New Non–Small Cell Lung Cancer Therapies Coming in 2021


In the United States, non–small cell lung cancer accounts for 80% to 85% of all lung cancers, with most patients initially diagnosed with advanced or metastatic disease.

Advances in the lung cancer space are all about biomarkers, explained Alexander Spira, MD, PhD, FACP, director, Virginia Cancer Specialists Research Institute, US Oncology Research, assistant professor of Oncology, Johns Hopkins School of Medicine, during a session at Community Oncology Alliance Virtual 2021 Conference.1

“It all started with EGFR way back when,” Spira said during the session. “The first targeted therapy was Gleevec in, I think, 2000. EGFR came about in 2005, and now these are all the targeted therapies and known genetic drivers among cancer. We need to be testing for them, most importantly, but there are now a lot more developing targets.”1

One of the primary targets that has been challenging in the lung cancer space has been KRAS. Spira explained that KRAS has been described as an “undruggable target,” which specifically relates to how intricate KRAS is in the signaling pathways for lung cancer.1

In the United States, non–small cell lung cancer (NSCLC) accounts for 80% to 85% of all lung cancers, with most patients (66%) initially diagnosed with advanced or metastatic disease. One of the most common driver mutations in patients with NSCLC is KRAS G12C, which is a subset of oncogenic drivers specifically in the KRAS gene.2

Currently, data have shown that there is both a high unmet need and poor outcomes associated with the second-line treatment of KRAS G12C-driven NSCLC. Each year, there are approximately 25,000 new patients diagnosed with KRAS G12C-mutated NSCLC across the country.2

Spira noted that KRAS has specifically been referred to in the field as “undruggable” for many years; however, not for a lack of trying by investigators, as numerous therapies were thoroughly assessed for potential benefit.1

“They all have failed. So, it’s been a very frustrating area,” Spira said during the session. “So how do we target it right now? There are 2 drugs that are emerging with a likely FDA-approval soon.”1

Sotorasib, which treats patients with KRAS G12C–mutated locally advanced or metastatic NSCLC, is one such treatment that is likely to receive approval this year following a priority review designation by the FDA in February.1

A first-in-class, highly selective, irreversible KRAS G12C inhibitor, sotorasib works by binding KRAS in the inactive state in order to hinder downstream signaling effects.1

The FDA’s decision to grant sotorasib priority review was based on the phase 2, open-label multicenter study CodeBreaK 100. During this study, the investigators enrolled patients with KRAS G12C-mutant solid tumors, with the study’s primary endpoint set as centrally reviewed objective response rate (ORR).1,2

In order to be eligible, patients need to have received a prior line of systemic anticancer therapy that was consistent with both their tumor type and disease stage. In total, the trial enrolled 126 patients, 124 of whom had centrally evaluable lesions at baseline.1,2

The topline results from the trial demonstrated that 80% of patients achieved disease control, including 3 complete responses (CRs) and 43 partial responses (PRs). The best ORR was approximately 2% CRs, 34% PRs, and 40% stable disease.1

“There’s a pretty deep response that was seen in many of our patients,” Spira said during the session. “It works, and in many of our patients it works very well. Keeping also in mind that many of these patients have multiple lines of therapy, making it of course less likely that you can have a deeper response to tumor volume. So, pretty impressive results.”1

A similar drug that will potentially receive FDA approval this year is adagrasib, according to Spira. Adagrasib was specifically designed to be a differentiated selective inhibitor of KRAS G12C.1

Spira noted that adagrasib was designed to be even more specific than sotorasib, as it is a highly potent inhibitor with a very high selectivity for the KRAS G12C protein. Additionally, it was designed to have a long half-life, oral bioavailability, and tissue distribution.1

Results from the phase 1/1b/2 KRYSTAL-1 study demonstrated adagrasib yielded durable responses and broad disease control, while also providing extensive coverage throughout the dosing interval.1,3

At a dose of 600 mg given twice-daily, adagrasib yielded an ORR of 43% in the phase 1/1b cohort (n = 14), and 45% in the pooled population of the phase 1/1b and 2 cohorts (n = 51), which are data comprised of all PRs.1,3

Furthermore, the results demonstrated a disease control rate of 100% in the phase 1/1b cohort and 96% in the phase 1/1b and 2 cohort, with 57% and 51% of patients having stable disease, respectively. Additionally, in the phase 1/1b cohort, disease progression did not occur, whereas in the phase 1/1b and 2 cohort it occurred in 2% of patients.1,3

“Almost never seen before in this phase 1/1b cohort [is] a 100% disease control rate,” Spira said during the session. “I don’t think I’ve ever seen that in a study before. It did drop down to 96% in the pooled population, but it’s pretty remarkable numbers here.”1


  1. Spira A. New Advances in Lung Cancer Therapies Coming in 2021; April 9, 2021. Presented at: Community Oncology Alliance Virtual 2021 Conference; Accessed April 9, 2021.
  2. FDA Grants Sotorasib Priority Review Designation For The Treatment Of Patients With KRAS G12C-Mutated Locally Advanced Or Metastatic Non-Small Cell Lung Cancer. Thousand Oaks, CA: Amgen; Feb 16, 2021. Accessed April 9, 2021.
  3. Virgil H. Adagrasib Demonstrates Favorable Efficacy, Pharmacokinetic Profile in Advanced KRAS G12C+ NSCLC. OncLive. March 25, 2021. Accessed April 9, 2021.
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