NSCLC with uncommon EGFR mutations treated with atezolizumab plus bevacizumab and chemotherapy.
Authors: Trummer Arne Rainer , Bethge Andre , Dickgreber Nicolas J. , Dittrich Ina , Golpon Heiko , Hoffknecht Petra , Overbeck Tobias R. , Wesseler Claas , Reck Martin 
Published: June 2022

e21076

Background: Results of IMpower-150 and Orient-31 have demonstrated a favorable effect of combining anti-angiogenic therapy and checkpoint inhibition for refractory NSCLC patients with EGFR mutations. However, both studies included only very few patients with uncommon EGFR mutations, not allowing further analysis. For those patients, representing about 10% of EGFR mutant NSCLCs, treatment options are still limited. Methods: Analysis included 16 stage IV NSCLC patients with uncommon EGFR mutations from 9 different German centers which started treatment in first or further line with Atezolizumab, Bevacizumab, Carboplatin and (nab-)Paclitaxel (ABCP) between October 2018 and January 2022. EGFR mutations were detected by NGS (n = 15) or COBAS-PCR (n = 1). PFS was evaluated from start of ABCP and OS from time of initial diagnosis of stage IV. Results: 5 men and 11 women received ABCP therapy in first (n = 4), second (n = 9) or further line (n = 3). Mean age was 56 (36-77) years. Patients had either an Exon 20 insertion (n = 9) or point mutation (n = 2, S768I), an Exon 18 mutation (n = 3, G719X or E709A), an Exon 21 mutation (L861Q) or a compound mutation (G719C/S768I). 9 patients received a TKI therapy in first line (4x Afatinib; 5x Osimertinib) with an ORR of 66.7% (CR = 1; PR = 5; SD = 1; PD = 2) and a median time-to-next-treatment of 6.7 months (range: 2.1-39.1 months). Median number of full ABCP cycles were 4 (1-6), with 3 patients (23.1%) requiring a dose reduction of chemotherapy and 4 patients (30.8%) suffering from grade 3 or 4 toxicity (one immune related pneumonitis). 13 patients (84.6%) received a maintenance with AB and the median follow-up after initial diagnosis was 19.6 months (2.3-38.4). ORR was 81.3% with 2 CR, 11 PR, 1 SD and 1 PD (not available = 1). Median PFS by Kaplan-Meier analysis was 13.0 months for both the entire cohort (95%-CI: 8.4-17.6) and for Exon 20 insertions (95%-CI: 9.3-16.7). Corresponding median OS was either not reached or 30.7 months (95%-CI: 13.8-47.6). Landmark analysis at 12 months gave a PFS of 42.8% and an OS of 93.3%. Univariate Cox regression showed no association of PFS or OS with patient or treatment parameters, including PD-L1 expression, type of mutation or prior TKI treatment. 4 patients were rechallenged with ABCP while progressing under AB maintenance and responded again. 4 patients received mobocertinib as further treatment, but only one showed a clinical benefit. Conclusions: In this retrospective analysis, ABCP achieves an encouraging outcome for patients with uncommon EGFR mutations, comparable to results for common EGFR mutations in IMpower150 (ORR 71%, mPFS: 9.7 months, mOS 29.4 months). This in contrast to immunotherapy alone which shows poor ORR and PFS. Together with new targeted treatment options for Exon 20 insertions like amivantamab (ORR 40%, mPFS 8.3 months) or mobocertinib (ORR 28%, mPFS 7.3 months), ABCP is a valuable option in the early course of treatment for this patient cohort.