Sotorasib

Combining Amgen's KRAS G12C inhibitor Lumakras (sotorasib) with the EGFR antibody Vectibix (panitumumab) showed a promising overall survival (OS) trend in patients with chemorefractory metastatic colorectal cancer (mCRC) harbouring the KRAS G12C mutation, according to data from the CodeBreaK 300 trial presented Monday at the American Society of Clinical Oncology (ASCO) annual meeting.The late-breaking presentation provided the final OS analysis from the Phase III study, which had previously met its primary endpoint of improved progression-free survival (PFS) at both tested doses of Lumakras compared to investigator's choice of therapy. Those PFS results were reported last December at the European Society for Medical Oncology (ESMO) conference.The study included 160 patients randomly assigned to receive Lumakras at doses of either 960mg or 240mg together with Vectibix, or investigator's choice of treatment consisting of either trifluridine/tipiracil or Bayer's Stivarga (regorafenib).Trial not powered to show OS benefitIn the ASCO update, researchers reported that 82 deaths had occurred as of the December 18 cut-off, after a median follow-up of 13.6 months; 24 were in the higher-dose Lumakras group, 28 in the lower-dose group, and 30 in the investigator's choice arm.Median OS was not reached with Lumakras 960mg and was 11.9 months for the 240mg dose and 10.3 months for those who received investigator's choice of therapy. The hazard ratios for OS favoured the Lumakras combinations, with a HR of 0.70 for the 960mg dose and 0.83 for the 240mg dose, both in comparison to investigator's choice."While CodeBreaK 300 was not powered to detect a statistically significant difference in OS, the study showed a trend toward improved OS" for patients randomised to the higher dose of Lumakras plus Vectibix, researchers concluded.Other key efficacy data showed a 30.2% objective response rate (ORR) for the higher Lumakras dose combination, including one complete response (CR) and 15 partial responses (PRs). The median duration of response was 10.1 months in this arm. The disease control rate was also highest at 71.7% with the 960mg combination. There was 1 CR and 3 PRs at the lower dose, and 1 PR for investigator's choice.Criticism of higher doseAmgen is testing the lower 240mg dose of Lumakras once daily due to the drug's non-linear pharmacokinetic properties. However, the company's decision to maintain the higher 960mg dose in its approved labeling has drawn criticism from US Senator Richard Durbin, who accused Amgen of "putting profits before patients" and disregarding concerns over harsh side effects.Lumakras won accelerated approval from the FDA in 2021 for KRAS-mutated non-small-cell lung cancer (NSCLC), although the agency recently rejected Amgen's bid for full approval. In response to Durbin's criticism last month, the company stated that "based on data from several clinical trials across numerous cancer types, as well as real-world evidence, we are confident that patients with lung cancer are benefiting from the once-daily 960mg dose of Lumakras."

Given the lack of overall survival data and a debatable meaningfulness in its progression-free survival result, Bristol Myers Squibb could have a hard time convincing the FDA to grant Krazati a full approval. After Amgen’s KRAS confirmatory trial results were rejected by the FDA as uninterpretable, Bristol Myers Squibb has divulged details of its rival study. While Bristol Myers says the study doesn't share the same design problems as Amgen's program, the results still leave open questions about Krazati's regulatory outlook. BMS’ Krazati significantly improved the risk of tumor progression or death by 42% compared with the chemotherapy docetaxel in patients with previously treated KRAS G12C-mutated non-small cell lung cancer (NSCLC), according to results from the phase 3 KRYSTAL-12 trial presented at the American Society of Clinical Oncology annual meeting in Chicago. Despite the large magnitude of risk reduction meeting the study’s primary endpoint, Krazati only added 1.65 months of progression-free survival (PFS) time on top of docetaxel, reaching 5.49 months at median. The small effect size in median PFS could make it difficult for the drugmaker to win over the FDA. Previously, during a 2019 meeting the FDA conducted with Amgen about the phase 3 trial design for the KRAS inhibitor Lumakras, the agency expressed concerns that the proposed study’s targeted 3.2-month difference in median PFS would not be considered clinically meaningful, an FDA document has shown. But BMS’ Chief Medical Officer Samit Hirawat, M.D., argued that the median only represents a singular data point and should be interpreted in the context of the entire range of PFS results. In KRYSTAL-12, patients in the Krazati arm experienced a PFS range between 4.5 months and 6.7 months, versus a range of 2.7 months to 4.7 months for those in the control group. “So, the upper bound of the docetaxel range is the lower bound of the [Krazati] range,” Hirawat said in an interview with Fierce Pharma. “And it’s important that we have to think about from a patient’s perspective: Would you rather have your disease controlled for two and a half months? Or would you like to take a chance to six and a half?” During that 2019 meeting Amgen had with the FDA, the agency “advised that in order to potentially support a marketing application based on an improvement in PFS, the magnitude of effect on PFS would need to be considered clinically meaningful or be supported by a statistically significant difference in [overall survival],” the FDA document shows. So far, KRYSTAL-12 hasn’t accrued enough deaths for an overall survival analysis, and BMS remained blinded on that endpoint, Hirawit said.  KRYSTAL-12 is serving as the confirmatory trial for Krazati’s accelerated approval in second-line KRAS G12C-mutated NSCLC. In December 2023, the FDA refused to convert Lumakras’ accelerated approval into a full nod for Amgen after raising several issues with that drug’s phase 3 confirmatory trial, dubbed CodeBreaK 200. In the Amgen trial, significantly more patients who were enrolled in the control arm versus the Lumakras arm dropped out. Plus, doctors were found to be more likely to call early progression for the chemotherapy group before a blinded central review of tumor progression, so that the patients could cross over to receive the KRAS inhibitor. Because the trial was open label, patients and doctors knew what drug they were getting. The BMS trial, which is also open label, uses a blinded independent central review to determine progression before allowing crossovers. By investigators’ analysis, Krazati led to a similar 43% improvement in PFS. The discontinuation rate due to adverse events was 13% for Krazati and 18% for chemo, according to Hirawat. In terms of safety, liver toxicity has been a key area of focus in the KRAS space. In KRYSTAL-12, the majority of liver-related treatment-related adverse events were grade 1 and manageable with known protocols, a BMS spokesperson told Fierce Pharma. Although the FDA denied Lumakras a full approval, the agency for now has agreed to let the first-in-class KRAS inhibitor stay on the market while Amgen runs another confirmatory study. That work is expected to be completed no later than February of 2028. Given the lack of overall survival data and the debatable meaningfulness of the PFS result, the FDA might do the same for Krazati should BMS file for full approval based on the current data. Hirawat declined to comment on BMS’ regulatory strategy but pointed to PFS as an acceptable regulatory endpoint, adding that the company will engage with drug authorities about potential filings, Hirawat said. The company got its hands on Krazati from the up to $5.8 billion acquisition of Mirati Therapeutics. Part of the company's strategy for the deal was to grow the reach of the medicine. A phase 3 study is testing Krazati in combination with Merck & Co.’s Keytruda in first-line KRAS G12C-mutated NSCLC with high PD-L1 expression as measured by a TPS score of at least 50%. BMS will initiate another first-line phase 3 trial to combine Krazati with Keytruda and chemotherapy in patients with TPS scores below 50%, including those with PD-L1-negative tumors, Hirawat said. The exact trial design has yet to be confirmed, but BMS expects to announce the details later this year for a potential initiation this year or early next.