KRAZATI (adagrasib) in Combination with Cetuximab Demonstrates Clinically Meaningful Activity as a Targeted Treatment Option for Patients with Previously Treated KRAS G12C-Mutated Locally Advanced or Metastatic Colorectal Cancer (CRC)

Rhea-AI Summary

Bristol Myers Squibb presents promising data on KRAZATI (adagrasib) in combination with cetuximab for KRASG12C-mutated colorectal cancer at AACR annual meeting. The study shows an objective response rate of 34%, with a median progression-free survival of 6.9 months and median overall survival of 15.9 months. Disease control was observed in 85% of patients, highlighting the potential of adagrasib for this specific patient group.

Insights

Oncology Doctor

From an oncological perspective, the reported data on KRAZATI® combined with cetuximab presents a significant advancement in the treatment of KRASG12C-mutated colorectal cancer (CRC). Historically, CRC patients with this mutation have had limited treatment options and poor outcomes. The objective response rate of 34% and the median overall survival of 15.9 months are promising figures, particularly when compared to the historical data for this patient subgroup. The disease control rate of 85% also suggests a substantial proportion of patients are deriving benefit from this combination therapy.

The concept of 'undruggable' targets in oncology, such as the KRAS mutation, has been a challenge for decades. The positive outcomes from this study may represent a paradigm shift in how these mutations are approached in drug development. However, it is important to recognize that these results need to be seen in the context of the drug's safety profile, which appears manageable but will require ongoing monitoring as the treatment is introduced into broader clinical practice.

Medical Research Analyst

The acceptance of a supplemental new drug application by the FDA and the assignment of a PDUFA goal date indicates a regulatory milestone for Bristol Myers Squibb and its subsidiary, Mirati Therapeutics. The priority review status reflects the unmet medical need in this patient population. From a research standpoint, the progression-free survival of 6.9 months is noteworthy as it represents a benchmark for future studies in this area. Additionally, the simultaneous publication of the data in a reputable journal like Cancer Discovery underscores the scientific community's interest in these findings.

It is also important to consider the implications for biomarker testing in CRC. The emphasis on the identification of KRASG12C mutations could drive increased demand for diagnostic testing, potentially influencing the strategies of companies involved in the diagnostics sector. The broader impact on the precision medicine approach in oncology could be substantial, with a move towards more personalized treatment regimens based on specific genetic profiles.

Market Research Analyst

For investors and stakeholders in the pharmaceutical and biotechnology sectors, the clinical success of KRAZATI® in combination with cetuximab represents a potential catalyst for Bristol Myers Squibb's stock performance. The specificity of the treatment for KRASG12C-mutated CRC could position the company as a leader in a niche, yet significant market segment. The market potential for this combination therapy could be further extrapolated by examining the prevalence of the KRASG12C mutation in the CRC patient population, which stands at approximately 3-4%.

Moreover, the strategic implications for Bristol Myers Squibb's oncology pipeline and potential market share in the CRC therapeutics market are considerable. The company's ability to innovate and address unmet needs with targeted therapies could strengthen its competitive position. However, it is important to monitor the outcome of the PDUFA date and any subsequent market adoption and insurance coverage decisions, which will ultimately influence the commercial success of the drug.

Late-breaking data to be featured in an oral presentation at the American Association for Cancer Research (AACR) annual meeting on Monday, April 8 and highlighted as part of the official meeting press program

PRINCETON, N.J.--(BUSINESS WIRE)-- Bristol Myers Squibb (NYSE: BMY) today announced data from the cohorts of the Phase 1/ 2 KRYSTAL-1 study evaluating KRAZATI^® (adagrasib) in combination with cetuximab for the treatment of patients with previously treated KRAS^G12C-mutated locally advanced or metastatic colorectal cancer (CRC).

These late breaking data (abstract #CT013) will be featured in an oral presentation at the 2024 American Association for Cancer Research (AACR) annual meeting on Monday, April 8 at 11:10 a.m. Pacific Time and will be highlighted as part of the meeting’s official press program. The data will also be published simultaneously in Cancer Discovery.

With a median follow up of 11.9 months in 94 patients, KRAZATI plus cetuximab demonstrated an objective response rate, the primary endpoint, of 34%, median progression-free survival of 6.9 months (95% CI, 5.7-7.4), and median overall survival of 15.9 months (95% CI, 11.8-18.8) in pre-treated patients with KRAS^G12C-mutated locally advanced or metastatic CRC. The median duration of response was 5.8 months. Disease control was observed in 85% of patients. The safety profile for KRAZATI plus cetuximab was manageable and consistent with previous reports, and with the known safety profile of each drug individually.

KRAS^G12C mutations act as oncogenic drivers and occur in approximately 3-4% of colorectal cancers. In previous studies, treatment with cetuximab as a single agent did not offer a clinical benefit in patients with KRAS-mutated colorectal cancer.

“Patients with KRAS^G12C-mutated colorectal cancer have historically faced poor prognoses and remain in need of additional treatment options,” said Scott Kopetz, M.D., Ph.D, FACP, associate vice president for translational research, and Professor, Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center. “Although KRAS had previously been considered ‘undruggable,’ these data from KRYSTAL-1 reinforce the potential benefit of adagrasib for these specific patients.”

“While there has been progress in the treatment of colorectal cancer, there remain groups of patients, such as those with KRAS-mutated cancers, who continue to need new, targeted treatment options,” said Anne Kerber, senior vice president, head of late clinical development, Hematology, Oncology, Cell Therapy (HOCT) at Bristol Myers Squibb. “These data highlight the significance of testing and identification of KRAS^G12C mutations in patients with CRC.”

The company announced in February 2024 that the FDA had accepted a supplemental new drug application for KRAZATI in combination with cetuximab as a targeted treatment option for patients with previously treated KRAS^G12C-mutated locally advanced or metastatic CRC for priority review and assigned a Prescription Drug User Fee Act (PDUFA) goal date of June 21, 2024.

Bristol Myers Squibb thanks the patients and investigators involved in the KRYSTAL-1 clinical trial.

This study was funded by Mirati Therapeutics, Inc., a Bristol Myers Squibb company. KRAZATI is a registered trademark of Mirati Therapeutics, Inc., a Bristol Myers Squibb company.

ABOUT KRAZATI^® (adagrasib)

KRAZATI (adagrasib) is highly selective and potent oral small-molecule inhibitor of KRAS^G12C that is optimized to sustain target inhibition, an attribute that could be important to treat KRAS^G12C-mutated cancers, as the KRAS^G12C protein regenerates every 24-48 hours. KRAS^G12C mutations act as oncogenic drivers and occur in approximately 14% of NSCLC (adenocarcinoma), 3-4% of colorectal cancers, and 1-2% of several other cancers.

In 2022, KRAZATI was granted accelerated approval for 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 objective response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial(s). In 2024, the European Commission (EC) granted conditional marketing authorization for KRAZATI as a targeted treatment option for adult patients with KRAS^G12C-mutated advanced NSCLC and disease progression after at least one prior systemic therapy.

KRAZATI continues to be evaluated as monotherapy and in combination with other anti-cancer therapies in patients with advanced KRAS^G12C-mutated solid tumors, including NSCLC and colorectal cancer.

In 2022, the FDA granted breakthrough therapy designation for KRAZATI in combination with cetuximab in patients with KRAS^G12C-mutated advanced colorectal cancer (CRC) whose cancer has progressed following prior treatment with chemotherapy and an anti-VEGF therapy.

For Prescribing Information, visit https://mirati.com/KRAZATI_USPI/.

ABOUT KRYSTAL-1

KRYSTAL-1 is an open-label, multicenter, multiple expansion cohort Phase 1/2 trial to determine the safety and efficacy of KRAZATI in patients with advanced solid tumors that harbor a KRAS^G12C mutation. The primary endpoint for the Phase 2 cohort of the KRYSTAL-1 study was objective response rate. Secondary endpoints included duration of response, progression-free survival, overall survival and safety.

INDICATION

KRAZATI 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 objective response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial(s).

IMPORTANT SAFETY INFORMATION

GASTROINTESTINAL ADVERSE REACTIONS

• In the pooled safety population, serious gastrointestinal adverse reactions observed were gastrointestinal obstruction in 1.6%, including 1.4% grade 3 or 4, gastrointestinal bleeding in 0.5% of patients, including 0.5% grade 3, and colitis in 0.3%, including 0.3% grade 3. In addition, nausea, diarrhea, or vomiting occurred in 89% of 366 patients, including 9% grade 3. Nausea, diarrhea, or vomiting led to dosage interruption or dose reduction in 29% of patients and permanent discontinuation of KRAZATI in 0.3%
• Monitor and manage patients using supportive care, including antidiarrheals, antiemetics, or fluid replacement, as indicated. Withhold, reduce the dose, or permanently discontinue KRAZATI based on severity

QTC INTERVAL PROLONGATION

• KRAZATI can cause QTc interval prolongation, which can increase the risk for ventricular tachyarrhythmias (e.g., torsades de pointes) or sudden death
• In the pooled safety population, 6% of 366 patients with at least one post-baseline electrocardiogram (ECG) assessment had an average QTc ≥501 ms, and 11% of patients had an increase from baseline of QTc >60 msec. KRAZATI causes concentration-dependent increases in the QTc interval
• Avoid concomitant use of KRAZATI with other products with a known potential to prolong the QTc interval. Avoid use of KRAZATI in patients with congenital long QT syndrome and in patients with concurrent QTc prolongation
• Monitor ECGs and electrolytes prior to starting KRAZATI, during concomitant use, and as clinically indicated in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, and in patients who are taking medications that are known to prolong the QT interval. Withhold, reduce the dose, or permanently discontinue KRAZATI, depending on severity

HEPATOTOXICITY

• KRAZATI can cause hepatotoxicity
• In the pooled safety population, hepatotoxicity occurred in 37%, and 7% were grade 3 or 4. A total of 32% of patients who received KRAZATI had increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST); 5% were grade 3 and 0.5% were grade 4. Increased ALT/AST leading to dose interruption or reduction occurred in 11% of patients. KRAZATI was discontinued due to increased ALT/AST in 0.5% of patients
• Monitor liver laboratory tests (AST, ALT, alkaline phosphatase, and total bilirubin) prior to the start of KRAZATI, and monthly for 3 months or as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Reduce the dose, withhold, or permanently discontinue KRAZATI based on severity

INTERSTITIAL LUNG DISEASE /PNEUMONITIS

• KRAZATI can cause interstitial lung disease (ILD)/pneumonitis, which can be fatal. In the pooled safety population, ILD/pneumonitis occurred in 4.1% of patients, 1.4% were grade 3 or 4, and 1 case was fatal. The median time to first onset for ILD/pneumonitis was 12 weeks (range: 5 to 31 weeks). KRAZATI was discontinued due to ILD/pneumonitis in 0.8% of patients
• Monitor patients for new or worsening respiratory symptoms indicative of ILD/pneumonitis (eg, dyspnea, cough, fever). Withhold KRAZATI in patients with suspected ILD/pneumonitis and permanently discontinue KRAZATI if no other potential causes of ILD/pneumonitis are identified

ADVERSE REACTIONS

• The most common adverse reactions (≥25%) are nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, renal impairment, edema, dyspnea, decreased appetite

FEMALES AND MALES OF REPRODUCTIVE POTENTIAL

• Infertility: Based on findings from animal studies, KRAZATI may impair fertility in females and males of reproductive potential

Please see U.S. Full Prescribing Information for KRAZATI at https://mirati.com/KRAZATI_USPI/.

About Colorectal Cancer

Colorectal cancer (CRC) is cancer that develops in the colon or the rectum, which are part of the body’s digestive or gastrointestinal system. CRC is the third most commonly diagnosed cancer in the world. In 2020, it is estimated that there were approximately 1,931,000 new cases of the disease; it is the second leading cause of cancer-related deaths among men and women combined.

Bristol Myers Squibb: Creating a Better Future for People with Cancer

Bristol Myers Squibb is inspired by a single vision — transforming patients’ lives through science. The goal of the company’s cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine and, through innovative digital platforms, are turning data into insights that sharpen their focus. Deep understanding of causal human biology, cutting-edge capabilities and differentiated research platforms uniquely position the company to approach cancer from every angle.

Cancer can have a relentless grasp on many parts of a patient’s life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. As a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future.

About Bristol Myers Squibb

Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube, Facebook and Instagram.

Cautionary Statement Regarding Forward-Looking Statements

This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, that future study results may not be consistent with the results to date, and that KRAZATI (adagrasib) in combination with cetuximab may not achieve its primary study endpoint or KRAZATI (adagrasib) in combination with cetuximab may not achieve its primary study endpoint or receive regulatory approval for the additional indication described in this release in the currently anticipated timeline or at all, any marketing approvals, if granted, may have significant limitations on their use, and, if approved, whether such combination treatment for such additional indication described in this release will be commercially successful. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2023, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise.

corporatefinancial-news

View source version on businesswire.com: https://www.businesswire.com/news/home/20240407754891/en/

Bristol Myers Squibb

Media Inquiries:

media@bms.com

Investors:

investor.relations@bms.com

Source: Bristol Myers Squibb

FAQ

What data did Bristol Myers Squibb present at the AACR annual meeting regarding KRAZATI?

Bristol Myers Squibb presented data from the Phase 1/2 KRYSTAL-1 study evaluating KRAZATI (adagrasib) in combination with cetuximab for the treatment of patients with previously treated KRASG12C-mutated locally advanced or metastatic colorectal cancer.

What was the objective response rate observed in the study?

The study showed an objective response rate of 34%.

What was the median progression-free survival in the study?

The median progression-free survival was 6.9 months.

What was the median overall survival in the study?

The median overall survival was 15.9 months.

What percentage of patients showed disease control in the study?

Disease control was observed in 85% of patients.

What is the significance of KRASG12C mutations in colorectal cancer?

KRASG12C mutations act as oncogenic drivers and occur in approximately 3-4% of colorectal cancers.

What did the safety profile of KRAZATI plus cetuximab demonstrate?

The safety profile was manageable and consistent with previous reports and the known safety profile of each drug individually.

What did the FDA accept in February 2024 regarding KRAZATI?

The FDA accepted a supplemental new drug application for KRAZATI in combination with cetuximab as a targeted treatment option for patients with previously treated KRASG12C-mutated locally advanced or metastatic CRC for priority review.