On June 21, 2024 BCI Pharma reported that the company has been acquired by Gedeon Richter (Press release, BCI Pharma, JUN 21, 2024, View Source [SID1234644488]).

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Dominique Surleraux, former BCI Pharma CEO, said : "This acquisition will ensure the continuity and development of the BCI and also further clinical development of our assets/research projects. I would like to take the opportunity to thank BCI scientists for their input, BCI investors and the Belgium Walloon region Ministry of economic (SPW wallonie) for their financial support. I’m pretty confident that our assets will improve the quality of life of patients suffering from cancer and endometriosis."

On June 21, 2024 Takeda (TSE:4502/NYSE:TAK) reported that the European Commission (EC) approved FRUZAQLA (fruquintinib) as a monotherapy indicated for the treatment of adult patients with metastatic colorectal cancer (mCRC) who have been previously treated with available standard therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies, anti-VEGF agents, and anti-EGFR agents, and who have progressed on or are intolerant to treatment with either trifluridine-tipiracil or regorafenib (Press release, Takeda, JUN 21, 2024, View Source [SID1234644489]). The decision follows a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) on April 25, 2024, and approval by the U.S. Food and Drug Administration (FDA) for adults with mCRC who have been previously treated with oxaliplatin- and irinotecan-based regimens on November 8, 2023.1,2

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"People living with metastatic colorectal cancer face numerous difficulties, stemming both from their illness and the adverse effects of therapies. Given the complex nature of the disease, introducing innovative treatments such as fruquintinib – an oral, chemotherapy-free targeted agent – is essential. I am looking forward to having a new choice for appropriate patients," said Josep Tabernero, MD, PhD, director of Vall d´Hebron Institute of Oncology (VHIO).

The approval is based on results from the Phase 3 multi-regional FRESCO-2 trial. The trial investigated FRUZAQLA plus best supportive care (BSC) versus placebo plus BSC in patients with previously treated mCRC. FRESCO-2 met all its primary and key secondary efficacy endpoints and showed consistent benefit among patients treated with FRUZAQLA, regardless of the prior types of therapies they received. FRUZAQLA demonstrated a manageable safety profile in FRESCO-2. Adverse reactions leading to treatment discontinuation occurred in 20% of patients treated with FRUZAQLA plus BSC versus 21% of those treated with placebo plus BSC. Data from FRESCO-2 were published in The Lancet in June 2023.3

"Today’s approval marks an important moment for the colorectal cancer community in the EU. For the first time in over a decade, patients with previously treated metastatic colorectal cancer have a new targeted treatment option that can be used irrespective of whether their tumors harbor actionable mutations," said Teresa Bitetti, president of the Global Oncology Business Unit at Takeda. "We look forward to offering patients a novel treatment option that has a manageable safety profile and can be effective regardless of the prior types of therapies they have received."

About FRUZAQLA (fruquintinib)

FRUZAQLA is a selective oral inhibitor of all three VEGF receptors (-1, -2 and -3). VEGFR inhibitors play a pivotal role in blocking tumor angiogenesis. FRUZAQLA was designed to have enhanced selectivity that limits off-target kinase activity, allowing for high drug exposure, sustained target inhibition, and flexibility for potential use as part of combination therapy.

Takeda has the exclusive worldwide license to further develop, commercialize, and manufacture fruquintinib outside of mainland China, Hong Kong and Macau. FRUZAQLA was approved by the U.S. Food and Drug Administration (FDA) in November 2023. A submission to the Japan Pharmaceuticals and Medical Devices Agency (PMDA) took place in September 2023. Fruquintinib is developed and marketed in China by HUTCHMED. Fruquintinib was approved for marketing by the China National Medical Products Administration (NMPA) in September 2018 and commercially launched in China in November 2018 under the brand name ELUNATE.

EUROPEAN UNION IMPORTANT SAFETY INFORMATION

Please consult the FRUZAQLA (fruquintinib) Summary of Product Characteristics (SmPC) before prescribing.

Guidance for use: FRUZAQLA should be initiated by a physician experienced in the administration of anticancer therapy. Patients should be given the package leaflet.

CONTRAINDICATIONS: Hypersensitivity to the active substance or to any of the excipients.

SPECIAL POPULATIONS: Renal impairment: No dose adjustment is required for patients with mild, moderate, or severe renal impairment; Hepatic impairment: No dose adjustment is required for patients with mild or moderate hepatic impairment. FRUZAQLA is not recommended for use in patients with severe hepatic impairment as FRUZAQLA has not been studied in this population; Elderly: No dose adjustment is required in patients aged 65 years or above; Paediatric population: There is no relevant use of FRUZAQLA in the paediatric population for the indication of metastatic colorectal cancer; Women of childbearing potential/Contraception in females: Women of childbearing potential should be advised to use highly effective contraception during treatment and for at least 2 weeks following the last dose of FRUZAQLA; Pregnancy: There are no clinical data available on the use of FRUZAQLA in pregnant women. Based on its mechanism of action, FRUZAQLA has the potential to cause foetal harm. Animal studies have shown reproductive toxicity, including foetal malformations. FRUZAQLA should not be used during pregnancy unless the clinical condition of the woman requires treatment with FRUZAQLA. If FRUZAQLA is used during pregnancy or if the patient becomes pregnant while on treatment, the patient must be informed of the potential hazard to the foetus; Breast-feeding: The safe use of FRUZAQLA during breast-feeding has not been established. It is not known whether FRUZAQLA or its metabolites are excreted in human milk. There are no animal data on the excretion of FRUZAQLA in animal milk. A risk to the breastfeeding newborns/infants cannot be excluded. Breastfeeding should be discontinued during treatment and for 2 weeks after the last dose; Fertility: There are no data on the effects of FRUZAQLA on human fertility. Results from animal studies indicate that FRUZAQLA may impair male and female fertility.

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Hypertension: Hypertension, including hypertensive crisis, has been reported in patients treated with FRUZAQLA. Pre-existing hypertension should be monitored and adequately controlled in accordance with standard medical practices before starting FRUZAQLA treatment.

Hypertension should be medically managed with antihypertensive medicinal products and adjustment of the FRUZAQLA dose, if necessary. FRUZAQLA should be permanently discontinued for hypertension that cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis.
Haemorrhagic events: Haemorrhagic events have been reported in patients treated with FRUZAQLA, including gastrointestinal (GI) tract events. Serious and sometimes fatal bleeding events have been reported in patients after treatment with FRUZAQLA.

Haematologic and coagulation profiles should be monitored in accordance with standard medical practices in patients at risk for bleeding, including those treated with anticoagulants or other concomitant medicinal products that increase the risk of bleeding. In the event of severe bleeding requiring immediate medical intervention, FRUZAQLA should be permanently discontinued.
Gastrointestinal perforation: GI perforation events, including fatal events, have been reported in patients treated with FRUZAQLA.

Symptoms of GI perforation should be periodically monitored during treatment with FRUZAQLA.

FRUZAQLA should be permanently discontinued in patients developing GI perforation.
Proteinuria: Proteinuria events have occurred in patients treated with FRUZAQLA.

Proteinuria should be monitored before initiation and during treatment with FRUZAQLA in accordance with standard medical practices. If urine dipstick proteinuria ≥ 2 g / 24 hours is detected, dose interruptions, adjustments, or discontinuation may be necessary. FRUZAQLA should be permanently discontinued in patients developing nephrotic syndrome.
Palmar-plantar erythrodysaesthesia syndrome (PPES): PPES is the most frequently reported dermatological adverse reaction.

If Grade ≥ 2 skin reactions are detected, dose interruptions, adjustments, or discontinuation may be necessary.
Posterior reversible encephalopathy syndrome (PRES): PRES has been reported in 1 patient (0.1%) treated with FRUZAQLA in clinical studies. PRES is a rare neurologic disorder that can present with headache, seizure, lethargy, confusion, altered mental function, blindness, and other visual or neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). In patients developing PRES, discontinuation of FRUZAQLA, along with control of hypertension and supportive medical management of other symptoms, are recommended.
Impaired wound healing: Impaired wound healing has been reported in 1 patient (0.1%) treated with FRUZAQLA in clinical studies.

Patients are recommended to withhold FRUZAQLA for at least 2 weeks prior to surgery. FRUZAQLA should not be resumed for at least 2 weeks after surgery, as clinically indicated when there is evidence of adequate wound healing.
Arterial and venous thromboembolic events: It is recommended to avoid starting treatment with FRUZAQLA in patients with a history of thromboembolic events (including deep vein thrombosis and pulmonary embolism) within the past 6 months or if they have a history of stroke and/or transient ischemic attack within the last 12 months. If arterial thrombosis is suspected, FRUZAQLA should be discontinued immediately.
INTERACTIONS

Effects of other medicinal products on the pharmacokinetics of FRUZAQLA

CYP3A inducers

Co-administration of FRUZAQLA with rifampicin (a strong CYP3A inducer) 600 mg once daily decreased FRUZAQLA AUCinf by 65% and decreased Cmax by 12%. The concomitant use of FRUZAQLA with strong and moderate CYP3A inducers should be avoided.

CYP3A inhibitors

Co-administration of FRUZAQLA with itraconazole (a strong CYP3A inhibitor) 200 mg twice daily did not result in clinically meaningful changes in the area under the concentration-time curve (AUC) and Cmax of FRUZAQLA. No dose adjustment of FRUZAQLA is needed during concomitant use with CYP3A inhibitors.

Gastric acid lowering agents

Co-administration of FRUZAQLA with rabeprazole (a proton pump inhibitor) 40 mg once daily did not result in clinically meaningful changes in the AUC of FRUZAQLA. No dose adjustment of FRUZAQLA is needed during concomitant use with gastric acid lowering agents.

Effect of FRUZAQLA on the pharmacokinetics of other medicinal products

Medicinal products that are substrates of P-glycoprotein (P-gp)

Co-administration of a single dose of dabigatran etexilate 150 mg (a P-gp substrate) with a single dose of FRUZAQLA 5 mg decreased AUC of dabigatran by 9%. No dose adjustment is recommended for P-gp substrates during concomitant use with FRUZAQLA.

Medicinal products that are substrates of breast cancer resistance protein (BCRP)

Co-administration of a single 10 mg dose of rosuvastatin (a BCRP substrate) with a single 5 mg dose of FRUZAQLA decreased AUC of rosuvastatin by 19%. No dose adjustment is recommended for BCRP substrates during concomitant use with FRUZAQLA.

UNDESIRABLE EFFECTS: The most commonly reported adverse reactions with FRUZAQLA are:

Very common

(frequency ≥1/10)

Thrombocytopenia, hypothyroidism, anorexia, hypertension, dysphonia, diarrhoea, stomatitis, aspartate aminotransferase increased, total bilirubin increased, alanine aminotransferase increased, palmar-plantar erythrodysaesthesia syndrome, musculoskeletal discomfort, arthralgia, proteinuria, asthenia, and fatigue

Common

(≥1/100 to <1/10)

Pneumonia, upper respiratory tract infection, bacterial infections, leukopenia, neutropenia, hypokalemia, epistaxis, throat pain, gastrointestinal haemorrhage, gastrointestinal perforation, pancreatic enzymes increased, oral pain, rash, and mucosal inflammation

About CRC

CRC is a cancer that starts in either the colon or rectum. According to the International Agency for Research on Cancer, CRC is the third most prevalent cancer worldwide and was associated with more than 1.9 million new cases and 900,000 deaths in 2022. In Europe, CRC was the second most common cancer in 2022, with approximately 538,000 new cases and 248,000 deaths.4 In the U.S., it is estimated that 153,000 patients will be diagnosed with CRC and 53,000 deaths from the disease will occur in 2024.5 In Japan, CRC was the most common cancer in 2022, with more than 145,000 new cases and 60,000 deaths.4 Although early-stage CRC can be surgically resected, metastatic CRC remains an area of high unmet need with poor outcomes and limited treatment options. Some patients with metastatic CRC may benefit from personalized therapeutic strategies based on molecular characteristics; however, most patients have tumors that do not harbor actionable mutations.6,7,8,9,10

About the Phase 3 FRESCO-2 Trial

The FRESCO-2 study is a multi-regional clinical trial conducted in the U.S., Europe, Japan and Australia investigating FRUZAQLA plus BSC vs placebo plus BSC in patients with previously treated mCRC (NCT04322539). The study met all of its primary and key secondary endpoints, demonstrating that treatment with FRUZAQLA resulted in statistically significant and clinically meaningful improvement in OS and PFS. The safety profile of FRUZAQLA in FRESCO-2 was consistent with previously reported fruquintinib monotherapy studies. Results from the study were presented at ESMO (Free ESMO Whitepaper) in September 2022 and subsequently published in The Lancet in June 2023.

On June 21, 2024 Bristol Myers Squibb (NYSE: BMY) reported that the European Medicines Agency (EMA) has validated the extension application to introduce a new route of administration (subcutaneous use) for Opdivo (nivolumab) that includes a new pharmaceutical form (solution for injection) and a new strength (600 mg/vial) across multiple previously approved adult solid tumor indications as monotherapy, monotherapy maintenance following completion of nivolumab plus ipilimumab combination therapy, or in combination with chemotherapy or cabozantinib, based on the results from the Phase 3 CheckMate -67T study (Press release, Bristol-Myers Squibb, JUN 21, 2024, View Source [SID1234644490]). Validation of the application confirms the submission is complete and begins the EMA’s centralized review procedure.

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"Subcutaneous nivolumab has the potential to change the way patients living with cancer receive Opdivo treatment and to significantly reduce administration time by utilizing a single injection in three-to-five minutes. By providing patients the same quality of care as IV Opdivo in a fraction of the time, patients can focus on what is important to them rather than spending a longer wait time at the infusion center," said Susan Parker, vice president, global program lead, product design & development, Bristol Myers Squibb. "We are committed to advancing medicines that improve the patient experience and are evaluating innovative formulations across our broad portfolio. We look forward to working with the EMA to advance this application with the goal of introducing the subcutaneous option of Opdivo."

In the Phase 3 CheckMate -67T trial, subcutaneous nivolumab demonstrated noninferiority of Cavgd28 (time-averaged Opdivo serum concentration over 28 days) and Cminss (trough serum concentration at steady state), the study’s primary endpoints, vs. intravenous (IV) Opdivo in patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC) who have received no more than two prior lines of systemic therapy. Additionally, subcutaneous nivolumab showed noninferiority of the key secondary endpoint of objective response rate (ORR) as assessed by Blinded Independent Central Review (BICR) vs. IV Opdivo. The safety profile of subcutaneous nivolumab was consistent with the IV formulation. The pharmacokinetics, efficacy and safety results from CheckMate -67T were presented at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Genitourinary Cancers Symposium. Additional safety analyses and patient reported outcomes were recently presented at the 2024 ASCO (Free ASCO Whitepaper) Annual Meeting.

About CheckMate -67T
CheckMate -67T is a Phase 3 randomized, open-label trial evaluating subcutaneous administration of Opdivo co-formulated with Halozyme’s proprietary recombinant human hyaluronidase, rHuPH20, or subcutaneous nivolumab (nivolumab and hyaluronidase) compared to intravenous Opdivo, in patients with advanced or metastatic ccRCC who have received prior systemic therapy. This trial presents an opportunity to potentially bring a subcutaneous formulation of Opdivo to patients. A total of 495 patients were randomized to either subcutaneous nivolumab or intravenous Opdivo. The co-primary endpoints of the trial are time-averaged serum concentration over 28 days (Cavgd28) and trough serum concentration at steady-state (Cminss) of subcutaneous nivolumab vs. intravenous Opdivo. Objective response rate (ORR) is a key secondary endpoint.

On June 21, 2024 Arvinas, Inc. (Nasdaq: ARVN), a clinical-stage biotechnology company creating a new class of drugs based on targeted protein degradation, reported it presented new preclinical data from its investigational BCL6 PROTAC degrader ARV-393 at the European Hematology Association (EHA) (Free EHA Whitepaper) 2024 Annual Congress that took place June 13-16, 2024 in Madrid, Spain, and presented new preclinical data from its PROTAC LRRK2 degrader program at the Biennial International LRRK2 Meeting that took place June 18-21, 2024 in Crete, Greece (Press release, Arvinas, JUN 21, 2024, View Source [SID1234644478]).

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Data presented at EHA (Free EHA Whitepaper) showed anti-tumor activity for the company’s investigational PROTAC BCL6 degrader, ARV-393, in preclinical models of B-cell lymphoma. In these preclinical models, ARV-393 potently and rapidly degraded the BCL6 protein and inhibited cell growth in diffuse large B-cell lymphoma (DLBCL) and Burkitt cell lines. ARV-393 showed tumor growth inhibition, including tumor regression, in various DLBCL cell line-derived xenograft (CDX) models and in multiple patient-derived xenograft (PDX) models of non-Hodgkin lymphoma (NHL), including germinal center B-cell-like (GCB), activated B-cell (ABC), GCB/ABC, BCL not otherwise specified (BCL/NOS) subtypes of DLBCL, and Burkitt lymphoma.

"These new preclinical data for ARV-393 demonstrate that in these models it can effectively target and induce the degradation of the BCL6 protein that is commonly deregulated in DLBCL," said John Houston, Ph.D., Chairperson, President, and Chief Executive Officer at Arvinas. "These encouraging results suggest that ARV-393 could be developed into a potential new treatment for patients with certain types of non-Hodgkin lymphoma, particularly those who have not responded to other treatments."

Preclinical data presented at the Biennial LRRK2 Meeting highlighted the potential of the company’s oral PROTAC LRRK2 degraders to treat neurodegenerative diseases. Preclinical studies in mice demonstrated full target engagement of LRRK2 kinase inhibitor and near-complete LRRK2 degradation with PROTAC LRRK2 degraders, but substantially less Type II pneumocyte enlargement compared to an experimental LRRK2 kinase inhibitor. In addition, the more noticeable Type II pneumocyte enlargement phenotype observed with the experimental LRRK2 kinase inhibitor was substantiated by the accumulation of surfactant protein C in lung, which was not observed after treatment with a PROTAC LRRK2 degrader.

"Nonclinical findings presented this week suggest the potential for a wide therapeutic index and manageable safety profile for PROTAC degraders versus experimental LRRK2 kinase inhibitors," said Angela Cacace, Ph.D., Chief Scientific Officer at Arvinas. "In earlier preclinical studies, Arvinas’ PROTAC LRRK2 degraders have been shown to cross the blood-brain barrier and degrade LRRK2, a large multidomain scaffolding kinase, in deep brain regions."

Arvinas’ oral PROTAC BCL6 degrader ARV-393 is currently in a phase 1 clinical trial in patients with NHL, and Arvinas also has an oral PROTAC LRRK2 degrader, ARV-102, currently being investigated in a phase 1 clinical trial in healthy volunteers.

About ARV-393

ARV-393 is an investigational PROTAC designed to degrade B-cell lymphoma 6 protein (BCL6), a transcriptional repressor and major driver of B-cell lymphomas. The BCL6 protein facilitates B cell tolerance of rapid proliferation and somatic gene recombination via repressing cell cycle checkpoints, terminal differentiation, apoptosis, and the DNA damage response. PROTAC-mediated degradation has the potential to address the traditional undruggable nature of BCL6. ARV-393 is currently in a phase 1 clinical trial in patients with non-Hodgkin lymphoma.

About ARV-102

ARV-102 is an investigational PROTAC designed to degrade Leucine-rich repeat kinase 2 (LRRK2) which is a large multidomain scaffolding kinase. Human genetics, increased activity and expressions of LRRK2 is genetically involved in the pathogenesis of neurological diseases including Parkinson’s Disease and progressive supranuclear palsy. Arvinas is developing oral, blood-brain-barrier penetrant PROTAC degraders of LRRK2.

On June 21, 2024 Bristol Myers Squibb reported that the U.S. Food and Drug Administration (FDA) has granted accelerated approval for KRAZATI (adagrasib) in combination with cetuximab as a targeted treatment option for adult patients with KRASG12C -mutated locally advanced or metastatic colorectal cancer (CRC), as determined by an FDA-approved test, who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy (Press release, Bristol-Myers Squibb, JUN 21, 2024, View Source [SID1234644479]). This indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR) results. Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial.

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"CRC with a KRASG12C mutation occurs in approximately 3-4% of CRC patients and has historically been challenging to treat,"2 said Rona Yaeger, MD, Gastrointestinal Oncologist & Early Drug Development Specialist, Memorial Sloan Kettering Cancer Center. "The FDA approval of KRAZATI combined with cetuximab now provides a new treatment option to these patients when their tumors do not respond well to prior therapies."

The approval is based on results from cohorts of the Phase 1/2 KRYSTAL-1 open-label study which evaluated KRAZATI (600 mg tablets administered orally twice daily) in combination with cetuximab in 94 patients with heavily pretreated CRC harboring a KRASG12C mutation. The study met its primary endpoint, with a confirmed ORR of 34% (n=94, 95% CI: 25-45) for KRAZATI with cetuximab, all of which were partial responses. The median DOR, one of the secondary endpoints, was 5.8 months (95% CI: 4.2-7.6).1 Current late-line standard of care options result in limited response rates (ORR 1-6%) after progression on chemotherapy ± VEGF/VEGFR inhibitors.3,4

KRAZATI is associated with the following Warnings & Precautions: Gastrointestinal adverse reactions including diarrhea, nausea, and vomiting, QTc interval prolongation, hepatotoxicity, and interstitial lung disease (ILD)/pneumonitis.1 Please see Important Safety Information below.

"Today’s approval of KRAZATI in CRC is the second in the U.S. for this therapy and the first for BMS’ recently expanded oncology portfolio. This is an important milestone for BMS and the patients we serve as we deliver on our commitment to provide innovative medicines for cancer," said Wendy Short Bartie, senior vice president, U.S. Oncology and Hematology at Bristol Myers Squibb. "We are proud to make KRAZATI – the first KRASG12C inhibitor to be FDA approved beyond non-small cell lung cancer – available to CRC patients, and look forward to further evaluating KRAZATI through our ongoing development program."

In 2022, the FDA granted breakthrough therapy designation for KRAZATI in combination with cetuximab for patients with KRASG12C -mutated advanced CRC whose cancer has progressed following prior treatment with certain chemotherapy and an anti-VEGF therapy.

KRAZATI is an irreversible inhibitor of KRASG12C with a long half-life (23 hours), dose-dependent pharmacokinetics (PK), and central nervous system (CNS) penetration, which, in combination with cetuximab may enhance inhibition of KRAS-dependent signaling or overcome adaptive feedback.

The company partnered with QIAGEN to develop a tissue-based companion diagnostic (CDx) for KRAZATI that is now available.

KRAZATI is a registered trademark of Mirati Therapeutics, Inc., a Bristol Myers Squibb company.

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 colorectal cancer (CRC) that harbor a KRASG12C mutation. The primary endpoint for the Phase 2 cohort of the KRYSTAL-1 study was objective response rate (ORR). Secondary endpoints included duration of response (DOR).

The KRYSTAL-1 study was funded by Mirati Therapeutics, Inc., a Bristol Myers Squibb company.

Select Safety Profile from KRYSTAL-1

The safety profile for KRAZATI plus cetuximab was evaluated in patients with KRASG12C -mutated, locally advanced or metastatic CRC, and is consistent with previous reports and known safety profile of each drug individually. Serious adverse reactions occurred in 30% of 94 patients who received KRAZATI in combination with cetuximab. The most common adverse reactions (≥20%) were rash, nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, headache, dry skin, abdominal pain, decreased appetite, edema, anemia, dizziness, cough, constipation, and peripheral neuropathy.1

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.5 CRC is the third most commonly diagnosed cancer in the world.6 In 2024, it is estimated that there will be approximately 106,590 new cases of the disease in the U.S.; it is the second leading cause of cancer-related deaths in the U.S. among men and women combined.7

KRAS is the most frequently mutated oncogene in human cancer and is one that drives oncogenesis in up to 50% of patients with CRC.2 The KRASG12C mutation occurs in approximately 3-4% of CRC cases.2

About KRAZATI (adagrasib)

KRAZATI (adagrasib) is a highly selective and potent oral small-molecule inhibitor of KRASG12C that is optimized to sustain target inhibition, an attribute that could be important to treat KRASG12 C-mutated cancers, as the KRASG12C protein regenerates every 24-48 hours.8 KRASG12C mutations act as oncogenic drivers and occur in approximately 14% of non-small cell lung cancer (NSCLC; adenocarcinoma) and 3% of several other cancers.9,10

In 2022, KRAZATI was granted accelerated approval for treatment of adult patients with KRASG12C -mutated locally advanced or metastatic 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.

KRAZATI continues to be evaluated as a monotherapy and in combination with other anti-cancer therapies in patients with advanced KRASG12C -mutated solid tumors, including NSCLC and CRC.

Please see U.S. Full Prescribing Information for KRAZATI.

INDICATIONS

KRAZATI in combination with cetuximab is indicated for the treatment of adult patients with KRASG12C -mutated locally advanced or metastatic colorectal cancer (CRC), as determined by an FDA-approved test, who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

KRAZATI, as a single agent, is indicated for the treatment of adult patients with KRASG12C -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.

These indications are approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for these indications may be contingent upon verification and description of a clinical benefit in confirmatory trials.

IMPORTANT SAFETY INFORMATION

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Gastrointestinal Adverse Reactions

KRAZATI can cause severe gastrointestinal adverse reactions.
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 (eg, torsades de pointes) or sudden death.
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, particularly potassium and magnesium, 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 unable to avoid concomitant medications that are known to prolong the QT interval. Correct electrolyte abnormalities. Withhold, reduce the dose, or permanently discontinue KRAZATI, depending on severity.
Hepatotoxicity

KRAZATI can cause hepatotoxicity, which may lead to drug-induced liver injury and hepatitis.
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.
Monitor patients for new or worsening respiratory symptoms indicative of ILD/pneumonitis (eg, dyspnea, cough, fever) during treatment with KRAZATI. Withhold KRAZATI in patients with suspected ILD/pneumonitis and permanently discontinue KRAZATI if no other potential causes of ILD/pneumonitis are identified.
ADVERSE REACTIONS

Serious adverse reactions occurred in 57% of 116 patients who received adagrasib in NSCLC patients. The most common adverse reactions in NSCLC patients (≥20%) were diarrhea, nausea, fatigue, vomiting, musculoskeletal pain, hepatotoxicity, renal impairment, dyspnea, edema, decreased appetite, cough, pneumonia, dizziness, constipation, abdominal pain, and QTc interval prolongation.
Serious adverse reactions occurred in 30% of 94 patients who received adagrasib in combination with cetuximab. The most common adverse reactions in CRC patients (≥20%) were rash, nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, headache, dry skin, abdominal pain, decreased appetite, edema, anemia, dizziness, cough, constipation, and peripheral neuropathy.
DRUG INTERACTIONS

Strong CYP3A4 Inducers: Avoid concomitant use.
Strong CYP3A4 Inhibitors: Avoid concomitant use until adagrasib concentrations have reached steady state (after ~8 days).
Sensitive CYP3A4 Substrates: Avoid concomitant use with sensitive CYP3A4 substrates.
Sensitive CYP2C9 or CYP2D6 Substrates or P-gp Substrates: Avoid concomitant use with sensitive CYP2C9 or CYP2D6 substrates or P-gp substrates where minimal concentration changes may lead to serious adverse reactions.
Drugs That Prolong QT Interval: Avoid concomitant use with KRAZATI.
Please see Drug Interactions Section of the Full Prescribing Information for additional information.

USE IN SPECIFIC POPULATIONS

Females and Males of Reproductive Potential

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

Advise not to breastfeed.
Please see U.S. Full Prescribing Information for KRAZATI

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.

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