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PFS Doubling Observed in Patients With EGFR+ NSCLC With Addition of Platinum to Gefitinib

Audrey Sternberg
Published Online:7:56 PM, Mon August 26, 2019
The addition of carboplatin and pemetrexed to therapy with gefitinib (Iressa) in patients with non–small cell lung cancer (NSCLC) and an EGFR-sensitizing mutation had a statistically significant effect on progression-free survival (PFS) and overall survival (OS) and represents a new therapy option for these patients.

The addition of the chemotherapeutic agents to the first-generation EGFR tyrosine kinase inhibitor (TKI) doubled PFS time and had an absolute OS improvement of 25%, wrote the study investigators, led by Vanita Noronha, MBBS, MD, DM, in their article published in the Journal of Clinical Oncology.  

Efficacy of the combination was assessed in a randomized, single-institution, open-label phase III trial against single-agent gefitinib in 350 patients with cytologically confirmed NSCLC with EGFR mutations in exon 19, 21, or 18. Mutation analysis was performed on biopsy or by cytology cell blocks by TaqMan-based real-time polymerase chain reaction. Patients had to have localized stage IIIb disease not amenable to radical therapy or stage IV disease planned for first-line systemic therapy, adequate organ function, no history of interstitial lung disease, and an ECOG performance status of ≤2.

Patients were assigned in a 1:1 randomization to either gefitinib 250 mg daily with pemetrexed 500 mg/m2 and carboplatin AUC 5 every 21 days for 4 cycles followed by maintenance pemetrexed until disease progression (n = 174) or once-daily gefitinib 250 mg (n = 176).

There were 139 patients (80%) in the combination arm who completed 4 cycles of chemotherapy, 14 (8%) who had 3 cycles, 5 (3%) who had 2 cycles, and 11 (7%) who had only 1 cycle. Twenty-two (13%) patients required dose reductions and 39 (22%) required dose delays >1 day during the first 4 cycles of chemotherapy. Gefitinib was taken for a median of 327 days in this group with 39 patients holding therapy for a median of 7 cumulative days.

In the single-agent gefitinib group, the EGFR TKI was taken for a median of 260 days. Dose holds occurred in 51 patients for a median of 5 cumulative days.

The primary objective was investigator-assessed PFS, defined as the time between randomization to the date of progressive disease or death. Responses were assessed using contrast-enhanced CT scans every 3 cycles in the chemotherapy group or every 2 months in the gefitinib group. Secondary endpoints included OS, toxicity, response rate, and quality of life.

The estimated median PFS in chemotherapy-treated patients was 16 months versus 8 months in those receiving gefitinib alone (unadjusted HR, 0.51; 95% CI, 0.39-0.66; P <.001), and these improvements were consistent across patient subgroups, including those with brain metastases. Second PFS events, defined as the time from randomization to the second progressive-disease event, occurred at a median of 23 months with chemotherapy and 14 months with gefitinib alone (HR, 0.69; 95% CI, 0.53-0.92; P <.001).

The addition of chemotherapy to gefitinib resulted in a prolonged median OS that was not reached versus 17 months in the single-agent arm (HR, 0.45; 95% CI, 0.31-0.65; P <.001). Rates of OS at 18 months were 74.3% and 48.7%, respectively.

The best radiologic responses observed in patients in the gefitinib-and-chemotherapy arm were complete remission (CR) in 5 (2.9%), partial remission (PR) in 126 (72.4%), and stable disease (SD) in 22 (12.6%) versus 1 CR (0.6%), 109 PRs (61.9%), and SD in 39 (22.2%) in the gefitinib-alone arm. Thus, the objective response rate was higher for patients with chemotherapy at 75.3% versus 62.5% without. Progressive disease was observed in 9 patients (5.2%) and 12 patients (6.8%), respectively.

Clinically relevant serious toxicities occurred more with chemotherapy added to gefitinib (51%) than with gefitinib alone (25%). Excessive toxicity in the experimental arm was primarily the result of increased myelosuppression, nephrotoxicity, and hypokalemia when compared with the control. Common grade ≥3 toxicities occurring in >5% of patients with chemotherapy included hypertension (26.2% vs 23.5% without chemotherapy), hyponatremia (23.8% vs 15.9%), anemia (19.5% vs 1.1%), neutropenia (15.9% vs 0%), diarrhea (14% vs 8.2%), febrile neutropenia (11% vs 0%), non-neutropenia infection (11% vs 5.9%) hypokalemia (7.9% vs 1.2%), renal dysfunction (6.1% vs 0.6%), and nausea (5.5% vs 1.8%).

Thirty patients discontinued pemetrexed as a result of toxicities—including nephrotoxicity, febrile neutropenia, non-neutropenic infections, and gastrointestinal toxicities—but continued therapy with gefitinib. One patient each in the gefitinib arm discontinued therapy as a result of interstitial lung disease and non-neutropenic infection. There were 2 fatal toxicities in the entire cohort; one occurred due to febrile neutropenia in the chemotherapy arm as well as one case of interstitial pneumonitis in the gefitinib-only arm.

“All the landmark trials in which an EGFR-directed oral TKI was compared with platinum-based doublet chemotherapy demonstrated a PFS benefit, but because of various factors including crossover, none demonstrated an OS benefit,” wrote the study investigators. “To the best of our knowledge…the [gefitinib plus chemotherapy] regimen used in the present trial is [one of] the only regimens that prolongs OS over standard of care in EGFR-mutated lung cancer.”  
Noronha V, Patil VM, Joshi A, et al. Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer [published online August 14, 2019]. J Clin Oncol. doi: 10.1200/JCO.19.01154.

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