2021 Pipeline Updates: Upcoming Innovations in Non–Small Cell Lung Cancer

The year 2021 saw the launch of numerous clinical trials in the non–small cell lung cancer (NSCLC) space, from pathway inhibitors inhibitors to immunotherapy to other technologic innovations. As the year comes to a close, CancerNetwork® highlights ongoing clinical trials in the pipeline featuring novel compounds and technologies as part of a 3-part series on promising ongoing research within the oncology space.

Partnership Leading to Innovation in KRAS G12C–Mutant NSCLC

Mirati Therapeutics partnered with Verastem Oncology to examine the combination of the KRAS G12Cinhibitor adagrasib (MRTX 849) with VS-6766 (formerly, CH5126766), a RAF/MEK inhibitor, in a population of patients with KRAS G12C­–mutant NSCLC in a phase 1/2 study.¹ The multicenter, single-arm, open-label will determine both the maximum tolerated dose and recommended phase 2 dose for the combination therapy. Additionally, investigators will determine the combination’s safety and efficacy.

Preclinical data have indicated a more robust inhibition of the ERK pathway may be achieved with adagrasib and VS-6766 and potentially lead to an enhanced anti-tumor effect. VS-6766 differs from other MEK inhibitors in that it inhibits both MEK and RAF, preventing phosphorylate MEK. This allows MEK signaling to be blocked without compensatory MEK activation that ordinarily decreases efficacy.

“We are pleased to collaborate with Verastem Oncology on this clinical study of VS-6766 and adagrasib. We believe the data from this trial will help to better understand how these agents, when combined, could help improve patient outcomes,” James Christensen, PhD, chief scientific officer at Mirati Therapeutics, Inc., said in a press release. “This clinical collaboration is an example of how Mirati is aggressively advancing the study of adagrasib both as a monotherapy and in rational combinations as part of its expanding development portfolio to benefit people living with difficult-to-treat cancers.”

Adagrasib has previously demonstrated efficacy in the phase 2 KRYSTAL-1 trial (NCT03785249), which assessed the clinical benefit of the agent in patients with mutations in KRAS G12C.² After a median follow up of 9 months, patients in the intent-to-treat arm who received 600 mg of adagrasib demonstrated an objective response rate of 43% and a disease control rate of 80%.

VS-6766 was previously granted a breakthrough therapy designation by the FDA in combination with the FAK inhibitor defactinib for treatment of patients with recurrent low-grade serous ovarian cancer after 1 or more therapies, regardless of KRAS status.

Electrifying the Treatment of NSCLC With Tumor Treating Fields

The efficacy of Tumor Treating Fields (TTFields) in conjunction with immune checkpoint inhibitors or docetaxel is currently under investigation in patients with stage IV NSCLC who have progressed on or after treatment with a platinum-based therapy as part of the phase 3 LUNAR trial (NCT02973789).³ The trial, which recently completed enrollment in November 2021, has a primary end point of superior overall survival (OS) vs immune checkpoint inhibitors or docetaxel alone. TTFields therapy is intended to enhance the efficacy of standard-of-care strategies.

TTFields are electric fields capable of interrupting cancer cell division. Treatment with this modality involves patients wearing 4 electrically insulated electrode arrays on their chest. Research on the modality has spanned 2 decades, with the therapy demonstrating consistent anti-miotic impact in preclinical findings.

Data from a prespecified interim update of the phase 3 LUNAR trial showed favorability of TTFields in advanced NSCLC with a recommendation to continue with the study.⁴ The analysis included data from 210 patients, with a data monitoring committee recommended reducing the sample size to roughly 276 patients from the previous target enrollment of 534 patients. Investigators did not report an added systemic toxicity with the addition of TTFields to systemic therapies.

“LUNAR marks Novocure’s second phase 3 pivotal study to complete enrollment this quarter and is our first of several late-stage clinical trials expected to deliver final data over the next two years,” William Doyle, executive chairman at Novocure, said in a press release. “LUNAR will provide the first randomized dataset to evaluate increased survival when Tumor Treating Fields is used together with immunotherapy, versus immunotherapy alone. I am proud of our employees and am grateful to our principal investigators and patients for their courage and dedication to advancing clinical studies.”

Investigators stated that patients will be followed for 12 months, and that final data is expected to read out towards the end of 2022.

Eftilagimod Alpha Expands Possibilities in Advanced NSCLC

Investigators recently announced that enrollment had completed across all cohorts for the expansion portion for part A of the phase 2 TACTI-002/KEYNOTE-798 trial (NCT03625323), assessing the role of LAG-3 fusion protein eftilagimod alpha (IMP321) plus pembrolizumab (Keytruda) in patients with unresectable/metastatic or PD-X refractory NSCLC.⁵ The trial includes a total of 185 patients in cohorts A (first-line NSCLC), B (second-line NSCLC), and C (second-line head and neck cancer).

“The completion of recruitment for our Phase 2 TACTI-002 trial marks the achievement of a major milestone for Immutep. Our clinical team and partners have worked hard to continue the pace of patient enrollment and finished recruitment much earlier than originally anticipated, despite some challenging conditions brought on by the COVID-19 pandemic,” stated Marc Voigt, chief executive officer at Immustep, said in a press release. “We are excited to be reporting further results from this trial in the coming months. We sincerely thank the patients and their families, and our various partners, for their ongoing support of this important trial.”

Findings from cohort A of the trial read out at the 2021 American Society of Clinical Oncology Annual Meeting,⁶ indicating that immunotherapy-naïve patients treated with eftilagimod alpha (n = 36) experienced a median progression-free survival of 8.2 months with a median OS that was not yet reached. Patients had a complete response rate of 6% by both blinded independent central review (BICR) and local read, as well as partial response rates of 36% and 31% in both respective groups. Patients had an overall response rate of 42% (95% CI, 25.5%-59.2%) by BICR and 36% (95% CI, 20.8%-53.8%) by local read. Investigators also reported disease control rates of 69% and 64% in both groups, respectively.

References

1. Mirati Therapeutics and Verastem Oncology partner to evaluate adagrasib in combination with VS-6766 in KRASG12C-mutant non-small cell lung cancer. News release. Mirati Therapeutics. November 22, 2021. Accessed November 22, 2021. https://yhoo.it/3r5DkCD
2. Mirati Therapeutics announces positive phase 2 topline results for investigational adagrasib in patients with KRAS G12C-mutated advanced non-small cell lung cancer. News release. Mirati Therapeutics, Inc. September 20, 2021. Accessed November 23, 2021. https://bit.ly/3zoRpLZ
3. Novocure announces last patient enrolled in phase 3 pivotal LUNAR trial of tumor treating fields in non-small cell lung cancer. News release. November 22, 2021. Accessed November 22, 2021. https://bit.ly/3cEl7Uh
4. Novocure announces update on phase 3 pivotal LUNAR trial of tumor treating fields in non-small cell lung cancer. News release. Novocure. April 13, 2021. Accessed November 23, 2021. https://bit.ly/2RsowhC
5. Immutep successfully completes recruitment for phase II TACTI-002 study of LAG-3 therapy, eftilagimod alpha. News release. Immutep. November 19, 2021. Accessed November 22, 2021. https://yhoo.it/3oR5oqO
6. Clay TD, Majem M, Felip E, et al. Results from a phase II study of eftilagimod alpha (soluble LAG-3 protein) and pembrolizumab in patients with PD-L1 unselected metastatic non-small cell lung carcinoma. J Clin Oncol. 2021;39(suppl 15):9046. doi:10.1200/JCO.2021.39.15_suppl.9046