) reported three new data sets from its thoracic oncology portfolio that will be presented at the International Association for the Study of Lung Cancer (IASLC) 2022 World Conference on Lung Cancer (WCLC) from August 6-9 in Vienna, Austria (Press release, Amgen, AUG 7, 2022, View Source [SID1234617719]). The data presented will include new combination study results: LUMAKRAS (sotorasib) with pembrolizumab or atezolizumab and LUMAKRAS with RMC-4630, a small molecule protein tyrosine phosphatase 2 (SHP2) inhibitor. In addition, new data will be featured from the DeLLphi300 clinical trial, a Phase 1 dose exploration and expansion study evaluating the safety and efficacy of tarlatamab, a first-in-class half-life extended bispecific T-cell engager (HLE BiTE) molecule targeting delta-like ligand 3 (DLL3), in small cell lung cancer (SCLC).

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"Amgen is working to deliver the next frontier of treatment in lung cancer to help change patient outcomes in these historically difficult-to-treat cancers, and we’re pleased to present LUMAKRAS data for non-small cell lung cancer and tarlatamab data for small cell lung cancer, a disease where there are no therapies specifically approved to treat patients in the third-line setting," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "As part of the LUMAKRAS comprehensive clinical trial program we are exploring multiple approaches to front-line treatment, including the initiation of a Phase 3 study combining LUMAKRAS with chemotherapy for patients with PD-L1-negative tumors and moving forward with the Phase 1 dose expansion of LUMAKRAS in combination with checkpoint inhibitors. We are also advancing novel approaches like the SHP2 inhibitor combination trials."

LUMAKRAS in Combination with Pembrolizumab or Atezolizumab (Abstract OA03.06)
In a Phase 1b CodeBreaK 100/101 dose exploration study, a total of 58 KRASG12C inhibitor-naïve patients with KRAS G12C-mutated non-small cell lung cancer (NSCLC) were treated across 12 cohorts at varying doses of LUMAKRAS (120–960 mg daily) in combination with intravenous atezolizumab (1200 mg) or pembrolizumab (200 mg) administered concurrently every three weeks until intolerability or disease progression. Half of the cohorts were lead-in, where patients received LUMAKRAS monotherapy for either 21 or 42 days before their first combination dose. The majority of patients (67%) received prior immunotherapy and the median follow-up time was 12.8 months.

In this mostly pre-treated NSCLC population, combining LUMAKRAS with immunotherapy showed an objective response rate (ORR) of 29% (17/58 patients across all cohorts). Among the 17 confirmed responders, five patients had an observed duration of response (DoR) greater than 10 months, with eight ongoing responders. The combination of LUMAKRAS with immunotherapy also led to a higher incidence of grade 3-4 treatment-related adverse events (TRAEs) than previously observed with LUMAKRAS monotherapy, primarily liver enzyme elevations. However, lead-in cohorts demonstrated durable clinical activity with lower rates of discontinuation and grade 3-4 TRAEs compared to concurrent cohorts. Nearly all grade 3-4 TRAEs occurred outside of the 21-day dose limiting toxicity window and were resolved. Dose expansion is ongoing in treatment-naïve patients using LUMAKRAS lead-in followed by combination of LUMAKRAS with pembrolizumab.

"For the first time, we demonstrated that sotorasib in combination with an immune checkpoint inhibitor such as pembrolizumab or atezolizumab produced durable responses in both pre-treated immunotherapy and in naive settings," said Bob T. Li, MD, PhD, MPH, medical oncologist and principal investigator at Memorial Sloan Kettering Cancer Center who is the study’s presenting author. "Insights from this CodeBreaK research show us that while hepatotoxicity events did occur, they tended to appear after the second or third cycle of immunotherapy administration, but all were resolved with appropriate clinical measures. The fact that we saw a median duration of response of 17.9 months and lower rates of adverse events in patients treated with sotorasib as a lead-in to the combination regimen informs our approach for ongoing investigation in the first-line setting."

LUMAKRAS in Combination with RMC-4630 (Abstract OA03.03)
In a separate dose exploration of the CodeBreaK 101 Phase 1b master study, a total of 27 patients with KRAS G12C-mutated tumors, including 11 patients with NSCLC, were treated with LUMAKRAS and escalating dose levels of RMC-4630. Patients had received a median of three prior lines of therapy, with 41% having prior KRASG12C inhibitor therapy.

"As with all of the CodeBreaK sotorasib combination arms, preclinical and biomarker rationale informed the evaluation of sotorasib with RMC-4630, as genomic alterations of receptor tyrosine kinase (RTK) were identified as a common resistance mechanism to sotorasib, highlighting the potential role for combining sotorasib with upstream RTK signaling inhibitors," said Gerald S. Falchook, M.D., principal investigator and director of drug development, Sarah Cannon Research Institute at HealthONE. "These first safety and efficacy data support further investigation to expand treatment options for patients with the KRAS G12C mutation."

The data demonstrated promising clinical activity in patients with KRAS G12C-mutated NSCLC treated with the LUMAKRAS and RMC-4630 combination, most notably in KRASG12C inhibitor-naïve patients. Of the 11 NSCLC patients enrolled, three patients (27%) achieved a confirmed partial response (PR) with two responses ongoing at the time of data cut-off, and seven patients (64%) achieved disease control. For the six KRASG12C inhibitor-naïve patients, an ORR of 50% was observed and all patients demonstrated disease control. Overall, TRAEs occurred in 63% of patients, the most common were edema (30%) and diarrhea (26%). The LUMAKRAS and RMC-4630 combination dose escalation was completed with grade 3 TRAEs occurring in 22% of patients and without any grade 4 and higher TRAEs.

Dose expansion is underway in both KRASG12C inhibitor-naïve and KRASG12C inhibitor-exposed NSCLC patients.

Advancing Tarlatamab (AMG 757) in Small Cell Lung Cancer (SCLC) (Abstract OA12.05)
Updated data from the DeLLphi300 clinical trial evaluating tarlatamab in SCLC will be presented during the Novel and Combination Strategies for SCLC oral session (OA12) on Monday, August 8, 2022.

"There remains an urgent need for additional treatment options for patients with small cell lung cancer, an aggressive form of lung cancer associated with poor prognosis and where there are no therapies specifically approved for third-line treatment," said Hossein Borghaei, DO, MS, chief of the Division of Thoracic Medical Oncology at Fox Chase Cancer Center. "Data that will be presented at WCLC show that tarlatamab has the potential to offer a new approach – binding a novel tumor antigen expressed on a majority of SCLC tumor cells, DLL3, while engaging T cells directly at the site of the tumor microenvironment to activate a better response."

Based on the latest data, a potentially registrational Phase 2 study of tarlatamab in the third-line treatment of SCLC is enrolling patients. Additional studies investigating tarlatamab are underway, including DeLLphi-303, a Phase 1b study testing tarlatamab in combination with standard of care in first-line SCLC and a Phase 1b study in de novo or treatment-emergent neuroendocrine prostate cancer.

Amgen to Webcast Investor Meeting at WCLC 2022
Amgen (NASDAQ: AMGN) will host a webcast call for the investment community in conjunction with the International Association for the Study of Lung Cancer (IASLC) 2022 World Conference on Lung Cancer (WCLC) at 12:00 p.m. ET on Monday, Aug. 8, 2022. David M. Reese, M.D., executive vice president of Research and Development at Amgen, along with members of Amgen’s clinical development team, will discuss the data being presented on LUMAKRAS (sotorasib) in combination with immunotherapy and in combination with a SHP2 inhibitor in non-small cell lung cancer, as well as tarlatamab data in small cell lung cancer.

The webcast, as with other selected presentations regarding developments in Amgen’s business given by management at certain investor and medical conferences, can be found on Amgen’s website, www.amgen.com, under Investors. Information regarding presentation times, webcast availability and webcast links are noted on Amgen’s Investor Relations Events Calendar. The webcast will be archived and available for replay for at least 90 days after the event.

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, including triplets, 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, expanded access and commercial use.

In May 2021, LUMAKRAS was the first KRASG12Cinhibitor to receive regulatory approval with its approval in the U.S., under accelerated approval. In total, LUMAKRAS/LUMYKRAS is approved in over 44 markets around the world, including the European Union, Japan, United Arab Emirates, South Korea, Hong Kong, Switzerland, Taiwan and Qatar, and in Australia, Brazil, Canada, Great Britain, Israel and Singapore under the U.S. FDA’s Project Orbis. Amgen has submitted MAAs in Argentina, Colombia, Kuwait, Malaysia, Mexico, 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) is fully enrolled 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 Tarlatamab
Tarlatamab is an investigational first-in-class half-life extended bispecific T-cell engager (BiTE) molecule that is uniquely designed to target delta-like ligand 3 (DLL3) in neuroendocrine cancers, such as small cell lung cancer (SCLC) and neuroendocrine prostate cancer – both of which have high unmet medical needs.14,15 DLL3 is highly upregulated on the cell surface of neuroendocrine tumors and rarely expressed on nonmalignant cells, making it a novel target for investigating a BiTE immuno-oncology molecule.15,16,17

Tarlatamab is being investigated in multiple studies, including DeLLphi-301, a potentially registrational Phase 2 study in relapsed/refractory SCLC; DeLLphi-303, a Phase 1b study testing tarlatamab in combination with standard of care therapies in first-line SCLC; DeLLphi-302, a Phase 1b combination study with AMG 404 in second-line or later SCLC; and DeLLpro-300, a Phase 1b study in de novo or treatment-emergent neuroendocrine prostate cancer.

About Small Cell Lung Cancer
Small cell lung cancer (SCLC) is a particularly aggressive form of the disease that accounts for about 10% to 15% of all lung cancers.18 SCLC tends to spread faster than NSCLC, with nearly 70% of people with SCLC having metastatic disease at the time of diagnosis.18

The five-year survival rate for advanced SCLC remains low at 3% and unfortunately treatment options have not changed much in several decades.5,19 Delta-like ligand 3 (DLL3) is an emerging treatment target that is expressed in greater than 80% of SCLC tumors with minimal expression in normal cells.20

About BiTE Technology
BiTE (bispecific T-cell engager) technology is a targeted immuno-oncology platform that is designed to engage 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 a number of BiTE molecules across a broad range of hematologic malignancies and solid tumors, further investigating BiTE technology with the goal of enhancing patient experience and therapeutic potential.

To learn more about BiTE technology, visit www.AmgenBiTETechnology.com.

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.