KRAS G12C mutation Solid 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.

Data demonstrated promising monotherapy activity with olomorasib across a range of KRAS G12C-mutant solid tumors, including non-small cell lung cancer, and a tolerability profile in combination with pembrolizumab that is well-suited to first-line lung cancer development INDIANAPOLIS, June 1, 2024 /PRNewswire/ -- Eli Lilly and Company (NYSE: LLY) today announced updated data from the Phase 1/2 clinical trial evaluating olomorasib as a monotherapy in patients with KRAS G12C-mutant advanced solid tumors and in combination with Merck's anti-PD-1 therapy KEYTRUDA® (pembrolizumab) in patients with KRAS G12C-mutant advanced non-small cell lung cancer (NSCLC). Olomorasib is an investigational, oral, potent, and highly selective second-generation inhibitor of the KRAS G12C protein. These data will be shared in oral presentations at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting. "Despite recent advances, there remains a significant unmet need for patients with KRAS G12C-mutant cancers," said Timothy Burns, M.D., Ph.D., Associate Professor of Medicine, University of Pittsburgh Medical Center Hillman Cancer Center. "These data show efficacy with olomorasib across tumor types and, importantly, tolerability that suggests it can be combined with immunotherapy, the backbone of first-line treatment for KRAS-mutant NSCLC. In NSCLC, it is also exciting to see promising activity in patients previously treated with a KRAS G12C inhibitor as well as central nervous system (CNS) activity, consistent with the improved potency of this second generation KRAS G12C inhibitor. Collectively, these data point to a promising emerging profile for olomorasib, particularly in NSCLC where new options are needed to improve outcomes for patients." "As a second generation KRAS G12C inhibitor, olomorasib was specifically designed to offer a differentiated profile that could potentially overcome limitations of currently available treatment options," said David Hyman, M.D., chief medical officer, Lilly. "With these updated data, we are pleased to see our thesis for olomorasib continuing to translate clinically. Through our SUNRAY-01 study, we look forward to further investigating the potential of olomorasib in combination with pembrolizumab-containing regimens in first-line NSCLC, where there remains great need to further impact the disease trajectory for patients with KRAS G12C-mutant lung cancers." Data from the LOXO-RAS-20001 Phase 1/2 Study Results presented at ASCO utilized a cutoff date of March 18, 2024. Efficacy results are based on investigator response assessments, and objective response rates (ORR) include responses that are confirmed, as well as those pending confirmation and ongoing. Olomorasib as Monotherapy in KRAS G12C-Mutant Advanced Solid Tumors An oral presentation (abstract #3007) detailed updated data for olomorasib monotherapy in patients with KRAS G12C-mutant advanced solid tumors. This dataset consisted of 184 patients, including 42 with NSCLC naïve to a KRAS G12C inhibitor (six with active brain metastases), 41 with NSCLC who had received a prior KRAS G12C inhibitor, 32 with colorectal cancer (CRC), 24 with pancreatic cancer, and 45 with other solid tumors. Patients had received a median of three prior lines of therapy (range 0-11). Efficacy for olomorasib monotherapy was consistent across a range of solid tumors with an ORR of 35% (37/105) in patients with non-CRC solid tumors. Median progression free survival (PFS) in all patients with KRAS G12C inhibitor-naive non-CRC solid tumors was 7.1 months (95% CI: 5.5-8.9) and 7.9 months (95% CI: 4.1-NE) in patients with KRAS G12C inhibitor-naive NSCLC. In patients with NSCLC previously treated with a KRAS G12C inhibitor, the ORR was 41% (16/39), with 63% having received a KRAS G12C inhibitor as their immediate prior therapy, and median PFS was 8.1 months (95% CI: 5.6-15.6). Preliminary CNS activity was seen, with CNS responses observed in patients with NSCLC and measurable brain metastases. Patients were on treatment for a median of 4.7 months and treatment-related adverse events (TRAEs) were predominantly grade 1 with only diarrhea seen in greater than 15% of patients. The most common TRAEs of any grade were diarrhea (23%), nausea (11%), and fatigue (10%). The safety profile for patients who discontinued a prior KRAS G12C inhibitor due to toxicity was similar to all patients treated with olomorasib monotherapy including patients who discontinued their previous first KRAS G12C inhibitor due to toxicity. TRAEs led to discontinuation of olomorasib in 1% of patients. Olomorasib in Combination with Pembrolizumab in KRAS G12C-Mutant Advanced NSCLC An oral presentation (abstract #8510) detailed updated data for olomorasib in combination with pembrolizumab in patients with KRAS G12C-mutant advanced NSCLC, studying the two doses (50mg and 100mg BID) under ongoing investigation in first-line NSCLC. This dataset consisted of 64 patients, including patients with first-line metastatic disease and those previously treated (prior KRAS G12C inhibitor, chemotherapy, and/or immunotherapy). Patients received a median of two prior lines of therapy (range: 0-8). In patients with first-line metastatic NSCLC, across a range of PD-L1 levels, the ORR for olomorasib in combination with pembrolizumab was 77% (13/17) and median PFS was not reached with follow-up ongoing. The most common TRAEs of any grade were diarrhea (23%), increased ALT (20%), pruritus (19%), increased AST (16%), and fatigue (16%). TRAEs led to discontinuation of olomorasib only in 3% of patients (2/64), pembrolizumab only in 11% of patients (7/64) and both drugs in 5% of patients (3/64). The SUNRAY-01 trial (NCT06119581), a global, registrational study investigating olomorasib in combination with pembrolizumab or pembrolizumab plus chemotherapy in first-line NSCLC, is currently enrolling. KEYTRUDA® is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. About the LOXO-RAS-20001 Study LOXO-RAS-20001 is an open-label, multicenter, Phase 1/2 study evaluating the safety, tolerability and preliminary efficacy of olomorasib in patients with KRAS G12C-mutant advanced solid tumors (NCT04956640). The study includes a Phase 1a dose escalation phase of olomorasib monotherapy in KRAS G12C-mutant solid tumors and a Phase 1b dose expansion and optimization phase which are evaluating olomorasib as a monotherapy and in combination with other treatments. About Olomorasib Olomorasib (LY3537982) is an investigational, oral, potent, and highly selective second-generation inhibitor of the KRAS G12C protein. KRAS is the most common oncogene across all tumor types, and KRAS G12C mutations occur in 13% of patients with non-small cell lung cancer (NSCLC) and 1-3% of patients with other solid tumors.1,2 Olomorasib was specifically designed to target KRAS G12C mutations and has pharmacokinetic properties which allow for high predicted target occupancy and high potency when used as monotherapy or in combination.3 Olomorasib is currently being studied in the LOXO-RAS-20001 Phase 1/2 trial (NCT04956640) in patients with KRAS G12C-mutant NSCLC and other advanced solid tumors and in the pivotal, registrational SUNRAY-01 global study (NCT06119581) investigating olomorasib in combination with pembrolizumab with or without chemotherapy for first-line treatment of KRAS G12C-mutant advanced NSCLC. For additional information about olomorasib clinical trials, please refer to clinicaltrials.gov. About Lilly Lilly is a medicine company turning science into healing to make life better for people around the world. We've been pioneering life-changing discoveries for nearly 150 years, and today our medicines help more than 51 million people across the globe. Harnessing the power of biotechnology, chemistry and genetic medicine, our scientists are urgently advancing new discoveries to solve some of the world's most significant health challenges: redefining diabetes care; treating obesity and curtailing its most devastating long-term effects; advancing the fight against Alzheimer's disease; providing solutions to some of the most debilitating immune system disorders; and transforming the most difficult-to-treat cancers into manageable diseases. With each step toward a healthier world, we're motivated by one thing: making life better for millions more people. That includes delivering innovative clinical trials that reflect the diversity of our world and working to ensure our medicines are accessible and affordable. To learn more, visit Lilly.com and Lilly.com/news, or follow us on Facebook, Instagram and LinkedIn. P-LLY © Lilly USA, LLC 2024. ALL RIGHTS RESERVED. Cautionary Statement Regarding Forward-Looking Statements This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about olomorasib as a potential treatment for people with certain KRAS G12C-mutant advanced solid tumors and reflects Lilly's current beliefs and expectations. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of drug research, development, and commercialization. Among other things, there is no guarantee that planned or ongoing studies will be completed as planned that future study results will be consistent with study results to date, that olomorasib will prove to be a safe and effective treatment for people with certain KRAS G12C-mutant advanced solid tumors, that olomorasib receive regulatory approval, or that Lilly will execute its strategy as expected. For further discussion of these and other risks and uncertainties that could cause actual results to differ from Lilly's expectations, see Lilly's Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release. 1 Canon J. et al. Nature 2019, 575, 217-223 2 Salem M. et al. Ann Oncol 2021, 32 (3 Suppl): S218 3 Peng S-B, Si C, Zhang Y, et al. Abstract 1259: Preclinical characterization of Ly3537982, a novel, highly selective and potent KRAS-G12C inhibitor. Cancer Research. 2021;81(13_Supplement):1259-1259. doi:10.1158/1538-7445.am2021-1259 SOURCE Eli Lilly and Company

Novartis has decided to discontinue development of its experimental KRAS G12C inhibitor opnurasib (JDQ443) across all studies following a strategic review, including halting the Phase III KontRASt-02 trial evaluating the drug in non-small-cell lung cancer (NSCLC)."This decision was made in light of the increasing options available to patients with KRAS G12C-driven cancers," Novartis told FirstWord in a statement. "It was not driven by clinical data and no new safety signals have been observed." The company added that it is continuing to "[explore] multiple modalities in our early pipeline" to treat lung cancer.The KontRASt-02 trial, which started in 2022, was comparing JDQ443 monotherapy to docetaxel chemotherapy in an estimated 360 previously treated patients with locally advanced or metastatic KRAS G12C-mutant NSCLC. It was expected to complete in 2025.Earlier-stage results for JDQ443 unveiled in 2022 had shown a remission rate of 57% at the recommended dose of 200mg twice daily. At the time, Novartis said the Phase Ib/II KontRASt-01 data pointed to "high systemic exposure" and a "favourable" safety profile at this dose.Another study that got underway last month, dubbed STRIDER, was evaluating the intracranial efficacy of JDQ443 in NSCLC patients with KRAS G12C mutations and asymptomatic, untreated or treated brain metastases.If it had reached the market, JDQ443 would have had to compete against two commercial KRAS inhibitors – Amgen's Lumakras/Lumykras (sotorasib) and Bristol Myers Squibb's Krazati (adagrasib). Other KRAS contenders in development include Eli Lilly's second-generation KRAS inhibitor olomorasib (LY3537982), currently in Phase III for NSCLC, and Roche's Phase I asset divarasib (GDC-6036) in testing for solid tumours.For related analysis, see KOL Views Q&A: LY3537982's safety profile may be make or break for Eli Lilly in oral KRAS tussle.