Adjuvant Gefitinib Delays Recurrence in EGFR+ NSCLC

Yi Long Wu, MD

Adjuvant gefitinib (Iressa) reduced the risk of disease recurrence by 40% versus standard chemotherapy in patients with EGFR-positive non—small cell lung cancer (NSCLC), according to findings from the phase III ADJUVANT (CTONG 1104) trial.¹

At a median follow-up of 36.5 months (range, 0.1-62.8), the median disease free survival (DFS) was 28.7 months (95% CI, 24.9-32.5) with gefitinib versus 18.0 months (95% CI, 13.6-22.3) with a regimen of vinorelbine plus cisplatin (HR, 0.60; 95% CI, 0.42-0.87; P = .005).

The 3-year DFS rates were 34.0% versus 27.0%, respectively (P = .013). At the time of the analysis, 76 (34.2%) overall survival (OS) events had occurred. The results were presented on a presscast held in advance of the 2017 ASCO Annual Meeting.

“Adjuvant gefitinib should be considered as an important option for stage II-IIIA lung cancer patients with an active EGFR mutation,” said lead study author Yi-Long Wu, MD, a director of the Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangzhou, China.

Between September 19, 2011, and April 24, 2014, CTONG 1104 (NCT01405079) accrued 222 patients with completely resected stage II-IIIA (N1-N2) NSCLC harboring an EGFR-activating mutation. Baseline characteristics were balanced. Patients were stratified by lymph node status (pN1/N2) and EGFR mutation status.

The study randomized patients to gefitinib at 250 mg daily for 24 months or vinorelbine (25 mg/m², day 1 and day 8) plus cisplatin (75 mg/m², day 1) every 3 weeks for 4 cycles. The primary endpoint was DFS. Secondary endpoints included 3-year DFS, 5-year DFS, OS, 5-year OS, safety, health-related quality of life, and exploratory biomarker analyses.

The median duration of treatment was 21.9 months with gefitinib and 4 cycles with chemotherapy. A subgroup analysis showed that in the gefitinib cohort, there was a significant correlation between lymph node status (pN1/N2) and DFS (P <.05).

Toxicities were lower in the gefitinib arm. All-grade adverse events (AEs) occurred in 57.5% of the gefitinib cohort, compared with 80.5% of the chemotherapy group. AEs of all grades occurring at higher rates with vinorelbine/cisplatin versus gefitinib included neutropenia (52.9% vs 2.8%), anemia (50.6% vs 1.9%), leukopenia (47.1% vs 3.8%), myelosuppression (13.8% vs 0%), nausea (43.7% vs 2.8%), vomiting (41.4% vs 4.7%), and anorexia (23% vs 1.9%).

All-grade AEs reported at higher rates with gefitinib versus chemotherapy included rash (40.6% vs 0%), elevated ALT (27.4% vs 3.4%), elevated AST (11.3% vs 1.1%), and diarrhea (26.4% vs 4.6%). The authors noted that there were no reported incidents of interstitial lung disease in the gefitinib arm.

The rate of grade ≥3 adverse events was 12.3% with gefitinib versus 48.3% with chemotherapy. Grade ≥3 AEs occurring at higher rates with chemotherapy versus gefitinib included neutropenia (34.5% vs 0%), leukopenia (16.1% vs 0%), vomiting (9.2% vs 0%), nausea (6.9% vs 0%), anemia (5.7% vs 0.9%), and myelosuppression (3.4% vs 0%).

Grade 3 AEs occurring at higher rates in the gefitinib arm included elevated ALT (1.9% vs 0%), elevated AST (1.9% vs 0%), rash (0.9% vs 0%), and diarrhea (0.9% vs 0%).

Previously reported trials in unselected NSCLC populations have fallen short when attempting to demonstrate a benefit for anti-EGFR tyrosine kinase inhibitors in the adjuvant setting.

In the phase III RADIANT trial, adjuvant erlotinib did not significantly improved DFS versus placebo in patients with completely resected stage IB to IIIA NSCLC with EGFR expression by IHC or EGFR amplification by FISH testing.² The median DFS was 50.5 months with erlotinib versus 48.2 months with placebo (HR, 0.90; 95% CI, 0.74-1.10; P = .324).

The phase III NCIC CTG BR19 study compared gefitinib with placebo in patients with completely resected stage IB, II, or IIIA NSCLC.³ At a median follow-up of 4.7 years, OS (HR, 1.24; 95% CI, 0.94-1.64; P = .14) and DFS (HR, 1.22; 95% CI, 0.93-1.61; P = .15) were not different between the gefitinib and placebo arms.

The FDA approved gefitinib (Iressa) in July 2015 for the frontline treatment of patients with metastatic, EGFR-positive NSCLC with an exon 19 deletion or exon 21 (L858R) substitution.

Commenting on the CTONG 1104 findings, Bruce E. Johnson, MD, ASCO president-elect, said, “The part that we will ultimately be interested in seeing is whether [gefitinib] will prolong overall survival in the longer follow-up study which Dr Wu’s group is planning to do.”

“Many doctors will begin testing these lung cancer tumors right after surgery to see if they actually have an EGFR mutation. That is not currently standard of care in the United States, where typically the testing doesn’t take place until the cancer recurs or becomes metastatic.”

If it is an option, Schilsky said that in addition to the upcoming survival data from CTONG 1104, other factors that must be considered are treatment length and cost.

“We’re talking about 12 weeks of chemotherapy versus 2 years of gefitinib chemotherapy. It’s a big commitment on the part of patients to adhere to 2 years of continuous treatment. Secondly…the cost of gefitinib treatment is far greater than the cost of the 12 weeks of chemotherapy. And so, doctors and patients are going to have to have very thoughtful discussions.”

References

1. Wu Y-L, Zhong W, Wang Q, et al. Gefitinib (G) versus vinorelbine+cisplatin (VP) as adjuvant treatment in stage II-IIIA (N1-N2) non-small-cell lung cancer (NSCLC) with EGFR-activating mutation (ADJUVANT): a randomized, phase III trial (CTONG 1104). J Clin Oncol. 2017 (suppl; abstr 8500).
2. Kelly K, Altorki NK, Eberhardt WE, et al. Adjuvant erlotinib versus placebo in patients with stage ib-iiia non-small-cell lung cancer (RADIANT): a randomized, double-blind, phase iii trial. J Clin Oncol. 2015;33(34):4007-40014. doi: 10.1200/JCO.2015.61.8918.
3. Goss GD, O'Callaghan C, Lorimer I, et al. Gefitinib versus placebo in completely resected non-small-cell lung cancer: results of the NCIC CTG BR19 study. J Clin Oncol. 2013;31(27):3320-3326. doi: 10.1200/JCO.2013.51.1816.

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View more from the 2017 ASCO Annual Meeting

Also commenting on the presscast, Richard L. Schilsky, MD, Chief Medical Officer of ASCO, said 1 impact of Wu et al’s study will be earlier EGFR testing in this patient population to determine whether using an EGFR inhibitor is an option.