No Benefit to Neoadjuvant Durvalumab/Chemo Followed by Adjuvant Durvalumab in EGFR+ NSCLC

David H. Harpole, MD

According to findings from the phase 3 AEGEAN trial (NCT03800134), adding durvalumab (Imfinzi) to chemotherapy prior to surgery, followed by adjuvant durvalumab, did not provide a clear clinical benefit in patients with early-stage non–small cell lung cancer (NSCLC) harboring an EGFR mutation, a presentation given at the 2023 IASLC World Conference on Lung Cancer revealed.¹

Data from a subgroup of patients with EGFR-mutated NSCLC who were enrolled in the trial before a protocol amendment (n = 51) showed that at a median follow-up of 16.6 months (range, 0.0-36.4), the median event-free survival (EFS) in the durvalumab arm (n = 26) was 30.8 months (95% CI, 11.4-not reached [NR]) by blinded independent central review (BICR) and RECIST v1.1 criteria vs 19.6 months (95% CI, 14.3-NR) in the placebo arm (n = 25; HR, 0.86; 95% CI, 0.35-2.19). The estimated 12-month EFS rates in the investigative and control arms were 65.2% and 77.8%, respectively; the estimated 24-month EFS rates were 59.3% and 44.9%, respectively.

Moreover, the pathologic complete response (pCR) rate reported in the durvalumab arm was 3.8% vs 0% in the placebo arm (difference, 3.8%; 95% CI, -10.0% to 19.1%). Major pathologic response (MPR) was achieved by 7.7% of those in the durvalumab arm vs 4% of those in the placebo arm (difference, 3.7%; 95% CI, -13.2% to 21.0%).

These data contrast with the outcomes observed for the overall patient population.^2,3 Previously reported data from the modified intention-to-treat population showed that at a median follow-up of 11.7 months (range, 0.0-46.1), the median EFS with durvalumab (n = 366) was not yet reached (95% CI, 31.9-NR) vs 25.9 months (95% CI, 18.9-NR) with placebo (n = 374; HR, 0.68; 95% CI, 0.53-0.88; P = .003902). The estimated 12-month EFS rates were 73.4% and 64.5%, respectively, and the 24-month rates were 63.3% and 52.4%, respectively.

The pCRs achieved in the durvalumab and placebo arms were 17.2% and 4.3%, respectively (difference, 13.0%; 95% CI, 8.7%-17.6%; P = .000036). The MPRs reported in these groups were 33.3% and 12.3%, respectively (difference, 21.0%; 95% CI, 15.1%-26.9%; P = .000002).

“In the EGFR-mutated subgroup, participants who received durvalumab had reasonably similar outcomes compared with those who received placebo. pCR was achieved by 4% of participants who received durvalumab vs none who received placebo, and the risk of cancer significantly worsening, returning, or the participant dying was 14% lower with durvalumab,” David H. Harpole, MD, a thoracic surgeon in the Department of Surgery at Duke University Medical Center, in Durham, North Carolina, and colleagues, wrote in a presentation of the data.¹

They added that “Interpreting the findings of this research is difficult, as AEGEAN was not designed to assess outcomes in this population and the EGFR-mutated subgroup contained only a small number of participants…Because the outcomes for the EGFR-mutated subgroup differed from the outcomes for the overall patient population enrolled in AEGEAN, testing for EGFR mutations should be considered at the earliest opportunity for patients with early-stage NSCLC.”

Patients with treatment-naïve, resectable NSCLC who had stage IIA to IIIB disease were enrolled to the phase 3 trial. To participate, patients must have been slated to undergo lobectomy, sleeve resection, or bilobectomy. They also needed to have an ECOG performance status of 0 or 1 and confirmed PD-L1 status.

Study participants (n = 802) were randomly assigned 1:1 to the durvalumab or placebo arms. Those in the investigative arm received intravenous (IV) durvalumab at 1500 mg plus platinum-based chemotherapy every 3 weeks for 4 cycles, followed by surgery, and adjuvant durvalumab at 1500 mg every 4 weeks for 12 cycles. Those in the control arm received IV placebo plus platinum-based chemotherapy every 3 weeks for 4 cycles, followed by surgery, and adjuvant placebo for every 4 weeks for 12 cycles.

Stratification factors included disease stage (stage II vs III) and PD-L1 expression (≥1% vs <1%).

Notably, investigators designed and initiated AEGEAN before external study findings suggested that patients with NSCLC who harbored EGFR or ALK aberrations may achieve limited responses with immunotherapy approaches. As such, in 2021, the trial protocol was amended to exclude this subgroup of patients, preventing further enrollment of this population.

Efficacy analyses were performed on a modified population that excluded the subgroup of patients with EGFR/ALK aberrations. Primary end points were pCR by central laboratory and per IASLC 2020 criteria, and EFS by BICR and RECIST v1.1 criteria. Secondary end points included MPR by central laboratory and IASLC 2020 criteria, disease-free survival by BICR and RECIST V1.1 criteria, and overall survival.

Investigators performed an analysis to evaluate outcomes in the subgroup of patients with EGFR-mutated disease, and these findings were shared at the 2023 IASLC WCLC. Of the 802 patients who underwent randomization, 41 harbored an EGFR mutation. “Several imbalances in baseline characteristics between the durvalumab and placebo arms are present within the EGFR-mutated subgroup,” Harpole said.

In the durvalumab arm, 30.8% of patients were male and 69.2% were female; in the placebo arms, these rates were 48% and 52%, respectively. Moreover, 57.7%, 38.5%, and 3.8% of those in the durvalumab arm were Asian, White, or other, respectively; in the placebo arm, these rates were 84%, 16%, and 0%, respectively.

Regarding EGFR mutation type, in the durvalumab arm, 53.8% had exon 19 deletions, 11.5% had L858R mutations, 3.8% had other, and 30.8% did not have this information specified; in the placebo arm, these rates were 36%, 16%, 24%, and 28%, respectively. In the durvalumab arm, 23.1% and 76.9% of patients received cisplatin or carboplatin as their planned neoadjuvant platinum agent; these rates were 36% and 64%, respectively, in the placebo arm.

At the time of the first planned interim analysis of EFS, which had a data cutoff date of November 10, 2022, the median follow-up for this measure among censored patients in this subgroup was 16.6 months (range, 0.0-36.4). In the neoadjuvant phase, all patients in the durvalumab and placebo arms received treatment; 84.6% vs 88% completed 4 cycles of durvalumab or placebo and 84.6% vs 88% underwent surgery. All patients in the durvalumab arm vs 90% of those in the placebo arm had an R0 resection. The adjuvant phase of the trial is ongoing.

Regarding safety in the EGFR-mutated subgroup, any-grade adverse effects (AEs) occurred in 96.2% of those in the durvalumab arm and 84% of those in the placebo arm; these effects were maximum grade 3 or 4 in 42.3% and 40% of patients, respectively. Serious AEs were observed in 34.6% vs 28% of patients.

AEs led to discontinuation in 15.4% of those who received durvalumab vs 4% of those who received placebo, and AEs resulted in the cancellation of surgery for 7.7% vs 4% of patients, respectively. No patients who received durvalumab experienced AEs that resulted in death vs 1 patient in the placebo arm.

Any-grade AEs considered to potentially be related to durvalumab, placebo, or chemotherapy were observed in 84.6% of those in the durvalumab arm vs 68% of those in the placebo arm; these effects were maximum grade 3 or 4 in 23.1% vs 32% of patients, respectively. Lastly, any-grade immune-mediated AEs occurred in 23.1% of those in the investigative arm vs 4% of those in the placebo arm, with one grade 3/4 event occurring in a patient who received durvalumab. Any-grade pneumonitis did not occur in any patients.

The AEs that were most frequently reported in the durvalumab and placebo arms were nausea (any grade, 38.5% vs 32%, respectively), constipation (any grade, 34.6% vs 40%), anemia (any grade, 30.8% vs 24%; grade ≥3, 3.8% vs 8%), reduced appetite (any grade, 19.2% vs 28%), procedural pain (any grade, 19.2% vs 16%), decreased neutrophil count (any grade, 15.4% vs 16%; grade ≥3, 3.8% vs 12%), insomnia (any grade, 15.4% vs 16%), neutropenia (any grade, 15.4% vs 12%; grade ≥3, 7.7% vs 8%), rash (any grade, 15.4% vs 8%), alopecia (any grade, 15.4% vs 8%), pyrexia (any grade, 15.4% vs 4%), pruritus (any grade, 15.4% vs 4%; grade ≥3, 3.8% vs 0%), vomiting (any grade, 11.5% vs 12%), leukopenia (any grade, 11.5% vs 8%; grade ≥3, 0% vs 8%), cough (any grade, 11.5% vs 8%), hypothyroidism (any grade, 11.5% vs 0%), and COVID-19 (any grade, 11.5% vs 0%).

“With the robust clinical benefit demonstrated by adjuvant osimertinib in the phase 3 ADAURA trial [NCT02511106] for patients with EGFR-mutated, resected NSCLC, EGFR mutation testing should be considered prior to initiation of neoadjuvant therapy,” Harpole concluded.

_References:

_{1. He J, Gao S, Reck M, et al. Neoadjuvant durvalumab + chemotherapy followed by adjuvant durvalumab in resectable EGFR-mutated NSCLC (AEGEAN). Presented at: 2023 IASLC World Conference on Lung Cancer; September 9-12, 2023; Singapore, Republic of Singapore. Abstract OA12.06.}

_{2. Heymach JV, Harpole D, Mitsudomi T, et al. Abstract CT005: AEGEAN: a phase 3 trial of neoadjuvant durvalumab + chemotherapy followed by adjuvant durvalumab in patients with resectable NSCLC. Cancer Res. 2023;83(suppl 8):CT005. doi:10.1158/1538-7445.AM2023-CT005}

_{3. Mitsudomi T, Heymach JV, Reck et al. Surgical outcomes with neoadjuvant durvalumab + chemotherapy followed by adjuvant durvalumab in resectable NSCLC (AEGEAN). Presented at: International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer; September 9-12, 2023; Singapore. Abstract OA12.05.}