Afatinib Shows Encouraging Efficacy and Safety in Late Stage EGFR-Mutant NSCLC

Andrew John Piper-Vallillo, MD

Integrating afatinib (Gilotrif) into standard-of-care chemoradiation with or without surgery demonstrated encouraging efficacy, feasibility, and safety results in patients with stage III EGFR-mutation positive non–small cell lung cancer (NSCLC), according to final results of the ASCENT trial (NCT01553942) presented during the International Association for the Study of Lung Cancer 2021 Targeted Therapies of Lung Cancer Meeting.¹

The role of neoadjuvant EGFR tyrosine kinase inhibitors (TKIs), as well as adjuvant EGFR TKIs in unresectable disease, remains unclear, although results from the ADAURA trial (NCT02511106) showed that disease-free survival in patients with stage IB to IIIA EGFR mutation–positive NSCLC was significantly longer in patients who received osimertinib (Tagrisso) than in those who received placebo.2 When the ASCENT trial was undergoing design, there were no data for EGFR TKIs in stage III NSCLC, said Andrew John Piper-Vallillo, MD, presenting author and clinical fellow in hematology/oncology at Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, Massachusetts.

In ASCENT, patients received 40 mg afatinib once a day for 2 months and then underwent restaging based on the primary end point assessment, objective response rate (ORR). Patients then received chemoradiation therapy (60-72 Gy) and concurrent cisplatin at 75 mg/m² and pemetrexed at 500 mg/m² every 3 weeks for up to 4 cycles, or induction chemoradiation comprised of neoadjuvant radiation therapy (45-54 Gy) and concurrent cisplatin and pemetrexed for 2 cycles and surgical resection. If there was no evidence of progressive disease, patients then received adjuvant afatinib for 2 years (FIGURE on page 411). Surgery involved lobectomy or pneumonectomy. Secondary end points were progression-free survival (PFS), overall survival (OS), and safety.

Afatinib is a pan-ERBB TKI indicated for advanced EGFR mutation–positive NSCLC. Approval was based on demonstration of durable responses in a subset of 32 afatinib-treated patients with metastatic NSCLC whose tumors harbor nonresistant EGFR mutations enrolled in 1 of 3 clinical trials (LUX-Lung 2, NCT00525148; LUX-Lung 3, NCT00949650; or LUX-Lung 6, NCT01121393).³

The study was planned for 30 patients, but closed for slow accrual in 2020, enrolling 19 patients between September 2012 and January 2020. The median age was 56 years (range, 34-75) with 14 female patients. Twelve (63%) patients were determined to have exon 19 deletion and 9 (37%) had the L858R mutation. Patients were White (68%) or of Asian descent (32%). Fifty-three percent were never smokers, and all patients had adenocarcinoma. Of the 19 participants, 10 underwent resection. Resectability was determined at diagnosis after multidisciplinary team discussion, per protocol, Piper-Vallillo said.

“ORR was 58% [95% CI, 33%-80%], determined after 2 months of treatment with neoadjuvant afatinib,” Piper-Vallillo said. “Of the 9 patients with unresectable disease who completed neoadjuvant therapy, 1 patient progressed, 1 patient converted to operable, [and] 7 patients proceeded to definitive chemoradiotherapy,” he said.

In patients who were unresectable and received definitive chemotherapy, 1 patient declined to receive adjuvant afatinib. Six patients received adjuvant afatinib for 2 years. In the resectable arm, 10 patients received neoadjuvant chemoradiotherapy and surgery. In this subgroup, the median radiotherapy dose was 54 Gy and patients underwent 2 median chemotherapy cycles. Ten patients underwent surgical resection, and 7 had a major pathology response. Three patients declined adjuvant afatinib.

A total of 13 patients from both arms received adjuvant afatinib with a median duration of 22.4 months, excluding 4 patients who remained on therapy. Five patients completed the planned 2 years of therapy, 3 patients discontinued early, 1 patient had recurrent disease while on adjuvant afatinib, and 4 remain on adjuvant therapy.

In the intention-to-treat population (n = 19), the median PFS was 34.6 months (95% CI, 16.9-66.1), median OS was 69.1 months (95% CI, 29.4-not releasable), and the 2-year OS rate was 88% (95% CI, 59%-97%). Further outcome measures demonstrated a recurrent tumor in 9 of 19 patients (47%), CNS-only recurrence in 5 of 9 patients (55%), recurrence post surgery in 3 of 10 patients (30%), and recurrence postchemoradiotherapy in 5 of 7 patients (71%).

Regarding safety, 47% (9 of 19) of patients required neoadjuvant afatinib dose reduction from 40 mg to 30 mg, and 1 patient had a perisurgical adverse effect, which was atrial fibrillation that required treatment. Thirty-eight percent (5 of 13) of patients required adjuvant afatinib dose reduction from 40 mg to 30 mg or 30 mg to 20 mg. An additional 23% (3 of 13) discontinued adjuvant afatinib because of toxicity.

Notable grade 3 or 4 adverse effects included 6 patients with rash, 5 with diarrhea, 3 with esophagitis, and 3 with nausea. Two patients experienced grade 2 pneumonitis while receiving chemoradiotherapy or adjuvant afatinib. There were no treatment-related deaths.

Results from this integration of afatinib with standard of care chemoradiation, along with the interim results of ADAURA, support the use of genotype-directed therapies in stage III EGFR-mutant NSCLC, although the optimal sequence of TKI therapy needs to be defined, Piper-Vallillo said. Because this trial was closed due to slow accrual, future studies will require multicenter participation, he said.

_References:

_{1. Piper-Vallillo AJ, Mak R, Lanuti, et al. The ASCENT trial: A phase II study of neoadjuvant/adjuvant afatinib, chemoradiation +/- surgery for stage III EGFR-mutant NSCLC. Presented at International Association for the Study of Lung Cancer 2021 Targeted Therapies of Lung Cancer Meeting. February 17-20, 2021; virtual. Accessed March 9, 2021. https://bit.ly/2Nn23Rq}

_{2. Wu YL, Tsuboi M, He J, et al. Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2020;383(18):1711-1723. doi:10.1056/NEJMoa2027071}

_{3. FDA broadens afatinib indication to previously untreated, metastatic NSCLC with other non-resistant EGFR mutations. FDA. News release. Updated January 16, 2018. Accessed February 15, 2021. https://bit. ly/3eIbhTQ}