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Krazati-Keytruda Combo Boasts 63 Percent Response Rate in Frontline Lung Cancer Study at ESMO

NEW YORK – Mirati Therapeutics' KRAS inhibitor Krazati (adagrasib) with Merck's checkpoint inhibitor Keytruda (pembrolizumab) was well tolerated and effective as a frontline treatment for KRAS G12C-mutant advanced non-small cell lung cancer, according to data presented at the European Society for Medical Oncology Congress on Friday.

Researchers presented updated results from the Phase II KRYSTAL-7 trial exploring the activity of Krazati plus Keytruda in treatment-naïve KRAS G12C-mutant advanced NSCLC patients with a range of PD-L1 expression levels. Out of 51 patients with PD-L1 expression in at least half their tumor cells, 63 percent responded to the Krazati-Keytruda combination. In this subset of high PD-L1 expressers, duration of response and median progression-free survival on Krazati-Keytruda were not reached at a median follow-up of 10.1 months.

Marina Garassino, a professor of medicine at the University of Chicago who presented the KRYSTAL-7 results, highlighted that the response rate seen in this analysis in the first-line setting for the Krazati-Keytruda combination was better than the response rates seen historically with Keytruda monotherapy, which are between 39 percent and 45 percent.

Mirati is focusing on the subset of advanced NSCLC patients with KRAS G12C mutations and high PD-L1 expression. The firm announced this week that, by the end of the year, it will begin enrolling a Phase III trial pitting first-line Krazati-Keytruda against Keytruda alone in this population.

Researchers also looked at how patients with PD-L1 expression in less than 1 percent of tumor cells fared on Krazati-Keytruda, but these patients will not be included in the upcoming Phase III trial, according to Garassino. Results from this subgroup will be presented at a future meeting.

With combination regimens there is always a concern that more drugs will mean more toxicities for patients. Garassino noted, however, the overall favorable tolerability of the combination, especially when it came to liver toxicity, an adverse event that can occur with checkpoint inhibitor-based regimens. In KRYSTAL-7, the liver enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT) increased in 32 percent and 38 percent of patients, respectively, but no patients permanently stopped taking both drugs as a result.

"Treatment-related hepatic events [other than ALT/AST increase] occurred in less than 10 percent of the patients," Garassino said, adding that it took a median 22 days to reduce these enzyme levels in 80 percent of cases. And after starting combination treatment again, only three patients experienced increases in transaminases of any grade. 

Furthermore, among those who experienced liver toxicity in the trial, the response rate was still 70 percent, she added.

Fiona Blackhall, professor of thoracic oncology at the University of Manchester, who was not involved with the KRYSTAL-7 study, said the risk of severe liver toxicity appeared lower compared to studies of other KRAS inhibitor-immunotherapy combinations.

In results presented last year from the CodeBreaK 100/101 master protocol trial, which evaluated Amgen's competing KRAS G12C inhibitor Lumakras (sotorasib) in combination with either Keytruda or Genentech's PD-L1 inhibitor Tecentriq (atezolizumab), the rates of grade 3 or higher liver toxicity were between 30 percent and 50 percent. The response rate in CodeBreaK 100/101, meanwhile, was 29 percent.

"Putting KRYSTAL-7 in context, there appears to be a reduced risk of hepatotoxicity," Blackhall said, noting that while the risk of liver toxicity is lower with Krazati-Keytruda, the risk is still there.

"It has been debated if this is a class effect [with KRAS inhibitors] or a [specific] drug effect. I think this is a class effect," Blackhall said. But she acknowledged that differences in chemistry between KRAS inhibitors could potentially lessen this risk, which could impact guidelines for managing adverse events with other KRAS inhibitors in development. 

Garassino also suggested that the chemistry of Krazati, such as its long half-life and ability to lock the KRAS pathway in an "off" state, could reduce the risk of liver toxicity. "We believe the reason why there is less off-target toxicity and less liver toxicity is because of the minimized cysteine reactivity and the steady state decay [of Krazati]," she said.

Blackhall also noted that further data is needed to confirm the efficacy signals from this KRYSTAL-7 readout, including data on the activity of Krazati-Keytruda in low PD-L1 expressers. "The efficacy signal [from Krazati-Keytruda], 63 percent, does compare favorably to either drug as monotherapy," Blackhall said, adding the caveat that the only available data on the activity of single-agent Krazati right now is from patients who have gotten it after first-line treatment.

Citing the KRYSTAL-1 study in which co-mutations appeared to impact patients' response and progression-free survival on Krazati, Blackhall noted the need to also consider the influence of co-mutations in genes such as KEAP1, CDKN2A, STK11, and TP53 on Krazati-Keytruda's efficacy.