Targeted Lung Cancer Drug Aces Confirmatory Trial in Frontline Setting

CHICAGO — An oral targeted drug reduced the risk of disease progression or death by 35% compared with chemotherapy when given as first-line treatment for non-small cell lung cancer (NSCLC) patients with EGFR exon 20 insertions, a randomized trial showed.

In patients with nonsquamous NSCLC, median progression-free survival (PFS) reached 10.3 months with sunvozertinib (Zegfrovy) monotherapy versus 7.5 months with carboplatin-pemetrexed chemotherapy (HR 0.65, 95% CI 0.50-0.85, P<0.001), reported John Heymach, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston.

Nearly twice as many patients responded to sunvozertinib (58.9% vs 31.1%), and the drug led to longer responses (median 11.2 vs 7.1 months) and greater levels of mean tumor shrinkage (42.1% vs 24.7%), according to findings presented at the American Society of Clinical Oncology (ASCO) annual meeting and published simultaneously in the New England Journal of Medicine.

“These results support sunvozertinib as first-line treatment for non-small cell lung cancer patients with EGFR exon 20 insertions, with the advantage of a single oral agent administration,” said Heymach, who added that the common side effects were largely related to wild-type EGFR inhibition and were mostly manageable.

Overall survival data were immature and confounded by crossover to sunvozertinib, with median values of 29 to 30 months in the two arms.

Sunvozertinib last year gained accelerated approval for advanced NSCLC in patients previously treated with platinum-based chemotherapy who harbor EGFR exon 20 insertions, which account for roughly 12% of EGFR-mutant NSCLC cases.

Findings of the current trial are likely to secure a first-line indication and full regulatory approval for the tyrosine kinase inhibitor (TKI). It is the only oral option for patients with EGFR exon 20 insertions, with the monoclonal antibody amivantamab (Rybrevant) available in intravenous and subcutaneous forms.

Further distinguishing the two agents is that amivantamab’s first-line indication is in combination with chemotherapy, based on results of the PAPILLON trial where the combination was associated with a median PFS of 11.4 months.

“Sunvozertinib now joins amivantamab-chemo as an evidence-based frontline option,” said ASCO discussant Daniel Shao-Weng Tan, MBBS, PhD, of National Cancer Centre Singapore, who pointed to the drug’s benefit in the exploratory endpoint of second progression-free survival (PFS-2).

Despite two-thirds of patients in the chemotherapy arm crossing over to sunvozertinib, PFS-2 reached 21.7 months in the sunvozertinib arm versus 15.5 months in the chemotherapy arm, “suggesting ongoing benefit in this cohort even after progression, and underscoring the importance of starting with the most effective therapies upfront,” said Tan.

Study Details

Heymach presented data on WU-KONG28, an international phase III trial that randomized 324 previously untreated patients with metastatic NSCLC and EGFR exon 20 insertions in a 1:1 ratio to either oral sunvozertinib (300 mg daily) or up to six cycles of carboplatin-pemetrexed chemotherapy followed by pemetrexed maintenance.

Patients had a median age of 62 years, a majority were women, and over 60% were Asian, with a little under one-third from North America or Europe. Baseline characteristics were generally well balanced between groups, but the sunvozertinib arm had a higher percentage of men, fewer never-smokers, and a greater number of patients with four or more organs involved. Overall, about 13% had brain metastases at baseline.

Landmark analyses of the primary endpoint of PFS showed 1- and 2-year rates of 46% and 23% with sunvozertinib, as compared with 27% and 10% in the chemotherapy arm. Subgroup analyses indicated a relatively greater PFS benefit in Asians versus non-Asians (HRs of 0.56 vs 0.93), in patients without versus with brain metastasis (HRs of 0.62 vs 0.96), and in those with near loop versus far loop exon 20 insertions (HRs of 0.59 vs 0.83).

Nearly all patients in each arm experienced treatment-related adverse events (TRAEs), the most common of which with sunvozertinib included diarrhea (87%), elevations in serum creatine kinase (58%), anemia (57%), rash (53%), and paronychia (49%).

Grade 3 or higher TRAEs occurred in 61.3% of the sunvozertinib group and in 49.3% of the chemotherapy group. Most common with sunvozertinib were serum creatine kinase elevations in 20.9%, diarrhea in 13.5%, and anemia in 9%.

Placing the safety of sunvozertinib in context with other EGFR TKIs, Heymach said the numbers for rash and diarrhea appeared worse than with osimertinib (Tagrisso) but better than with earlier-generation drugs.

“At the end of the day, only 7.4% of patients had to discontinue therapy,” he said, as compared with 11.3% in the chemotherapy arm. It “clearly takes management — those toxicities are real, but it’s also manageable without stopping the drug.”

TRAEs leading to dose reduction were observed in 40.5% of patients in the sunvozertinib arm and 24% of those in the chemotherapy arm. There were no grade 5 TRAEs.