What's Next for Sotorasib in NSCLC?

In 2021, the FDA greenlighted the KRAS inhibitor sotorasib (Lumakras; Amgen) for previously treated KRAS^G12C-mutated non–small cell lung cancer (NSCLC). But based on the recently published results of the phase III CodeBreaK 200 trial, experts say that it and perhaps other KRAS inhibitors have yet to achieve their full potential.

In the study, 345 patients whose disease recurred after initial treatment were randomly assigned to receive either sotorasib or docetaxel. The trial met its primary endpoint of a statistically significant increase in progression-free survival (PFS; Lancet 2023;401:733–46). Median PFS was 5.6 months for sotorasib compared with 4.5 months with docetaxel. The overall response rate was also higher—28.1% versus 13.2%, respectively—with sotorasib also yielding more durable responses at 12 months. In addition, sotorasib led to a 34% decrease in relative risk of disease progression or death when compared with docetaxel.

However, there was no significant increase in overall survival with sotorasib. “It's not going to cure anyone,” says Roy Herbst, MD, PhD, deputy director and chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital in New Haven, CT, who also noted that “it's incredibly expensive.”

A 1-month supply of sotorasib costs about $20,000, whereas docetaxel runs just a few hundred dollars. Insurance companies generally cover the expense, but given that difference and the lack of a survival benefit, should sotorasib be prescribed?

Herbst says yes. “I think we should use it because it's much less toxic.” It can also be taken orally at home, eliminating the need for regular intravenous infusions. Even so, “we need more science,” Herbst adds.

The next step should be “looking at drug combinations and trying to understand what genomic alterations are implicated in resistance or potential benefit to sotorasib in NSCLC tumors that harbor KRAS^G12C,” says Abdul Rafeh Naqash, MD, of the Stephenson Cancer Center at the University of Oklahoma in Norman, who was not involved in the study. “Teasing out these signals will be crucial to find the right patients for the appropriate combination approaches.”

“It is important to recognize that non–small cell lung cancer is very heterogeneous, even within this group of patients that all have KRAS^G12C mutations,” says Melissa Johnson, MD, of Sarah Cannon Research Institute in Nashville, TN, and a CodeBreaK 200 investigator. “Some have secondary STK11 and KEAP co-alterations, while others have a secondary p53 mutation. In prior studies with chemotherapy and immunotherapy, it was these co-mutations which predicted a different prognosis. Those subgroup analyses from CodeBreaK 200 are ongoing.”

Additional clinical trials are evaluating KRAS inhibitors in combination with other treatments. A phase II trial is assessing sotorasib and RMC-4630 (Revolution Medicines), a SHP2 inhibitor, as a second-line therapy for KRAS^G12C-mutated NSCLC. The phase III KRYSTAL-7 study is evaluating adagrasib (Krazati; Mirati) plus the PD-1 inhibitor pembrolizumab (Keytruda; Merck) compared with pembrolizumab plus chemotherapy as an initial treatment for inoperable, locally advanced or metastatic NSCLC with a KRAS^G12C mutation and a PD-L1 tumor proportion score of less than 50%. Adagrasib received FDA approval in December for advanced KRAS^G12C-mutated NSCLC.

Other questions about sotorasib, adagrasib, and KRAS inhibitors in development need to be answered as well, says Johnson. For example: Does the extent of the disease correlate with response? How might radiation therapy augment the drugs’ activity? Another area ripe for exploration is whether the agents can be administered as initial therapy for patients with newly diagnosed or early-stage disease.

“We are beginning to ask research questions about how to incorporate these drugs earlier in a patient's disease course, but you've got to start somewhere,” Johnson says. –Aaron Tallent and Suzanne Rose

For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.