Phase 2 Data Signal a Potential Role for Neoadjuvant Osimertinib in EGFR-mutant NSCLC

Collin M. Blakely, MD, PhD

Updated data from a phase 2 trial (NCT03433469) presented at the 2021 World Conference on Lung Cancer showed that neoadjuvant osimertinib (Tagrisso) induced a pathologic complete response (pCR) among patients with surgically resectable EGFR-mutant non–small cell lung cancer (NSCLC).¹

Specifically, the pCR rate among 13 patients was 69%; 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 an 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 Collin M. Blakely, MD, PhD, associate professor of medicine and principal investigator of the study at the University of California, San Francisco, in poster of the data.

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.

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

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

For patients del19, 5 patients had a partial response. For responders the durations of treatment were 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 durations of treatment were 57 and 59 days, respectively, and the best radiographic response rates were 0% and –24%, respectively.

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

In an update of the trial progress, Blakely noted that 2 sites joined UCSF and have begun enrollment—the University of California, Davis, and the University of Colorado, in Denver. Thus far, 30 patients have been screened and 15 of 27 planned patients have enrolled on the study. Of the 15 patients, 14 have successfully undergone resection and 1 patient is on 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 towards improvements in pathologic response rates. Both gefitinib (Iressa) and erlotinib (Tarceva) have induced pCRs of approximately 50% in phase 1 and 2 studies; however, patient populations are small.²

Osimertinib is approved as for adjuvant therapy after tumor resection in patients with NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations.³ The 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 neoadjuvant osimertinib with or without chemotherapy to chemotherapy alone in patients with resectable, stage II-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: 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, John T, 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