WCLC: Lumakras' first Keytruda combo data flag safety concern. But Amgen presses ahead

Amgen has given a much-anticipated first look at Lumakras’ combination with checkpoint inhibitors. As many industry watchers have feared, the pairing raised a safety red flag that the efficacy results couldn't compensate for. But the company is pressing ahead with a possible solution.

Treatment with Lumakras alongside either Merck & Co.’s Keytruda or Roche’s Tecentriq in KRAS G12C-mutated non-small cell lung cancer led to a marked increase in liver toxicities, according to early clinical data presented at the 2022 World Conference on Lung Cancer (WCLC) in Vienna.

Specifically, among 29 patients in the phase 1b CodeBreak 100/101 trials testing various Lumakras dosing strengths concurrently with either Keytruda or Tecentriq, there was a roughly 50% rate of severe liver toxicity at grade 3 or 4. The main manifestation was increased liver enzyme levels.

Overall, treatment-related side effects caused about half the patients on concurrent combo dosing to discontinue either Lumakras or the immuno-oncology agent.

Lumakras’ combo safety data came in stark contrast to what Mirati Therapeutics reported in June for its rival KRAS inhibitor, adagrasib. In a small group of patients in the phase 2 Krystal-7 trial, adagrasib and Keytruda only led to 5% of grade 3/4 elevations of liver enzymes ALT and AST, respectively, similar to that observed with adagrasib monotherapy.

The liver safety problem that came with coupling Lumakras with Keytruda or Tecentriq looked even more problematic, because the combos only triggered a response in 29% of all 58 patients across the various cohorts. By comparison, Lumakras monotherapy already has a 36% response rate, or 41% after a longer follow-up. And Mirati's regimen checked in above 50%, according to an early adagrasib and Keytruda combo readout from Kyrstal-1 and Kyrstal-7 trials, though the data was based on a previously untreated NSCLC population. Both Lumakras and adagrasib are being tested in lower dosages in their combo trials than when they're used as a monotherapy.

Amgen’s R&D chief, David Reese, acknowledged that liver toxicity is a challenge for PD-1/L1 combinations with small molecule targeted therapies. But in an interview with Fierce Pharma, he noted that the vast majority of the cases—97% to be exact—in the CodeBreak studies actually resolved mostly after corticosteroids.

As for the adagrasib data, Reese cautioned against a side-by-side comparison because of several key differences between the trials.

First of all, about two-thirds of Lumakras patients had previously received a PD-1/L1 inhibitor before getting into the trials. By comparison, the adagrasib trial only enrolled newly diagnosed patients.

  Lumakras (lead-in) + Tecentriq (N=10) Lumakras (concurrent) + Tecentriq (N=10) Lumakras (lead-in) + Keytruda (N=19) Lumakras (concurrent) + Keytruda (N=19)
Liver toxicity Gr 3/4 3 (30%) 5 (50%) 8 (42%) 9 (47%)
ORR 20% 20% 37% 32%
Median OS 8.1 months 11.5 months Not reached 14.1 months

Liver toxicity was already a concern for Lumakras’ KRAS/PD-1 combo heading into the readout and is a well-known autoimmune-related side effect of checkpoint inhibitors. A real-world study had described a high 31% rate of severe liver toxicity in Lumakras takers following checkpoint blockade, several Wall Street analysts have noted. What’s more, the closer the Lumakras treatment from checkpoint inhibitor the stronger the liver toxicity appeared to be, that study found.

Another point Reese noted was the difference in trial duration. Amgen collected the liver safety data after a median follow-up of 12.8 months, whereas the Krystal-7 data was a bit over two months.

Most of Lumakras’ high-grade liver toxicity event emerged outside of the 21-day dose limiting toxicity window.

Despite the liver toxicity signal, Amgen thinks it has a viable solution to the problem. The company is now moving forward with the Keytruda combo in a dose-expansion phase of the study in treatment-naïve NSCLC patients. Rather than concurrent use of both agents, the trial will use a lower, 240mg dosing of Lumakras alone during a lead-in phase before adding Keytruda, Reese said. The current recommended dosage of Lumakras is 960 mg once a day.

“The fact that we saw a median duration of response of 17.9 months and lower rates of adverse events in patients treated with [Lumakras] as a lead-in to the combination regimen informs our approach for ongoing investigation in the first-line setting,” Bob Li, M.D., Ph.D., from Memorial Sloan Kettering Cancer Center, who presented the CodeBreak results at WCLC, said in a statement.

Results from the dose-expansion cohort will come out sometime next year, Reese said.

In addition, Amgen is launching a phase 3 trial combining Lumakras with chemotherapy in first-line NSCLC patients whose tumors don’t express PD-L1.