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Amgen's Sotorasib Phase I Trial Results Bolster Hopes in Quest to Target KRAS Mutations

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NEW YORK – Investigators shared new data on Sunday from a Phase I clinical trial in which Amgen's experimental KRAS G12c inhibitor sotorasib showed notable anti-cancer activity in patients with heavily pretreated KRAS-mutant advanced solid tumors, especially lung and colorectal cancers.

At the European Society for Medical Oncology's Virtual Congress, researchers discussed a subset of results in non-small cell lung cancers, while the full study was published simultaneously in the New England Journal of Medicine. According to the authors, the median progression-free survival for the most responsive cancer subgroups in the trial, called CodeBreaK100, was significantly longer than what would be expected for the same types of patients receiving standard-of-care treatment.

The ESMO meeting featured new data on a variety of drugs being investigated as treatments for patients with KRAS mutations, as well as genomic analyses exploring the potential role KRAS targeting plays across cancer types, but Amgen's sotorasib trial represents the most advanced data so far on a therapeutic in this class.

David Hong, deputy chair of the department of investigational cancer therapeutics at MD Anderson Cancer Center, reported during a presentation that Amgen's compound showed a very favorable safety profile, which was what investigators were primarily interested in exploring in the Phase I trial. In lung cancer, he and his colleagues also observed durable disease control across a heavily pretreated cohort and consistent activity regardless of KRAS mutant allele frequency or the presence of co-mutations and additional biomarkers, such as PD-L1 expression and tumor mutational burden.

Because KRAS is mutated in so many cancers, finding a way to target alterations in the gene has been a thorn in the side of precision oncology experts for decades, with pharma companies long deeming its protein product "undruggable" due to a structure that seemed to resist the binding of small molecules. But over the last few years, new compounds and preclinical data have prompted renewed optimism.

Amgen's Phase I trial recruited 129 patients, 59 with NSCLC, 42 with colorectal cancer, and 28 with other solid tumors across dose escalation and expansion cohorts. Patients had received a median of three prior lines of anticancer therapies for metastatic disease and were followed for a median of about 11 months by the data cutoff for the publication and conference presentation this weekend.

Across the board, study investigators said they saw no dose-limiting toxic effects or treatment-related deaths; 73 patients had some treatment-related adverse event, with 15 (about 12 percent) experiencing grade 3 or 4 side effects. The most common events included diarrhea, fatigue, and nausea. Treatment was discontinued in 107 patients (83 percent), mostly because of disease progression, and 54 patients have died thus far, something authors described as a reasonable outcome given this was a late-stage, heavily treated cohort.

The lung cancer subgroup showed the most promising response rates in the trial. At the ESMO meeting, Hong reported that of 59 NSCLC patients, 42 showed some level of tumor shrinkage from baseline by their six-month assessment.

This included 19 patients who had a confirmed partial response and 33 who showed stable disease for at least a few months — yielding an overall response rate of 32 percent and a disease control rate of 88 percent. Median progression-free survival was 6.3 months ranging from 0 to 14.9 months, and 10 out of the 19 responders were still in response as of the study's June 1 data cutoff, Hong said.

Based on the safety and efficacy data emerging from the dose escalation portion of the trial, investigators identified the highest tested dose, 960 milligrams, as the recommended Phase II dose for sotorasib. As a result, additional patients were recruited for an expansion of the Phase I cohort at that dose level.

In the subset of 34 NSCLC patients who got this 960 mg dose either in the escalation or expansion portion of the trial, responses were even better than in the larger NSCLC group, with 12 patients achieving at least a partial response and 19 with stable disease. This translated to an overall response rate of 35 percent and a disease control rate of 91 percent.

In his presentation, Hong highlighted the case of a patient who he said exemplifies the depth and durability of some of the responses seen in the trial's NSCLC sub-cohort. The 59-year-old man had progressed on five prior drugs, including three targeted therapies, chemotherapy, and a checkpoint inhibitor, as well as gamma knife radiation for brain metastases.

This individual was started on sotorasib at a 360 mg dose in December 2018 and had a complete response in target lesions and partial responses across tumor sites after about a month and a half of treatment. As of the study cutoff point, his response had endured for 13.6 months with no significant adverse events. However, he more recently began to show progression in non-target lesions, albeit after more than a year-and-a-half reprieve.

Apart from the more dramatic responses in the trial, investigators argued that even the six-month median PFS looks a lot better than what these types of patients might expect otherwise.

In a statement announcing the NEJM publication, co-lead author Marwan Fakih, a medical oncologist at City of Hope, said that sotorasib, in some cases, "demonstrated a median progression-free survival that is two times longer than what we encounter in patients today.”

The subgroup with colorectal cancer also showed benefit, albeit not as striking as in lung cancer, with 7.1 percent (3 patients) having a confirmed response, and 73.8 percent (31 patients) showing disease control. According to Fakih, considering the poor prognosis for metastatic CRC patients and the lack of effective treatments for this disease, "controlling tumor progression for a few additional months with an oral therapy is a significant and meaningful outcome."

Authors reported in the NEJM paper that positive effects were also observed in patients with melanoma, and pancreatic, endometrial, and appendiceal cancers.

Colin Lindsay, a clinical senior lecturer at the University of Manchester in the UK and a discussant for the CodeBreaK100 presentation, said that the results imply that sotorasib and competing agents like Mirati Therapeutics' MRTX849 have clear anti-cancer effects.

He also highlighted that sotorasib's efficacy appeared to be encouragingly dose independent, as it elicited good responses in some patients, even at low doses. That said, based on the data so far, it also appears that many patients fail to derive either any benefit, or any significant benefit, despite being KRAS G12C mutation carriers.

According to Lindsay, earlier reports have identified the "usual suspects" as playing a role in driving resistance to G12C inhibition, including EGFR, CDK4, SHP2, MEK, and the Aurora Kinase. As KRAS inhibitor trials are advancing through the clinic, the research community isn't wasting any time studying these resistance pathways as well, he said. 

For its part, Amgen is continuing to explore sotorasib as a monotherapy in Phase II of the current trial, with additional CodeBreaK100 experimental arms also combining the KRAS inhibitor with anti-PD-1/PD-L1 treatments and assessing the drug on its own in treatment-naive NSCLC.

The company has also begun a trial called CodeBreaK101, which is exploring the activity of sotorasib in combination with drugs targeting PD-1/PD-L1, MEK, SHP2, EGFR, a Pan-ErbB tyrosine kinase inhibitor, and chemotherapy across solid tumors. Another Phase III randomized-controlled trial, CodeBreaK200, is recruiting NSCLC patients and comparing sotorasib with docetaxel.

Similarly, in Mirati's Phase I/II trial of its KRAS G12C inhibitor, pilot arms are exploring MRTX849 with the checkpoint inhibitor pembrolizumab (Merck's Keytruda), an anti-EGFR monoclonal antibody cetuximab (Eli Lilly's Erbitux), and the EGFR inhibitor afatinib (Boehringer Ingelheim's Gilotrif).

Lindsay stressed that sotorasib and similar drugs don't address the larger population of cancer patients whose tumors are driven by different alterations in KRAS. "Make no mistake about it, these drugs will not work beyond G12C mutations, and G12C is present in only about 10 percent to 15 percent of lung adenocarcinomas," he added.

This gap may be filled by firms like Gritstone Oncology, Moderna Therapeutics, and Revolution Medicines, which are seeking to advance drugs for cancer patients with KRAS G12D mutations, and other companies like Elicio Therapeutics, which is pursuing potential pan-KRAS inhibitors.

Investigators are also hoping to begin human trials of a KRAS-targeting exosome-based technology this year.

In his discussion, Lindsay said that the field is currently focused on figuring out which drug combinations are the most promising for ongoing development, and in particular, whether KRAS-targeting drugs might be combined safely with immune checkpoint inhibitors.

"This will be crucial to [future] development … because RAS-mutant lung cancer is now anchored by immunotherapy treatment," he said.