Amgen Presents New Lumakras® (Sotorasib) Plus Vectibix® (Panitumumab) Data In Patients With Kras G12C-Mutated Metastatic Colorectal Cancer

Amgen today announced data from the global Phase 3 CodeBreaK 300 trial evaluating two doses of LUMAKRAS® (sotorasib) (960 mg or 240 mg) in combination with Vectibix® (panitumumab). Both doses demonstrated a statistically significant superiority in progression-free survival (PFS) over the investigator's choice of therapy in patients with chemorefractory KRAS G12C-mutated metastatic colorectal cancer (mCRC). The results are being presented today at the Presidential Symposium 2 session as a late-breaking oral presentation (LBA10) during the European Society for Medical Oncology (ESMO) 2023 Congress in Madrid, Spain, with simultaneous publication in the New England Journal of Medicine.

"The CodeBreaK 300 trial demonstrated the benefit of LUMAKRAS plus Vectibix to deliver statistically significant PFS outcomes for patients compared to the investigator's choice of therapy, offering new hope to this population with historically poor outcomes," said David M. Reese, M.D., executive vice president, Research and Development at Amgen.

After a median follow-up of 7.8 months, the median PFS was 5.6 months and 3.9 months with LUMAKRAS 960 mg plus Vectibix and LUMAKRAS 240 mg plus Vectibix respectively, versus 2.2 months with investigator's choice of therapy (trifluridine and tipiracil, or regorafenib). The improvement in PFS for patients treated with LUMAKRAS plus Vectibix was seen across key subgroups, including tumor sidedness, primary tumor location, prior lines of therapy and presence or absence of liver metastases. Among secondary endpoints, higher objective response rate (ORR) and disease control rate (DCR) were observed in patients treated with LUMAKRAS plus Vectibix at both doses versus investigator's choice of care. Patients at both dose regimens of LUMAKRAS plus Vectibix experienced a longer duration of treatment than those treated with investigator's choice therapy.

"With these new data, sotorasib plus panitumumab showed consistent efficacy across key subgroups at both doses and supports the biologic rationale of combining these two biomarker-directed therapies," said Filippo Pietrantonio, M.D., Fondazione IRCCS Istituto Nazionale dei Tumori. "Fewer than 20% of people diagnosed with mCRC survive beyond five years, and additional treatment options are clearly needed, particularly for the patients with KRAS mutations for whom evidence-based targeted options were not yet available." 

The most common Grade ≥3 treatment-related adverse events (TRAEs) with LUMAKRAS plus Vectibix were dermatitis acneiform (960 mg: 11%; 240 mg: 4%), hypomagnesemia (960 mg: 6%; 240 mg: 8%), rash (960 mg: 6%; 240 mg: 2%), and diarrhea (960 mg: 4%; 240 mg: 6%).

Based on the CodeBreaK 300 primary analysis results, Amgen is planning to submit these data to regulatory authorities.

About CodeBreaK 300

The CodeBreaK 300 trial enrolled 160 participants and compared LUMAKRAS at doses of 960 mg and 240 mg in combination with Vectibix to investigator's choice of standard of care (trifluridine and tipiracil, or regorafenib) in patients with chemorefractory KRAS G12C-mutated metastatic colorectal cancer (mCRC).

The primary endpoint was PFS, and key secondary endpoints were overall survival (OS) and objective response rate (ORR).

The median PFS for patients treated with the 960 mg dose of LUMAKRAS plus Vectibix (n=53) was 5.6 months (Hazard Ratio (HR) 0.49 (95% Confidence Interval (CI): 0.30, 0.80)).

The median PFS for patients treated with the 240 mg dose of LUMAKRAS plus Vectibix (n=53) was 3.9 months (HR 0.58 (95% CI: 0.36, 0.93)).

The median PFS for patients treated with investigator's choice (n=54) was 2.2 months.

LUMAKRAS plus Vectibix combination regimens demonstrated higher ORR compared with investigator's choice (95% CI; 960 mg: 26% [15.3–40.3]; 240 mg: 6% [1.2–15.7]; investigator's choice of care: 0% [0–6.6]). Similarly, consistent improvement in DCR was observed in patients treated with LUMAKRAS plus Vectibix (95% CI; 960 mg: 72% [57.7–83.2]; 240 mg: 68% [53.7–80.1]; investigator's choice: 46% [32.6–60.4]). Tumor shrinkage of any level from baseline was observed in 81%, 57% and 20% of patients in the 960 mg dose, 240 mg dose and investigator's choice cohorts, respectively. The OS was immature at the time of the data cutoff.

About LUMAKRAS®/LUMYKRAS® (sotorasib)

LUMAKRAS received accelerated approval from the U.S. Food and Drug Administration on May 28, 2021. The supplemental New Drug Application (sNDA) for full approval of LUMAKRAS was accepted by the FDA for standard review and a Prescription Drug User Fee Act (PDUFA) target action date of December 24, 2023, has been set.

About Advanced Colorectal Cancer and the KRAS G12C Mutation

Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide, comprising 10% of all cancer diagnoses.1 It is also the third most commonly diagnosed cancer globally.2 Patients with previously treated metastatic CRC need more effective treatment options.

KRAS mutations are among the most common genetic alterations in colorectal cancers, with the KRAS G12C mutation present in approximately 3-5% of colorectal cancers.3,4,5

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. 

About Vectibix® (panitumumab)

Vectibix is the first fully human monoclonal anti-EGFR antibody approved by the FDA for the treatment of mCRC. Vectibix was approved in the U.S. in September 2006 as a monotherapy for the treatment of patients with EGFR-expressing mCRC after disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy. 

In May 2014, the FDA approved Vectibix for use in combination with FOLFOX, as first-line treatment in patients with wild-type KRAS (exon 2) mCRC. With this approval, Vectibix became the first-and-only biologic therapy indicated for use with FOLFOX, one of the most commonly used chemotherapy regimens, in the first-line treatment of mCRC for patients with wild-type KRAS mCRC. 

In June 2017, the FDA approved a refined indication for Vectibix for use in patients with wild-type RAS (defined as wild-type in both KRAS and NRAS as determined by an FDA-approved test for this use) mCRC. 

INDICATION AND LIMITATION OF USE

Vectibix® is indicated for the treatment of patients with wild-type RAS (defined as wild-type in both KRAS and NRAS as determined by an FDA-approved test for this use) metastatic colorectal cancer (mCRC): as first-line therapy in combination with FOLFOX, and as monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy. 

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