KRAS G12C mutation positive tumors

Roche is set to initiate the Phase III KRASCENDO 1 trial later this month, pitting its KRAS-blocking drug divarasib (GDC-6036) against established competitors in second-line non-small-cell lung cancer (NSCLC). The head-to-head study, recently posted on ClinicalTrials.gov, marks a bold move by Roche as it looks to set its treatment apart in the increasingly competitive KRAS inhibitor landscape.The trial gets under way this month and aims to enroll 320 participants with KRAS G12C-positive advanced or metastatic NSCLC who have received at least one prior systemic therapy, but no more than three in the metastatic setting. Patients will be randomised to receive oral divarasib once daily, Amgen's Lumakras (sotorasib) once daily or Bristol Myers Squibb's Krazati (adagrasib) twice a day.The primary endpoint compares progression-free survival (PFS) between divarasib and either of the two other drugs. Key secondary goals include overall survival, objective response rate and duration of response, among others. The study is expected to reach primary completion around mid-2026, with full completion anticipated by mid-2028.Promising early dataThe head-to-head trial follows early-stage data for divarasib presented last year. Results published in the NEJM from a Phase I study showed durable clinical responses across various KRAS G12C-positive tumours. In NSCLC patients, divarasib demonstrated a 53.4% confirmed response rate and a median PFS of 13.1 months. The drug's safety profile appeared manageable, with mostly low-grade adverse events reported.Lumakras received accelerated FDA approval in 2021 for second-line KRAS G12C-mutated NSCLC based on response rate data. However, despite achieving top-line success, subsequent PFS results fell short of expectations, showing only a five-week improvement over chemotherapy. The slim benefit prompted US regulators to issue Amgen a complete response letter requesting an additional confirmatory study to support conversion to full approval.Meanwhile, Krazati secured its own accelerated FDA nod for second-line KRAS-mutated NSCLC in late 2022, also based on response rate data. The drug met its primary endpoint in the confirmatory KRYSTAL-12 trial, but detailed results presented at this year's ASCO annual meeting showed a benefit of less than 1.7 months compared to docetaxel. For more, see – BMS's Krazati adds another underwhelming KRAS datapoint.Crowding fieldThe pending start of KRASCENDO 1 comes as Novartis recently announced the discontinuation of its KRAS G12C inhibitor programme. In May, the company said it halted development of opnurasib (JDQ443) across all studies, including the Phase III KontRASt-02 trial in NSCLC, citing "increasing options available to patients with KRAS G12C-driven cancers."Other KRAS contenders in development include Eli Lilly's second-generation KRAS inhibitor olomorasib (LY3537982), currently in the Phase III SUNRAY-01 study for untreated advanced NSCLC, as well as Merck & Co.'s MK-1084, which is in Phase III testing in combination with Keytruda (pembrolizumab), also as a first-line NSCLC treatment.

Krazati came to Bristol Myers Squibb as part of the New Jersey pharma's recent acquisition of Mirati Therapeutics. Bristol Myers Squibb looks on track to overtake Amgen as the KRAS leader in lung cancer after following up its rival’s FDA setback with a positive confirmatory trial readout. BMS’ Krazati significantly reduced the risk of tumor progression or death compared with chemotherapy in patients with pretreated KRAS G12C-mutated non-small cell lung cancer (NSCLC), the company said Thursday. The KRAS inhibitor came to the New Jersey pharma as part of its recent acquisition of Mirati Therapeutics. The assessment was made by a blinded central review committee of the pivotal phase 3 KRYSTAL-12 study, which serves as the confirmatory trial for Krazati’s accelerated approval as a second-line therapy. BMS said it’s finishing a full evaluation of the data and will share results with regulators. Besides declaring that the trial met its primary endpoint of progression-free survival, the independent data reviewers noted that Krazati was better than chemo at shrinking tumors, which was one of the trial’s secondary endpoints. The improvements on both endpoints were statistically significant and clinically meaningful, according to BMS. The trial remains ongoing to evaluate whether Krazati can extend patients’ lives. BMS didn’t specify which direction Krazati’s survival outcomes are trending right now. Progression-free survival has typically been an approval-worthy endpoint in second-line NSCLC, unless there’s a negative trend in overall survival. As for Amgen, the California drugmaker recently applied for full approval of its first-to-market KRAS inhibitor, Lumakras, based on progression-free survival data from the phase 3 CodeBreaK 200 trial. The study would have served its purpose had it been done properly. But the FDA figured its results couldn’t be reliably interpreted, and a group of external advisers agreed. The agency and its advisory committee experts voiced concerns about disproportionate patient dropout rates between the two trial arms in Lumakras’ CodeBreaK 200 study as well as a bias for investigators to be more likely to call tumor progression early for patients on chemo so that they could cross over to receive Lumakras. Both problems were chalked up to the enthusiasm around Lumakras as the first FDA-approved KRAS inhibitor. By comparison, Krazati’s KRYSTAL-12 requires confirmation from a blinded central review to determine tumor progression before crossover. Despite the compromised trial results, the FDA has let Lumakras stay on the market while Amgen runs another confirmatory trial to be completed no later than February 2028. The recently launched phase 3 CodeBreaK 202 trial is comparing Lumakras against Merck’s Keytruda in their respective combinations with chemotherapy for patients with newly diagnosed, advanced, PD-L1-negative, KRAS G12C-positive nonsquamous NSCLC. Lumakras’ setback gives Krazati an opportunity to catch up. Before the BMS buyout, Krazati in the third quarter posted $16.4 million in sales, coming in below analysts’ expectations. Lumakras generated $52 million sales during the same period. BMS' Krazati also appears to hold more potential in the first-line setting. While Amgen was forced to combine Lumakras with chemo alone, a better liver toxicity profile has allowed BMS to pair Krazati with drugs in the PD-1 inhibitor class. A phase 3 trial is testing the Krazati-Keytruda combo in first-line KRAS G12C-mutated PD-L1-high NSCLC. And the company expects phase 2 results this year to guide its development path in PD-L1-low disease. Both BMS and Amgen are also gunning for approvals in colorectal cancer, which is a smaller market than NSCLC. Amgen recently reported that Lumakras, at its currently approved 960-mg dose and used in combination with Vectibix, extended the median progression-free survival to 5.6 months versus 2.2 months for standard treatments in patients with chemo-refractory KRAS G12C colorectal cancer. The result came from the phase 3 CodeBreaK 300 trial. A regulatory submission based on the study was planned in the first half of 2024, Amgen said during its fourth-quarter report. The company recently also launched a phase 3 trial for Lumakras in combination with Vectibix and chemo in first-line colorectal cancer. For its part, BMS has the phase 3 KRYSTAL-10 study for Krazati and Eli Lilly’s Erbitux in second-line colorectal cancer, with a readout expected this year.

BOSTON and SOUTH SAN FRANCISCO, Calif., March 06, 2024 (GLOBE NEWSWIRE) -- Frontier Medicines Corporation, a clinical stage precision medicine company seeking to unlock the proteome to advance transformational therapies against otherwise undruggable disease-causing targets, today announced new preclinical data for FMC-376, a first-in-class direct dual inhibitor of ON+OFF KRASG12C currently being explored in a Phase 1/2 trial, will be shared at the upcoming American Association for Cancer Research (AACR) Annual Meeting 2024. Presentation details: Title: FMC-376 a dual inhibitor of ON and OFF states of KRASG12C is broadly active in PDX models of resistanceAbstract Number: 5948Poster Session Title: Novel Antitumor Agents 4Session Date and Time: Tuesday, April 9, 2024, 1:30-5 p.m. PT Title: The clinical dual KRASG12C inhibitor FMC-376 has demonstrated potential as both a monotherapy and in combination for the treatment of patients with KRASG12C mutation positive NSCLCAbstract Number: 5949Poster Session Title: Novel Antitumor Agents 4Session Date and Time: Tuesday, April 9, 2024, 1:30-5 p.m. PT About FMC-376FMC-376 was discovered by applying the Frontier™ Platform to directly engage both ON+OFF KRASG12C with exquisite selectivity. The differentiated dual direct mechanism of action of FMC-376 offers the potential to overcome the lack of response and resistance seen with current KRASG12C single-acting treatments. FMC-376 is currently being evaluated in the Phase 1/2 PROSPER clinical trial (NCT 06244771), an open-label, multi-center dose escalation and expansion study designed to evaluate the safety, tolerability, pharmacokinetics and efficacy of FMC-376 in participants with locally advanced unresectable or metastatic solid tumors which harbor the KRASG12C mutation. For more information on the PROSPER trial, please visit clinicaltrials.gov. About Frontier MedicinesFrontier Medicines is a clinical stage precision medicine company pioneering groundbreaking medicines to transform treatment for genetically-defined patient populations, starting with oncology and immunology. Our proprietary chemoproteomics powered drug discovery engine, the Frontier™ Platform, leverages covalent chemistry and machine learning to unlock hard-to-treat disease causing proteins for drug development. Today, we are advancing a diversified pipeline of wholly-owned precision medicines against the most important drivers of cancer and high-value immunology programs. Our lead candidate, FMC-376, is a dual inhibitor of ON+OFF KRASG12C. FMC-376 is a potential best-in-class therapy designed to completely block both forms of the KRAS mutation to overcome the lack of response and resistance seen with single-acting KRASG12C inhibitors. For more information, please visit www.frontiermeds.com. Follow Frontier on LinkedIn.