Novel Therapies Elicit Excitement in KRAS+ NSCLC

The early potential shown with the KRAS inhibitor AMG 510 coupled with several promising ongoing combination studies has ushered in the beginning of an exciting era for the treatment of KRAS-mutant non–small cell lung cancer.

Vassiliki Papadimitrakopoulou, MD

The early potential shown with the KRAS inhibitor AMG 510 coupled with several promising ongoing combination studies has ushered in the beginning of an exciting era for the treatment of KRAS-mutant non—small cell lung cancer (NSCLC), according to Vassiliki Papadimitrakopoulou, MD, at the 2019 International Lung Cancer Congress.

"Discussing KRAS was not a very exciting task a couple of years back, but this year it is a very exciting task, because we have made a lot of progress in KRAS," said Papadimitrakopoulou, chief, Section of Thoracic Medical Oncology, the University of Texas MD Anderson Cancer Center. "We're very, very excited that direct KRASG12C inhibitors in clinical trials are demonstrating, at least in early data, remarkable activity."

Findings for the first-in-class KRASG12C inhibitor AMG 510 were presented at the 2019 ASCO Annual Meeting, showing a 50% response rate in pretreated KRAS+ NSCLC. The study enrolled 35 patients with KRAS-mutant solid tumors, consisting of 14 with NSCLC, 19 with colorectal cancer, and 2 with appendix cancer. Overall, 10 patients with NSCLC were evaluable at the data cutoff of April 4, 2019.

Among the 10 evaluable patients with NSCLC, 5 had a partial response, of which 4 were confirmed. Those with a response continued to receive AMG 510 at the analysis. Adding to this effectiveness, AMG 510 was also fairly well tolerated, with no grade 4 treatment-related adverse events, no dose-limiting toxicities, and no serious treatment-related adverse events.

"This is great news...these are very significant and groundbreaking data, even with the small number of patients," Papadimitrakopoulou said. "We will need to deal with other subsets of KRAS mutations, and also we will need to think creatively as the data leads us and as we treat patients with the direct inhibitors."

Potential for SHP2 Inhibition

With the potential for an effective treatment on the horizon, there is renewed hope for other clinical studies looking at agents for patients with KRAS-positive NSCLC. A key target currently being explored, SHP2, sits higher in the RAS-RAF-MEK signaling cascade, allowing for potentially broader activity. In preclinical studies, SHP2 inhibition helped to prevent adaptive resistance to MEK inhibitors. Additionally, potential synergy was seen for SPH2 inhibition, antitumor immunity, and PD-1 inhibition.

The 2 leading SHP2 inhibitors currently in clinical trials are RMC-4630, from Revolution Medicines, and TNO155, manufactured by Novartis. Both agents are currently in dose-finding studies as monotherapy (RMC-4630, NCT03634982; TNO155, NCT03114319).

Additionally, a phase I/II study is exploring RMC-4630 in combination with the MEK inhibitor cobimetinib (Cotellic) for patients with solid tumors harboring aberrations in KRAS, BRAF, or NF1 (NCT03989115). A phase Ib study is looking at TNO155 in combination with the PD-1 inhibitor spartalizumab or the CDK4/6 inhibitor ribociclib in genetically specified advanced malignancies. An additional study, that is yet to begin, will look at TNO155 in combination with Mirati Therapeutics' KRAS G12C inhibitor MRTX849, which is also being examined as a single agent.

"Combination therapies will likely need to be employed," said Papadimitrakopoulou. "Combination therapies with SHP2 inhibitors may improve efficacy of MEK inhibitors and likely also the efficacy of direct KRAS inhibitors. A very impressive combination so far."

MEK Inhibition Explored in Combinations

A new wave of MEK inhibitor combinations are also beginning to emerge for KRAS-mutant NSCLC, with early signs of potential synergy in preclinical studies. Some of the most promising potential combinations are looking at dual targeted therapy combinations with MEK inhibitors and CDK4/6 inhibition, and also the combination of MEK and immune checkpoint inhibition.

The MEK inhibitor binimetinib (Mektovi) is being examined in a number of clinical trials for patients with KRAS-mutated lung cancer, including studies looking at the agent in combination with chemotherapy (NCT02185690, NCT02964689) and with palbociclib (NCT03170206).

Notably, a number of studies are also looking at binimetinib with immunotherapy, including a phase Ib/II study examining the agent plus the PD-L1 inhibitor avelumab (Bavencio) with or without the PARP inhibitor talazoparib (Talzenna) for patients with RAS-mutant solid tumors (NCT03637491). The MEK inhibitor trametinib (Mekinist) is also being examined with the PD-1 inhibitor pembrolizumab (Keytruda) in the phase Ib/II IM-BATTLE-2 trial (NCT03225664).

"Targeting downstream effectors may be able to induce a senescence phenotype that can recruit an immune response," said Papadimitrakopoulou. "MEK inhibitors and anti—PD-1 are still being explored, and in my opinion, the jury is still out."

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; abstr 3003).

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