Year in Review: Lung Cancer

Lung cancer developments in 2021 were highlighted by the approval of an agent for a target once considered “undruggable,” the first approval of an adjuvant immunotherapy, broader screening recommendations from the U.S. Preventive Services Task Force (USPSTF), and more.

First Approvals Targeting KRAS and a Rare EGFR Mutation

In May, the FDA granted accelerated approval to sotorasib (Lumakras) as a second-line agent for non-small cell lung cancer (NSCLC) harboring KRAS G12C mutations, the first and currently only drug targeting a KRAS mutation for any cancer.

G12C mutations, specifically, account for approximately 13% of all mutations in NSCLC.

“KRAS mutations have long been considered resistant to drug therapy, representing a true unmet need for patients with certain types of cancer,” Richard Pazdur, MD, director of FDA Oncology Center of Excellence, said in a statement at the time.

Approval was based on 124 patients with locally advanced or metastatic NSCLC in CodeBreaK 100 — a multicenter phase II study testing daily oral sotorasib. All participants had KRAS G12C mutations and had progressed on either platinum-based chemotherapy, an immune checkpoint inhibitor, or both. Treatment with sotorasib yielded an objective response rate (ORR) of 36%, with a majority of patients responding for at least 6 months.

The agency also approved two agents — amivantamab (Rybrevant) and mobocertinib (Exkivity) — for NSCLCs with EGFR exon 20 insertion mutations, the first-ever treatments for this rare target. These mutations are found in roughly 2%-3% of NSCLCs, and are associated with rapid tumor growth.

Support for amivantamab’s approval came from the phase I CHRYSALIS trial, which included 81 patients who received the agent on or after progressing on platinum-based chemotherapy. The bispecific antibody yielded an ORR of 40% and a median duration of response (DOR) of 11.1 months, with nearly two-thirds of responses lasting beyond 6 months.

Mobocertinib’s approval — a drug specifically designed to target these rare EGFR mutations — was based on results of a phase I/II study involving 114 patients pretreated with platinum-based chemotherapy. Here, the confirmed ORR was 28%, the disease control rate was 78%, median DOR was 17.5 months, and median overall survival (OS) reached 24 months.

First Checkpoint Inhibitor Approved in the Adjuvant Setting

The FDA also expanded the approval of the PD-L1 inhibitor atezolizumab (Tecentriq) to include the adjuvant treatment of stage II-IIIa NSCLC (following surgery and platinum-based chemotherapy) for patients whose tumors express PD-L1. The approval marks the first immunotherapy to get an adjuvant indication for NSCLC.

Support came from IMpower010, a randomized trial of more than 1,000 patients. Among those with PD-L1 expression ≥1%, disease-free survival (DFS) was significantly improved with atezolizumab plus best supportive care versus the latter alone (HR 0.66, 95% CI 0.50-0.88, P=0.004). Median DFS was not reached in the atezolizumab arm, as compared to 35.3 months in the best supportive care arm.

More patients in the atezolizumab arm were alive and disease free both at 2 years (74.6% vs 61.0% for the control arm) and 3 years (60.0% vs 48.2%, respectively).

USPSTF Broadens Lung Cancer Screening Eligibility

The USPSTF finalized new lung cancer screening recommendations in 2021, announcing that current and former heavy smokers should begin annual low-dose CT screening at age 50.

This update lowered the age to start screening by 5 years and also redefined “heavy smoker” as those with a 20 pack-year history (previously a 30 pack-year history).

“By screening people who are younger and who have smoked fewer cigarettes, we can save more lives and help people remain healthy longer,” said USPSTF member Michael Barry, MD, of Massachusetts General Hospital in Boston.

The broader criteria are expected to double the number of people eligible for screening, according to the task force, and will likely lead to an increase in screening access for Black individuals and women.

Withdrawn Indication in SCLC

In March, Merck announced that pembrolizumab’s (Keytruda) indication in small-cell lung cancer (SCLC) would be withdrawn after consultation with the FDA. The PD-1 inhibitor had received an accelerated approval 2 years earlier as a second-line agent for SCLC, but while the confirmatory KEYNOTE-604 trial demonstrated improved progression-free survival with the drug, no OS benefit was seen.

The move followed Bristol Myers Squibb’s announcement, before the start of the year, that it would withdraw the SCLC indication for nivolumab (Opdivo) after two confirmatory trials also failed to demonstrate improvements in OS.

Neoadjuvant Immunotherapy Gains Traction in NSCLC

Several studies this year reported positive findings with immunotherapy in the pre-operative setting.

In the phase III CheckMate 816 study presented at the American Association for Cancer Research meeting, pathologic complete response (pCR) rates in operable NSCLC increased from 2.2% with neoadjuvant chemotherapy to 24% with the addition of nivolumab.

Meanwhile in the phase II NEOSTAR study, 38% of operable NSCLC patients randomized to nivolumab plus ipilimumab (Yervoy) achieved a major pathological response (MPR), which compared favorably to the MPR rate for those assigned to nivolumab alone (22%) and historical rates with neoadjuvant chemotherapy (7-27%).

And at the virtual World Conference on Lung Cancer in January, the Lung Cancer Mutation Consortium 3 study showed positive results in operable early-stage NSCLC, with 21% of patients achieving an MPR with neoadjuvant atezolizumab, while more than 40% had pathologic downstaging and 7% achieved pCRs. An exploratory analysis also suggested improved OS with the approach compared to historical data.

Other recent developments in lung cancer:

New Drug OK’d for Chemo-Induced Myelosuppression in SCLC

TROP2 Antibody-Drug Conjugate Shows Promise in Lung Cancer

Entrectinib Impresses in Certain Lung Cancers

Antibody-Drug Conjugate Active in Resistant Lung Cancer

MedPage Today‘s Charles Bankhead and Mike Bassett contributed to this year in review.