KRAS G12C Inhibitors Enter the Spotlight in NSCLC

The era of direct inhibitors to treat KRAS G12C-mutated non-small cell lung cancer (NSCLC) has arrived in the clinic, thoracic oncologist Gregory J. Riely, MD, said during his presentation at the 16th Annual New York Lung Cancers Symposium.

For years, investigators considered KRAS an “undruggable” target, but Sang Min Lim, PhD, and colleagues in 2013 developed sotorasib to specifically target KRAS G12C. Approximately 13% of patients with lung cancer harbor the mutation, which is also found in up to 3% of those with colorectal cancer, as well as other solid tumors.¹

In May 2021, the FDA issued an accelerated approval for sotorasib (Lumakras), a RAS GTPase family inhibitor, for adults with KRAS G12C-mutated locally advanced or metastatic NSCLC who have received at least 1 prior systemic therapy. Ferdinandos Skoulidis, MD, PhD, and colleagues, published data in New England Journal of Medicine in June 2021 from the phase 2 CodeBreaK 100 trial (NCT03600883).

The findings showed that sotorasib elicited an objective response rate (ORR) of 36% (95% CI, 28%-45%) in patients with KRAS G12C-mutated NSCLC who progressed following treatment with immunotherapy and/or chemotherapy. The median duration of response (DOR) with the treatment was 10 months, and 58% of patients experienced DOR of 6 months or more.²

The median progression-free survival (PFS) was 6.8 months, and the median overall survival (OS) was 12.5 months.

“Among the most impressive findings of the study were the durability and depth of responses, and it should be noted that 4 patients [3.2%] achieved a complete response,” Skoulidis, assistant professor of thoracic/head & neck medical oncology at The University of Texas MD Anderson Cancer Center, said to OncLive^® in August 2021. “The reported overall disease control rate [DCR] of 80.6%, with median progression-free survival [PFS] of 6.8 months, and median OS of 12.5 months further support the activity of sotorasib in this heavily pretreated patient population, and appear superior to historical data with docetaxel or docetaxel and ramucirumab.”

Investigators enrolled 126 patients into the trial, 124 of whom had centrally evaluable lesions per RECIST criteria at baseline. Eligible patients were required to have locally advanced or metastatic NSCLC with a KRAS G12C mutation, as assessed per central testing of tumor biopsies. Patients had to have progressed on prior standard therapies, and those with active brain metastases were excluded.

Patients were assigned to 960 mg of oral sotorasib until disease progression. Radiographic scans were done every 6 weeks for up to 48 weeks, and then once every 12 weeks thereafter.

The primary end point of the trial was ORR per RECIST v1.1 criteria by blinded independent central review, and key secondary end points included DOR, DCR, time to recovery, PFS, OS, and safety.

Twenty-eight (22.2%) patients experienced treatment related adverse effects (TRAEs) requiring dose modifications, and 9 (7.1%) discontinued treatment due to TRAEs.

There were 20 (15.9%) grade 5 AEs, although investigators concluded none were treatment-related. Investigators recorded 26 grade 3/4 AEs, the most common of which was grade 3 alanine aminotransferase increase (n = 8).

Currently, investigators are examining sotorasib vs docetaxel for the same patient population in the ongoing randomized phase 3 CodeBreak 200 trial (NCT04303780). The estimated study completion date is April 2026.

More To Come

Sotorasib is the first KRAS inhibitor to win FDA approval, but other agents are sure to follow. In June 2021, the FDA granted a breakthrough therapy designation to adagrasib (MRTX849) as a potential therapeutic option for patients with KRAS G12C–mutated NSCLC following previous systemic therapy.³ Adagrasib is a covalent inhibitor that irreversibly and selectively binds KRAS G12C in its inactive guanosine diphosphate–bound state. The agent has been optimized for desired properties, demonstrating high selectivity for KRAS G12C mutations over wild-type and favorable PK properties, including oral bioavailability, a half-life of approximately 24 hours, and extensive tissue distribution.

Pasi A. Jänne, MD, the 2021 Giants of Cancer Care^® award winner for lung cancer, led the registrational phase 1/2 KRYSTAL-01 trial (NCT03785249) that supported the designation. Riely presented updated preliminary data during the 2021 European Lung Cancer Conference demonstrating that, when administered at a twice-daily dose of 600 mg, adagrasib induced ORRs of 43% and 45% in the phase 1/1b (n = 14) and phase 2 (n = 51) cohorts, respectively. The disease control rate was 100% in in the phase 1/1b cohort and 96% in the phase 2 cohort.⁴

There were 2 grade 5 TRAEs, 1 case of recurrent pneumonitis and 1 case of cardiac failure. Thirty percent of patients experienced grade 3/4 TRAEs, most often fatigue (6%), alanine aminotransferase increase (5%), and aspartate aminotransferase (5%).

To date, KRAS G12C inhibitors have been evaluated largely as monotherapy, but investigators have started assessing these agents in combinations. Adagrasib is under phase 1 investigation in combination with pembrolizumab (Keytruda), cetuximab (Erbitux), and afatinib (Gilotrif) in the multi-arm KRYSTAL-01 study.

Sotorasib is being examined with several agents, including trametinib (Mekinist) and the novel PD­–1-inhibitor AMG 404 for KRAS G12C-mutated solid tumors, pembrolizumab and afatinib for NSCLC, and trametinib plus panitumumab (Vectibix) for advanced colorectal cancer.

GDC-6036, a novel KRAS G12C inhibitor thought to have potential antineoplastic activity, is being explored in combination with erlotinib (Tarceva) and with atezolizumab (Tecentriq) in a multi-arm phase 1/2 study (NCT04449874). Investigators are also assessing the agent for patients with solid tumors in combination with bevacizumab (Avastin) and with GRC-1971, a small molecule inhibitor of SHP2; and with cetuximab for colorectal cancer.

Finally, JDQ443, also thought to have potential antineoplastic activity, is being evaluated as a treatment for patients with advanced solid tumors as monotherapy, in combination with TNO155, a novel SHP2 inhibitor; and the anti-PD–1 inhibitor spartalizumab (PDR001); as well as in a triplet with both agents (NCT04699188).

When choosing drugs to pair with a KRAS G12C inhibitor, Riely recommended agents that target pathways that are important for KRAS signaling, those that affect other pathways that are important in tumor biology, and those that are otherwise a key part of NSCLC treatment.

References

1. Nassar AH, Adib E, Kwiatkowski DJ. Distribution of KRASG12C somatic mutations across race, sex, and cancer type. N Engl J Med. 2021; 384:185-187 doi: 10.1056/NEJMc2030638
2. Skoulidis F, Li BT, Dy GK, et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med. 2021;384(25):2371-2381. doi: 10.1056/NEJMoa2103695
3. FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC. Accessed November 8, 2021. https://bit.ly/3qeKkwF
4. Riely GJ, Ignatius Ou SH, Rybkin II, et al. KRYSTAL-1: Activity and pre-liminary pharmacodynamic (PD) analysis of adagrasib (MRTX849) in pa-tients (pts) with advanced non-small-cell lung cancer (NSCLC) harboring KRASG12C mutation. Presented at: European Lung Cancer Virtual Confer-ence 2021; March 25-27, 2021. Abstract 99O_PR