Assessing the Actionability of KRAS Mutations in NSCLC

KRAS mutations are found in approximately in 25% of all non–small cell lung cancers (NSCLC), said David Barbie, MD, who added that it was not until recently that the previously coined “undruggable target” showed signals of actionability with KRAS mutation–specific therapy, tumor-suppressor­–specific therapy, and anti-inflammatory therapy.

KRAS Mutation-Specific Therapy

In a presentation during the 4th Annual International Congress on Oncology and PathologyTM, Barbie, associate director of the Robert and Renée Belfer Center for Applied Cancer Research and associate professor of medicine at Harvard Medical School, Dana-Farber Cancer Institute, explained that mutations in KRAS were thought to lock the gene in its guanosine triphosphate (GTP)–bound state that trigger downstream pathway activations when in fact, KRAS mutations impair the binding of GTPase-activating proteins that can catalyze the conversion back to its inactive guanosine diphosphate (GDP)-bound state.¹

In 2013, research led by Kevan Shokat, PhD, of the University of California, San Francisco, showed that KRAS inhibitors that bind to the G12 cysteine can return GTP-bound KRAS to its inactive GDP-bound state.²

Although a number of KRAS G12C inhibitors previously showed efficacy in vivo in G12C cell line xenograft and patient-derived xenograft models, it was not until the 2019 ASCO Annual Meeting that the first breakthrough reported was AMG 510, said Barbie.

Preliminary results from the phase 1 dose-escalation/-expansion study showed that of 10 patients with previously treated KRAS G12C-mutant NSCLC, 5 achieved a partial response (PR), with 4 confirmed PRs, and 4 experienced stable disease.³ At the 2019 World Conference on Lung Cancer, an expanded data set showed that among 23 evaluable patients who had completed the first 6-week CT scan or had early progressive disease, the objective response rate (ORR) was 48%. Thirteen of these patients received the phase 2 dose of 960 mg, and of these patients, 54% achieved a PR.⁴

On September 9, 2019, the FDA granted a fast track designation to the agent for the treatment of patients with previously treated KRAS G12C–mutant metastatic NSCLC, based on these early trial results.

At the 2020 ASCO Virtual Scientific Program, updated results from the cohort of patients with heavily pretreated advanced KRAS G12C–mutant colorectal cancer (n = 42) were more underwhelming, explained Barbie, with an ORR of 12%.⁵ 

The second compound that is in clinical development is MRTX849, which has shown similar responses in a small number of patients, said Barbie.

“The key question that is going to come out of all these studies once we have larger numbers is, ‘What’s the real durability of response?’” asked Barbie.

To that end, Mirati Therapeutics, the developer of MRTX849, partnered with Novartis in July 2019 to determine whether the addition of the SHP2 inhibitor TNO155 can lead to prolonged responses.

“The idea here is that now you have a double whammy. When you inhibit SHP2, you’re basically preventing the catalysis into the GTP-bound state and, with the KRAS G12C inhibitor, you’re trapping [KRAS] into the GDP-bound state,” said Barbie.

Anti-Inflammatory Therapy

Of parallel importance is the fact that inflammation fuels KRAS-driven lung cancers, said Barbie. The notion was first described in a paper published in Seminars in Cell and Developmental Biology⁶ and confirmed in coincident findings from a randomized, double-blind, placebo-controlled trial, which showed that interleukin (IL)-1β inhibition with canakinumab (Ilaris) led to a significant reduction in lung cancer incidence among patients with atherosclerosis (HR, 0.33; 95% CI, 0.18-0.59; P <.0001).⁷

The benefit of anti-inflammatory therapy will be further evaluated in the phase 2 CANOPY-N trial (NCT03968419), explained Barbie, in which investigators will evaluate canakinumab and pembrolizumab (Keytruda) as monotherapy or in combination as neoadjuvant therapy in patients with early-stage NSCLC.

Barbie also highlighted the phase 3 CANOPY-2 trial (NCT03626545), which evaluates canakinumab in combination with docetaxel in patients with previously treated advanced NSCLC.

Tumor-Suppressor-Specific Therapy

Apart from inflammatory cytokines, Barbie noted that LKB1, the protein that is encoded by STK11, is an important tumor suppressor gene and is mutated in approximately 20% to 30% of KRAS-mutant NSCLC.

Subsequent research led by Ferdinandos Skoulidis, MD, PhD, MRCP, of The University of Texas MD Anderson Cancer Center, showed that one of the strongest predictors of lack of response to checkpoint inhibition is KRAS/LKB1 loss.⁸ In the study, patients with KRAS/LKB1 mutations had an ORR of only 7.4% ORR with PD-1 blockade, suggesting that KRAS/LKB1 alterations are a driver of primary resistance to PD-1 inhibition in NSCLC.⁹

Further research demonstrated that KRAS/LKB1-mutant NSCLC is also more likely to suppress STING and that LKB1 restoration can lead to an interferon response.

“When we looked at the tumors we had characterized with STING immunohistochemistry, we could recapitulate what had been shown, that LKB1-null tumors that lacked tumor-cell STING had T cells that were trapped in the intervening stroma, whereas LKB1 in-tact P53-mutant tumors had T-cell infiltration” said Barbie, suggesting that LKB1 inactivation could guide specific immunotherapies to restore STING activation and incite an immune response.

Moreover, preclinical models showed that AMG 510 could cause an infiltration of T cells, CD8+ T cells, macrophages, and dendritic cells.¹⁰ With this rationale, investigators launched the CodeBreak 101 study (NCT04185883) and the KRYSTAL-1 study (NCT03785249) which are evaluating AMG 510- and MRTX849-based combinations with PD-(L)1 inhibitors. Though, with the limitations of preclinical models, it’s unclear whether the activity of combined KRAS G12C/PD-(L)1 blockade will translate to the clinic, said Barbie.

“I think we can finally begin to develop a precision therapy model for KRAS-mutant lung cancer and argue that testing from a molecular diagnostics standpoint is becoming more important,” concluded Barbie.

References

1. Nussinov R, Jang H, Tsai CJ, et al. Intrinsic protein disorder in oncogenic KRAS signaling. Cell Mol Life Sci. 2017;74(17):3245-3261. doi:10.1007/s00018-017-2564-3

2. Ostrem JM, Peters U, Sos ML, et al. K-Ras (G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013;503(7477):548-551. doi:10.1038/nature12796

3. Fakih M, O'Neil B, Price TJ, et al. Phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 510, a novel small molecule KRASG12C inhibitor, in advanced solid tumors. J Clin Oncol. 2019;37(suppl 15):3003. doi:10.1200/JCO.2019.37.15_suppl.3003

4. Govindan R, Fakih M, Price T, et al. Phase 1 study of safety, tolerability, PK and efficacy of AMG 510, a novel KRASG12C inhibitor, evaluated in NSCLC. Presented at: IASLC 20th World Conference on Lung Cancer; September 7-10, 2019; Barcelona, Spain. Abstract OA02.02.

5. Fakih M, Desai J, Kuboki Y, et al. CodeBreak 100: activity of AMG 510, a novel small molecule inhibitor of KRASG12C, in patients with advanced colorectal cancer. J Clin Oncol. 2020;38(suppl 15):4018. doi:10.1200/JCO.2020.38.15_suppl.4018

6. Kitajima S, Thummalapalli R, Barbie DA, et al. Inflammation as a driver of vulnerability of KRAS mediated oncogenesis. Seminars Cell Dev Biol. 2016;58:127-135. doi:10.1016/j.semcdb.2016.06.009

7. Ridker PM, MacFadyen JG, Thuren T, et al. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390(10105):1833-1842. doi:10.1016/S0140-6736(17)32247-X

8. Skoulidis F, Byers LA, Diao L, et al. Co-occuring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov. 2015;5(8):860-877. doi:10.1158/2159-8290.CD-14-1236

9. Skoulidis F, Goldberg ME, Greenawalt DM, et al. Cancer Discov. 2018;8(7):1-14. doi:10.1158/2159-8290.CD-18-0099

10. Canon J, Rex K, Saiki AY, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumor immunity. Nature. 2019;575(7781):217-223. doi:10.1038/s41586-019-1694-1