Advances in Non–Small Cell Lung Cancer Therapies

Pharmacy Practice in Focus: OncologyAugust 2021
Volume 3
Issue 4

New treatments show promise for patients with KRAS G12C–mutated disease.

Advances in the lung cancer space are all about biomarkers, explained Alexander Spira, MD, PhD, FACP, director of the Virginia Cancer Specialists Research Institute at The US Oncology Network; and assistant professor of oncology at Johns Hopkins School of Medicine, during a session at the 2021 virtual Community Oncology Alliance Conference.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 receiving a diagnosis of advanced or metastatic disease. One of the most common driver mutations in patients with NSCLC is KRAS G12C, a subset of oncogenic drivers specifically in the KRAS gene.2

KRAS has been one of the primary targets posing a challenge in the lung cancer space. 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

Recent data have shown both a high unmet need and poor outcomes associated with the second-line treatment of KRAS G12C–driven NSCLC. Each year, approximately 25,000 new patients diagnosed are 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, it is not for a lack of trying by investigators, as numerous therapies have been 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?”1

One drug was recently FDA approved for adult patients with KRAS G12C–mutated locally advanced or metastatic NSCLC who have received at least 1 prior systemic therapy, and another has received a breakthrough therapy designation from the agency.3,4

The accelerated approval of sotorasib (Lumakras; Amgen) follows it being granted priority review by the FDA in February.3 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 approve sotorasib was based on the single-arm, open-label, multicenter study CodeBreaK 100 (NCT03600883).3 During this study, the investigators enrolled 124 patients with KRAS G12C–mutant solid tumors, with the study’s primary end point set as centrally reviewed objective response rate (ORR). To be eligible, patients needed to have received a prior line of systemic anticancer therapy that was consistent with both tumor type and disease stage.1-3

The top-line results from the phase 2 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. [Keep 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

The recommended sotorasib dose is 960 mg orally once daily with or without food.3

The most common adverse reactions (≥ 20%) reported in the CodeBreaK 100 trial were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. According to the FDA, the most common laboratory abnormalities (≥ 25%) were decreased lymphocytes, decreased hemoglobin, increased aspartate aminotransferase, increased alanine aminotransferase, decreased calcium, increased alkaline phosphatase, increased urine protein, and decreased sodium.3

A similar drug that will potentially receive approval from the FDA this year is adagrasib (MRTX849; Mirati Therapeutics, Inc), according to Spira.1 The drug received a breakthrough therapy designation from the FDA in June for the potential treatment of patients with NSCLC who harbor the KRAS G12C mutation following prior systemic therapy.4

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

The new designation was based on the phase 1/1b/2 KRYSTAL-1 study (NCT03785249).4 Results from the study demonstrated adagrasib yielded durable responses and broad disease control while also providing extensive coverage throughout the dosing interval.1,5

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).1,5

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, and in the phase 1/1b and 2 cohort, it occurred in 2% of patients.1,5

“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. Spira A. New advances in lung cancer therapies coming in 2021. Presented at: 2021 Community Oncology Alliance 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. News release. Amgen. February 16, 2021. Accessed April 9, 2021.

3. FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC. FDA. Updated May 28, 2021; FDA. Accessed July 16, 2021.

4. 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 16, 2021.

5. 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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