KRAS Inhibitors Reach New Milestones in NSCLC

Significant advances have been made regarding the development of KRAS G12C inhibitors in non–small cell lung cancer in recent years, explained Karen L. Reckamp, MD, who added that research regarding predictive co-mutations, acquired resistance, and combination strategies is expected to propel the utility of these agents even further.

Karen L. Reckamp, MD, MS

Karen L. Reckamp, MD, MS

Significant advances have been made regarding the development of KRAS G12C inhibitors in non–small cell lung cancer (NSCLC) in recent years, explained Karen L. Reckamp, MD, MS, who added that research regarding predictive co-mutations, acquired resistance, and combination strategies is expected to propel the utility of these agents even further.

“We’re still in the very early stages of understanding KRAS signaling, even though it has been studied for decades. We’re really at the tip of the iceberg in evaluating KRAS in NSCLC. The next steps are going to include defining the subsets that benefit and can be predictive for benefit to specific inhibitors or specific combinations,” said Reckamp, director of the Division of Medical Oncology, the associate director of Clinical Research, and the medical oncology director of the Lung Institute at the Samuel Oschin Cancer Center at Cedars-Sinai Medical Center.

In a presentation during the keynote lecture on KRAS pathway inhibitors in lung cancer at the 22nd Annual International Lung Cancer Congress®, a program hosted by the Physicians’ Education Resource®, LLC, Reckamp highlighted the data with adagrasib and sotorasib (Lumakras), 2 highly selective and potent oral small-molecule KRAS G12C inhibitors, and outlined ongoing research targeted toward improving patient selection and efficacy of these agents.

In the registrational phase 1/2 KRYSTAL-1 trial (NCT03785249), adagrasib was evaluated in previously treated patients with KRAS G12C–mutated NSCLC.

Among 51 patients evaluable for efficacy, 45% achieved a partial response to adagrasib (n = 23) at a twice-daily dose of 600 mg, with a disease control rate (DCR) of 96% (n = 49).1

“Most patients benefitted from this therapy, and the majority of patients had some tumor shrinkage,” said Reckamp.

“We’ve also seen some data with adagrasib on co-mutations, [suggesting that] KEAP1 mutations seem to be problematic and may be less responsive [to adagrasib] than patients with STK11 mutations,” added Reckamp.

On June 25, 2021, the FDA granted a breakthrough therapy designation to adagrasib for use in patients with KRAS G12C–mutated NSCLC following previous systemic therapy based on findings from KRYSTAL-1.2

In the phase 2 CodeBreaK 100 trial (NCT03600883), sotorasib was evaluated in patients with pretreated KRAS G12C–mutated NSCLC. Updated findings from the trial, which were presented during the 2021 ASCO Annual Meeting, demonstrated that at a median follow-up of 15.3 months, sotorasib, given at 960 mg once daily, was associated with a median overall survival (OS) of 12.5 months (95% CI, 10.0–not evaluable [NE]) and a median progression-free survival (PFS) of 6.8 months (95% CI, 5.1-8.2).3

The objective response rate (ORR) was 37.1% (95% CI, 28.6%-46.2%), which included 4 complete responses (CRs). The median duration of response (DOR) was 11.1 months (95% CI, 6.9–NE), and the DCR rate was 80.6% (95% CI, 72.6%-87.2%).3

The clinical activity observed with sotorasib was consistent across prespecified subgroups, including age, ECOG performance status, number of prior lines of treatment, and prior PD-1/PD-L1–directed therapy alone or in combination with platinum-based chemotherapy. Notably, for patients who received a prior PD-1/PD-L1 inhibitor but not chemotherapy, the ORR was 69.2% (95% CI, 38.6%-90.9%) and the median OS was 17.7 months (95% CI, 11.7–NE).

“As we get larger trials, we can start to tease out these subgroups a little bit more to see who is actually responding. For patients who had had only prior [treatment with a] PD-1 [inhibitor], we see the highest response rate and the longest OS,” said Reckamp.

Based on earlier findings of CodeBreaK 100, the FDA approved sotorasib in May 2021 as the first targeted treatment for adult patients with NSCLC whose tumors harbor KRAS G12C mutations and who have received at least 1 prior systemic therapy.4

Additionally, sotorasib demonstrated activity in molecularly-defined subgroups from exploratory analyses within the study, including in those with STK11-mutated tumors.

In patients with STK11-mutant, KEAP1 wild-type disease (n = 22), the ORR with sotorasib was 50%, the median PFS was 11.0 months, and the median OS was 15.3 months.3 The ORR was 23% in patients with STK11-mutant, KEAP1-mutant disease (n = 13); 14% in STK11 wild-type, KEAP1-mutant disease (n = 7); and 42% in patients with STK11 wild-type, KEAP1 wild-type disease (n = 62). Also in these subgroups, the median PFS was 2.6 months, 5.5 months, and 6.8 months, respectively; the median OS was 4.8 months, 7.5 months, and not evaluable, respectively.

“The numbers are incredibly small, and I hesitate to make decisions based on these mutations, but we will be looking at these further,” said Reckamp.

To that end, the phase 2 Lung-MAP S1900E study (NCT04625647) is evaluating sotorasib specifically in patients with co-mutations, including TP53, STK11, and others.

Another research avenue is exploring the utility of SHP2 inhibitors in overcoming resistance to KRAS G12C inhibitors, said Reckamp. In an ongoing phase 1 trial (NCT03114319), the orally bioavailable, selective, first-in-class allosteric inhibitor of wild-type SHP2, TNO155, is being studied in patients with advanced solid tumors.

Initial findings from the study, which were presented during the 2021 ASCO Annual Meeting, demonstrated a best response of stable disease, lasting a median duration of 5.6 months (95% CI, 1.6-32.9).5

In another phase 1 trial (NCT03634982), results of which were presented during the 2021 AACR Annual Meeting, demonstrated a DCR of 75% (n = 12 of 16) with the SHP2 inhibitor RMC-4630 in patients with KRAS G12C–mutant NSCLC.6

However, the modest single-agent activity of these agents and emerging data regarding the complexity of resistance to KRAS G12C inhibitors, including the activation of other RAS isoforms, other KRAS activating mutations, the loss of G12C through a mutational switch to a different KRAS mutation, and alteration of drug binding through KRAS Y96D,7,8 underscore the importance of identifying effective combination strategies, explained Reckamp.

“Now, we’re trying to find the most rationale combinations by looking at MEK inhibitors, CDK4/6 inhibitors, SOS inhibitors, and SHP2 inhibitors, [targets] in adjacent pathways, such as EGF, and immunotherapy,” concluded Reckamp.


  1. Jänne PA, Rybkin II, Spira AI, et al. KRYSTAL-1: activity and safety of adagrasib (MRTX849) in advanced/metastatic non–small-cell lung cancer (NSCLC) harboring KRAS G12C mutation. Eur J Cancer. 2020;138(suppl 2):S1-S2. doi:10.1016/S0959-8049(20)31076-5
  2. Mirati Therapeutics’ adagrasib receives breakthrough therapy designation from US Food and Drug Administration for patients with advanced non-small cell lung cancer harboring the KRAS G12C mutation. News release. Mirati Therapeutics, Inc. June 24, 2021. Accessed July 31, 2021.
  3. Skoulidis F, Li BT, Govindan R, et al. Overall survival and exploratory subgroup analyses from the phase 2 CodeBreaK 100 trial evaluating sotorasib in pretreated KRAS p.G12C mutated non-small cell lung cancer. J Clin Oncol. 2021;39(suppl 15):9003. doi:10.1200/JCO.2021.39.15_suppl.9003
  4. FDA approves first targeted therapy for lung cancer mutation previously considered resistant to drug therapy. News release. FDA. May 28, 2021. Accessed July 31, 2021.
  5. Brana I, Shapiro G, Johnson ML, et al. Initial results from a dose finding study of TNO155, a SHP2 inhibitor, in adults with advanced solid tumors. J Clin Oncol. 2021;39(suppl 15):3005. doi:10.1200/JCO.2021.39.15_suppl.3005
  6. Koczywas M, Haura E, Janne PA, et al. Anti-tumor activity and tolerability of the SHP2 inhibitor RMC-4630 as a single agent in patients with RAS-addicted solid cancers. Cancer Research. 2021;81(13):LB001. doi:10.1158/1538-7445.AM2021-LB001
  7. Tanaka N, Lin JJ, Li C, et al. Clinical acquired resistance to KRASG12C inhibition through a novel KRAS switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation. Cancer Discov. Published online June 16, 2021. doi:10.1158/2159-8290.CD-21-0365
  8. Akhave NS, Biter AB, Hong DS. Mechanisms of resistance to KRAS G12C-targeted therapy. Cancer Discov. 2021;11(6):1345-1352. doi:10.1158/2159-8290.CD-20-1616
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