Sotorasib

SAN DIEGO — In early cuts of data, the next iteration of KRAS drugs for lung cancer appears to bear more promise than the first. KRAS mutations drive around a quarter of all cancer cases and had been an elusive target until recently. The first two KRAS agents — Bristol Myers Squibb’s Krazati and Amgen’s Lumakras — were developed for one mutation called G12C that makes up roughly 1 in 8 non-small cell lung cancer cases. They represented a scientific breakthrough but ultimately elicited marginal benefit in lung cancer. A bevy of drugmakers now hope to outdo those agents or capitalize on other KRAS mutations in lung cancer. Among them, Revolution Medicines, high off a stunning Phase 3 readout in pancreatic cancer, and D3 Bio reported findings from early-stage studies on their targeted drugs for certain lung cancer patients on Sunday at the annual American Association for Cancer Research meeting in San Diego. City of Hope lung cancer physician-scientist Christine Lovly called the first iteration of KRAS G12C agents “a monumental leap forward.” But “nobody ever thought that these would be the only drugs that we have,” she said. Shanghai-based D3 Bio is calling its drug elisrasib a next-generation option for non-small cell lung cancer patients with G12C mutations. In a Phase 1/2 study for previously-treated advanced lung cancer patients, D3 Bio tested its treatment both in patients who had tried a different KRAS G12C inhibitor and those who had not. Among the 84 patients who hadn’t previously received a KRAS G12C inhibitor, 58.8% of patients responded to a 600 mg dose of the treatment. In these patients, the therapy staved off cancer progression for about a year, with a median duration of response of 16.5 months. Meanwhile, in 31 patients who had received a previous KRAS G12C agent, the drug still elicited responses in roughly a third of patients, with a median progression-free survival of 8.1 months. Overall survival data were not mature for either group of patients. Researchers from the multi-country trial reported that grade 3 treatment-related adverse events occurred in 11.5% of patients. Presenter Byoung Chul Cho of Yonsei University called the safety profile of the drug favorable, but discussant Adrian Sacher of UHN Princess Margaret Cancer Centre in Toronto pointed to some cases of elevated liver enzymes in the study, which could signal liver toxicities. D3 Bio in December announced a $108 million raise to fund Phase 3 trials for elisrasib, but the company has yet to share additional details on its plans. Others, including RevMed and BridgeBio Oncology Therapeutics, are likewise developing G12C agents. “This is a very crowded field,” said Lovly. “It’s going to come down to combinability.” RevMed on Sunday shared new data on zoldonrasib, which is the next-furthest along asset in its pipeline after the ‘pan-RAS’ drug daraxonrasib that was part of the company’s buzzy Phase 3 pancreatic cancer readout. Zoldonrasib targets KRAS G12D, which is present in roughly 5% of lung cancer patients. The drugmaker reported that among 27 patients with previously treated lung cancer, 14 saw their tumors shrink substantially — good for a 52% response rate. The drug helped stave off cancer progression for a median of 11.1 months in these patients, and 73% of patients were still alive at one year. The most common adverse events included nausea, vomiting, diarrhea and rash, most of which were considered mild-to-moderate. Dose interruptions from adverse events occurred in 15% of patients, while 5% discontinued treatment. RevMed’s chief development officer Alan Sandler called the company’s second-line pancreatic cancer data a “watershed moment” that helped validate its pipeline, and said the zoldonrasib data built on that. “We’re not done,” he said. RevMed said in February that it plans to start a Phase 3 trial called RASolve 308 in the first half of 2026 to study a zoldonrasib combination for first-line patients with metastatic KRAS G12D-mutated lung cancer. It’s also studying daraxonrasib in second- and third-line lung cancers as part of a registrational trial called RASolve 301 that’s expected to be completed at the end of 2027. When asked about the overlap across indications with its experimental drugs, Sandler said, “It’s a wonderful dilemma.” “We don’t know which is going to be best in which setting, but we know that all of them have the opportunity for success,” he said, noting that the company is not only testing its agents individually and in combination with chemotherapy, but also in combination with each other. Meanwhile, Astellas last month shared results on a KRAS G12D protein degrader, which is the first of its kind. RevMed reported last week that daraxonrasib doubled survival time in patients with second-line pancreatic cancer, marking a breakthrough for the deadly cancer. On Tuesday, the company will also share highly anticipated updated results of daraxonrasib in first-line pancreatic cancer.

Kestrel Therapeutics, a Massachusetts-based biotechnology company, has opened a first-in-human Phase I clinical trial for KST-6051, an oral small-molecule inhibitor designed to block mutant KRAS across multiple oncogenic alleles. The study targets adults with advanced or metastatic KRAS-mutant solid tumors — primarily non-small cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC), and colorectal cancer (CRC) — and positions KST-6051 as a potential pan-KRAS agent at a moment when the field is moving beyond the allele-specific inhibitors that defined the first generation of direct KRAS-targeted therapy. The open-label, multicenter, sequential dose-escalation study (NCT07458347) plans to enroll up to 145 participants across four US sites, including Moffitt Cancer Center in Tampa and NEXT Oncology in San Antonio. Primary completion is expected in Q2 2027, with full study completion projected for Q2 2028. Primary endpoints center on safety and tolerability — specifically the incidence of treatment-related adverse events, treatment-emergent adverse events, and dose-limiting toxicities during the first 21-day cycle. Secondary endpoints include objective response rate, progression-free survival, disease control rate, duration of response, and pharmacokinetic parameters measured through week six. One key eligibility criterion distinguishes this population from trials of approved KRAS inhibitors: participants must not have received prior RAS or KRAS inhibitor therapy, potentially positioning KST-6051 as a first-line molecularly targeted option rather than a salvage strategy. KRAS mutations drive oncogenic signaling in roughly 25% of all human cancers, with the highest prevalence in PDAC (approximately 90%), CRC (approximately 40%–45%), and NSCLC (approximately 25%–30%). For decades, KRAS was considered pharmacologically intractable because its GTP-binding site offered no obvious drug-binding pocket and because the protein cycles rapidly between active and inactive states. The identification of the Switch-II pocket (SIIP) — a cryptic allosteric site that becomes accessible during conformational transitions — changed that calculus. Sotorasib and adagrasib, both FDA-approved for KRAS G12C-mutant NSCLC, exploit this pocket through covalent chemistry that traps the GDP-bound, inactive form of the protein. That approach is inherently allele-specific: the covalent warhead requires the unique cysteine introduced by the G12C substitution, and it is inactive against the GTP-loaded, signaling-competent state of KRAS. KST-6051 appears to have been designed to address both constraints. According to available source material, the compound binds the Switch-II pocket through non-covalent interactions and retains activity against KRAS in both its GDP-bound (OFF) and GTP-bound (ON) conformational states. That dual-state activity, if confirmed in humans, would represent a mechanistic departure from the approved agents: rather than trapping a single inactive conformation, KST-6051 would need to compete with intracellular GTP concentrations to suppress the active form — a pharmacological challenge that has driven much of the chemistry innovation in the pan-KRAS field. The trial’s condition keywords explicitly include “Pan KRAS,” and the eligibility criteria require only a documented KRAS mutation of any type, confirming the mutation-agnostic enrollment strategy. KST-6051 originates from a preclinical RAS program acquired from Anchiano Therapeutics, which Kestrel subsequently advanced through IND-enabling development. The pan-KRAS space has attracted several other entrants. Eli Lilly’s LY4066434, explicitly designated a pan-KRAS inhibitor in its trial title, is currently in a Phase I study (NCT06607185) in KRAS-mutant NSCLC, PDAC, and CRC that is listed as active but no longer recruiting. Treeline Biosciences’ TLN-372 is in a recruiting Phase I study (NCT07204340) in advanced KRAS-mutant solid tumors that also includes combination arms with cetuximab and pembrolizumab. What distinguishes KST-6051 from the approved G12C-selective covalent inhibitors — its claimed activity against the GTP-bound state — is a property it shares with other next-generation candidates in this cohort, but one that remains to be validated in human pharmacodynamic studies. Meta description: Kestrel Therapeutics opens first-in-human Phase I trial of pan-KRAS inhibitor KST-6051 in KRAS-mutant solid tumors. Your email address will not be published. Required fields are marked * Comment * Name * Email * Website