High pCR Rate Shows Potential for Neoadjuvant Osimertinib in EGFR+ NSCLC

Collin M. Blakely, MD, PhD

According to updated data from a phase 2 trial (NCT03433469) of neoadjuvant osimertinib (Tagrisso), the third-generation EGFR tyrosine kinase inhibitor (TKI) induced a pathologic complete response (pCR) rate of 69% in patients with surgically resectable EGFR-mutant non– small cell lung cancer (NSCLC).¹

Additionally, the major pCR rate was 15%. The treatment was well tolerated with no serious or grade 3/4 adverse effects, unanticipated delays to surgery, tumors that became unresectable, or any increase in surgical complications reported. The average duration of treatment was 59 days, and the objective response rate was 46%.

“Neoadjuvant osimertinib may lead to a better mechanistic understanding of what drives incomplete response and residual disease [for patients with EGFR-mutant NSCLC],” wrote principal investigator Collin M. Blakely, MD, PhD, an associate professor of medicine at the University of California, San Francisco (UCSF), in a poster presentation of the data.

In the study, participants receive osimertinib 80 mg orally once daily for 28 days for a minimum of 1 cycle prior to surgical resection or until disease progression or unacceptable toxicity. Investigators may give a second cycle of osimertinib prior to surgery if clinically indicated and patients may receive up to 2 weeks of additional therapy while awaiting surgery.

The primary outcome is major pCR, defined as at least 10% residual viable tumor following neoadjuvant osimertinib. Additional efficacy end points include tumor downstaging, objective response, pCR rate, and 5-year disease-free and overall survival rates.

In a detailed analysis, investigators reported pathologic response for the 13 patients treated with osimertinib. Six patients had L858R substitutions, and 7 had exon 19 deletions (del19).

Among patients with L858R substitutions, a partial response was observed in 1. This patient remained on treatment for 82 days and the best radiographic response was –50%. The duration of treatment for the remaining 5 patients with stable disease was 64, 37, 62, 62, and 43 days; the corresponding best radiographic response rates for these patients were –29%, –9%, 0%, –25%, and –7%, respectively.

Among those with del19, 5 had a partial response. For responders, the duration of treatment was 58, 74, 60, 42, and 69 days; the corresponding best radiographic response rates were –40%, –35%, –42%, –33%, and –40%. For the 2 patients with stable disease, the duration of treatment was 57 and 59 days and the best radiographic response rates were 0% and –24%, respectively.

Investigators noted that a loss of function RBM10 mutation was associated with tumors with a lack of pathologic response. Further, an analysis of immune cells for 3 patients revealed that those with residual disease following treatment with osimertinib had decreased macrophages and increased T-cell infiltration compared with the baseline analysis. Based on these results, the investigators hypothesized that T-cell infiltration may correlate with the degree of pathological response.

In an update of the trial’s progress, Blakely noted that 2 sites have joined UCSF and have begun enrollment—the University of California, Davis, and the University of Colorado Denver. Thus far, 30 patients have been screened and 15 of 27 planned patients have been enrolled in the study. Of those 15 patients, 14 have successfully undergone resection and 1 is receiving therapy. Recruitment is ongoing and the study has an estimated completion date of May 31, 2026.

There are no approved neoadjuvant EGFR TKIs for resectable NSCLC. Investigators have assessed various agents in this setting for patients with EGFR-mutant NSCLC, and results have demonstrated trends toward improvements in pathologic response rates. Both gefitinib (Iressa) and erlotinib (Tarceva) have induced pCRs of approximately 50% in phase 1 and 2 studies of patients with early-stage NSCLC; however, the patient populations are small.²

Osimertinib is approved as an adjuvant therapy after tumor resection in patients with NSCLC whose tumors have EGFR exon del19 or exon 21 L858R mutations.3 The drug’s approval was based on findings from the phase 3 ADAURA trial (NCT02511106), which compared the third-generation EGFR TKI with placebo in patients with fully resected stage IB to IIIA EGFR-mutant NSCLC.

In published data, the primary end point of disease-free survival for this patient population was not reached (95% CI, could not be calculated) in the experimental arm vs 27.5 months (95% CI, 22.0-35.0) in the placebo arm (HR, 0.20; 99.12% CI, 0.14-0.30; P < .001).⁴

Building on the demonstrated efficacy of osimertinib in the adjuvant setting and the results of the phase 2 study, investigators commenced the phase 3 neoADAURA trial (NCT04351555).2 The trial is designed to compare the use of neoadjuvant osimertinib with or without chemotherapy to chemotherapy alone in patients with resectable, stage II to IIIB EGFR-mutant NSCLC.

_REFERENCES:

_{1. Blakely C. A phase II trial of neoadjuvant osimertinib for surgically resectable EGFR-mutant non-small cell lung cancer: updated results. Presented at: International Association for the Study of Lung Cancer 2021 World Conference on Lung Cancer. September 8-14, 2021; Denver, Colorado. Abstract P26.02.}

_{2. Friedlaender A, Addeo A, Russo A, Gregorc V, Cortinovis D, Rolfo CD. Targeted therapies in early-stage NSCLC: hype or hope? Int J Mol Sci. 2020;21(17):6329. doi:10.3390/ijms21176329}

_{3. FDA approves osimertinib as adjuvant therapy for non–small cell lung cancer with EGFR mutations. FDA. December 18, 2020. Accessed September 9, 2021. bit.ly/3hipZB9}

_{4. Wu YL, Tsuboi M, He J, et al; ADAURA Investigators. Osimertinib in resected EGFR-mutated non–small-cell lung cancer. N Engl J Med. 2020;383(18):1711-1723. doi:10.1056/NEJMoa2027071}