Durvalumab Consolidation Should Be the Standard Therapy in Stage III EGFR-Mutant NSCLC After Chemoradiation

Abstract

The standard treatment for patients with unresectable stage III NSCLC without contraindications for the use of immune checkpoint inhibitors (ICIs) is concurrent chemoradiotherapy followed by consolidation durvalumab.1Ettinger D.S. Wood D.E. Aisner D.L. et al.NCCN guidelines insights: non-small cell lung cancer, version 2.2021.J Natl Compr Canc Netw. 2021; 19: 254-266Crossref PubMed Scopus (125) Google Scholar This recommendation is based on the results from the PACIFIC trial, wherein patients with unresectable stage III NSCLC who did not have tumor progression after at least two cycles of platinum-based chemotherapy with concurrent thoracic radiation were randomized in a 2:1 ratio to consolidation durvalumab 10 mg/kg or matching placebo every 2 weeks for up to 12 months. The two coprimary end points were progression-free survival (PFS) and overall survival (OS). Between May 2014 and April 2016, the study enrolled 713 patients including 476 in the durvalumab arm and 237 in the placebo arm. Treatment with durvalumab was associated with a significant increase in the median PFS compared with placebo (17.2 mo versus 5.6 mo, hazard ratio [HR] = 0.51, 95% confidence interval [CI]: 0.41–0.63).2Antonia S.J. Villegas A. Daniel D. et al.Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.N Engl J Med. 2018; 379: 2342-2350Crossref PubMed Scopus (1316) Google Scholar In a recent update, the median OS was 47.5 months in the durvalumab arm and 29.1 months in the placebo arm (stratified HR = 0.72, 95% CI: 0.59–0.89), with 5-year OS of 42.9% and 33.9%, respectively.3Spigel D.R. Faivre-Finn C. Gray J.E. et al.Five-year survival outcomes with durvalumab after chemoradiotherapy in unresectable stage III NSCLC: an update from the PACIFIC trial.J Clin Oncol. 2021; 39 (8511–8511)Google Scholar The probabilities of 5-year PFS for durvalumab and placebo were 33.1% and 19.0%, respectively (HR = 0.55, 95% CI: 0.45–0.68). Although consolidation durvalumab is approved regardless of mutation status, questions have been raised on the use of durvalumab in patients with locally advanced EGFR-mutant lung adenocarcinoma after chemoradiation. The main concern in using durvalumab as a consolidation strategy is the general perception that patients with EGFR-mutant lung adenocarcinoma have lower responses to ICI in advanced NSCLC in comparison to their wild-type counterparts. We argue here that patients with locally advanced unresectable EGFR-mutant lung adenocarcinoma should be considered for durvalumab consolidation after definitive chemoradiation. Our argument rests on two main factors. First, the subgroup analyses of the PACIFIC adenocarcinoma are not powered to draw meaningful interpretation of lack of efficacy for this subset alone. Second, although responses to ICI in patients with EGFR-mutant lung adenocarcinoma are lower than in those with wild-type tumors in the metastatic setting, these differences may not be applicable in locally advanced disease wherein the dual effects of chemotherapy and radiation altering the tumor microenvironment may increase the efficacy of ICIs. The efficacy of single-agent ICIs in patients with EGFR-mutant lung adenocarcinoma has been evaluated in both retrospective studies and subset analyses of randomized trials. In a multicenter retrospective study including 171 patients with EGFR mutation and 212 with wild EGFR type, the best overall responses for the 80 patients with EGFR exon 19 deletions, 46 patients with EGFR L858R, and those with EGFR wild type were 7%, 16%, and 22%, respectively.4Hastings K. Yu H.A. Wei W. et al.EGFR mutation subtypes and response to immune checkpoint blockade treatment in non-small-cell lung cancer.Ann Oncol. 2019; 30: 1311-1320Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar There were no significant differences in OS between patients with EGFR L858R mutation and wild type. In the IMMUNOTARGET registry study, which evaluated ICIs in advanced lung cancer with oncogenic driver alterations, there were 125 patients with EGFR mutations.5Mazieres J. Drilon A. Lusque A. et al.Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the immunotarget registry.Ann Oncol. 2019; 30: 1321-1328Abstract Full Text Full Text PDF PubMed Scopus (355) Google Scholar The best overall response and median PFS for these patients were 12.2% and 2.1 months, respectively. In a meta-analysis including 186 EGFR-mutant cases enrolled into comparing ICI to docetaxel, the OS for patients treated with ICI was significantly improved in the EGFR wild-type population (HR = 0.66, 95% CI: 0.58–0.76) but not for those with EGFR mutation (HR = 1.05, 95% CI: 0.70–1.55).6Lee C.K. Man J. Lord S. et al.Checkpoint inhibitors in metastatic EGFR-mutated non-small cell lung cancer—a meta-analysis.J Thorac Oncol. 2017; 12: 403-407Abstract Full Text Full Text PDF PubMed Scopus (467) Google Scholar The ATLANTIC study, which evaluated durvalumab as third-line therapy or beyond for advanced NSCLC, included 97 patients with EGFR mutation, 15 patients with ALK rearrangements, and one patient with both alterations.7Garassino M.C. Cho B.C. Kim J.H. et al.Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study.Lancet Oncol. 2018; 19: 521-536Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar In an exploratory post hoc analysis of the 64 patients with EGFR mutation and programmed death-ligand 1 (PD-L1) expression greater than or equal to 25% assessed by the SP263 assay, nine (14.1%) achieved objective responses and 21 (32.8%) stable disease, with 1-year OS of 57.4%. The objective responses and median PFS for patients with tumors wild type for EGFR and PD-L1 greater than or equal to 25% were 16.4% and 3.3 months, respectively. Among the 28 patients with PD-L1 less than 25%, the responses were not divided according to driver alterations and the only responder had EGFR mutation. The exploratory analysis of the ATLANTIC study raises the possibility that among patients with EGFR mutation treated with durvalumab, PD-L1 greater than or equal to 25% may identify a subgroup that may respond well to ICI, although this finding needs to be confirmed in future studies. However, these studies clearly reveal that a subset of patients with lung adenocarcinoma driven by EGFR activating mutation respond well to ICI monotherapy despite the overall inferior outcomes for EGFR mutants as a group. The decreased efficacy for single-agent ICIs in patients with EGFR mutation may be related to the decreased frequency of potential predictors for response to ICIs including tumor mutation burden and concurrent presence of CD8+ tumor-infiltrating lymphocytes and PD-L1 positivity.8Gainor J.F. Shaw A.T. Sequist L.V. et al.EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis.Clin Cancer Res. 2016; 22: 4585-4593Crossref PubMed Scopus (687) Google Scholar The decreased immunogenicity of EGFR-mutant tumors may be reverted by the changes in the tumor microenvironment induced by radiation therapy, which has multiple immunostimulatory effects, including immunogenic cell death, increase in MHC-I expression on the surface of tumor cells, and T-cell infiltration.9McLaughlin M. Patin E.C. Pedersen M. et al.Inflammatory microenvironment remodelling by tumour cells after radiotherapy.Nat Rev Cancer. 2020; 20: 203-217Crossref PubMed Scopus (127) Google Scholar In preclinical models, radiation therapy has been found to induce PD-L1 up-regulation in tumor cells and the combination with anti–programmed cell death-protein 1 or anti–PD-L1 antibodies improved outcomes compared with radiation alone.10Dovedi S.J. Adlard A.L. Lipowska-Bhalla G. et al.Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade.Cancer Res. 2014; 74: 5458-5468Crossref PubMed Scopus (677) Google Scholar Furthermore, the most commonly used chemotherapy drugs for NSCLC, including carboplatin, cisplatin, pemetrexed, and paclitaxel, may induce immunogenic cell death with release of damage-associated molecular pattern molecules, including calreticulin and HMGB1, and increase the immune infiltrate, including dendritic cells, CD8+ cytotoxic T cells, and macrophages.11Galluzzi L. Humeau J. Buqué A. Zitvogel L. Kroemer G. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors.Nat Rev Clin Oncol. 2020; 17: 725-741Crossref PubMed Scopus (164) Google Scholar Taxanes may also selectively reduce immunosuppressive cells leading to a decrease in regulatory T cells without affecting other CD4+ or CD8+ cells.12Heinhuis K.M. Ros W. Kok M. Steeghs N. Beijnen J.H. Schellens J.H.M. Enhancing antitumor response by combining immune checkpoint inhibitors with chemotherapy in solid tumors.Ann Oncol. 2019; 30: 219-235Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar Therefore, the combined immunomodulatory effects of both chemotherapy and radiation therapy may create an inflammatory microenvironment leading to increased efficacy of consolidation ICI compared with monotherapy in the metastatic setting. The PACIFIC study accrued 43 patients with EGFR mutation, including 29 randomized to durvalumab and 14 to placebo, representing 6% of the study population.2Antonia S.J. Villegas A. Daniel D. et al.Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.N Engl J Med. 2018; 379: 2342-2350Crossref PubMed Scopus (1316) Google Scholar In a recent update of the PACIFIC trial, neither the PFS (HR = 0.84, 95% CI: 0.40–1.75) nor the OS (HR = 0.97, 95% CI: 0.40–2.33) was improved with the use of consolidation durvalumab in patients with EGFR mutation.13Faivre-Finn C. Vicente D. Kurata T. et al.Four-year survival with durvalumab after chemoradiotherapy in stage III NSCLC—an update from the PACIFIC trial.J Thorac Oncol. 2021; 16: 860-867Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar There were several other subgroups that also had a lack of significant OS benefit from durvalumab, including stage IIIB, squamous tumors, use of carboplatin, enrollment in Asia or Europe, and PD-L1 less than 25%. Because the patients were not stratified by EGFR mutation status, the outcomes for this population may be affected by both the small number of patients and unbalances regarding other factors known to have an effect in the PFS or OS. Data for the use of consolidation durvalumab in patients with locally advanced unresectable EGFR-mutant tumors treated with chemoradiation are limited. In a retrospective study conducted by Aredo et al.,14Aredo J.V. Mambetsariev I. Hellyer J.A. et al.Durvalumab for stage III EGFR-mutated NSCLC after definitive chemoradiotherapy.J Thorac Oncol. 2021; 16: 1030-1041Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar which included 37 patients with unresectable stage III EGFR-mutated NSCLC, of whom 13 (35%) received consolidation durvalumab, 22 patients (59.4%) received pemetrexed-based regimens, most often in combination with carboplatin (40.5%). Among the patients who did not receive durvalumab, eight were treated with EGFR tyrosine kinase inhibitors (TKIs), four as induction and four as consolidation. The median PFS, measured from the day of chemoradiotherapy completion was 10.3 months for those who received durvalumab and 22.8 months for those who did not. Nevertheless, the use of EGFR TKI is expected to increase the PFS, and the median PFS for those treated without consolidation durvalumab or EGFR TKI was 6.9 months. Taken together, the number of patients with EGFR-mutant lung adenocarcinoma treated with ICI after chemoradiation is quite small to draw definitive conclusions. In patients with locally advanced NSCLC, the priority should be to maximize the probability of cure because the treatment at the time of relapse is essentially palliative. The suboptimal outcomes with chemoradiotherapy alone indicate that additional therapy is likely required as found in the PACIFIC trial.2Antonia S.J. Villegas A. Daniel D. et al.Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.N Engl J Med. 2018; 379: 2342-2350Crossref PubMed Scopus (1316) Google Scholar It is possible that consolidation with TKI may eventually become an option similarly to the ADAURA study with adjuvant osimertinib in patients with completely resected NSCLC,15Wu Y.L. Tsuboi M. He J. et al.Osimertinib in resected EGFR-mutated non-small-cell lung cancer.N Engl J Med. 2020; 383: 1711-1723Crossref PubMed Scopus (314) Google Scholar and this strategy is currently being evaluated in the LAURA trial.16Lu S. Casarini I. Kato T. et al.Osimertinib maintenance after definitive chemoradiation in patients with unresectable EGFR mutation positive stage III non-small-cell lung cancer: LAURA trial in progress.Clin Lung Cancer. 2021; 22: 371-375Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar Nevertheless, there are limited data on efficacy or safety for this approach after chemoradiotherapy, and the expected increase in disease-free survival may not translate into improved OS.17Zhong W.Z. Wang Q. Mao W.M. et al.Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC: final overall survival analysis of CTONG1104 phase III trial.J Clin Oncol. 2021; 39: 713-722Crossref PubMed Scopus (40) Google Scholar Although the four-year survival update of the PACIFIC trial revealed that neither the PFS nor the OS was significantly improved with consolidation durvalumab in patients with EGFR-mutant tumors, it should be noted that the study was not powered to detect differences according to mutational status, with a small number of patients and a wider confidence interval.4Hastings K. Yu H.A. Wei W. et al.EGFR mutation subtypes and response to immune checkpoint blockade treatment in non-small-cell lung cancer.Ann Oncol. 2019; 30: 1311-1320Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar Furthermore, there are several other factors associated with decreased benefit from consolidation durvalumab and unbalances in the treatment arms are likely to be present, preventing a better evaluation of the results. Subset analyses are hypothesis generating. Therefore, consolidation durvalumab should be considered the standard therapy for patients with stage III EGFR-mutant NSCLC without tumor progression after completion of chemoradiotherapy or contraindications for the use of ICIs until data from prospective studies provide more definitive guidance. Daniel Morgensztern, Ramaswamy Govindan: Conceptualization, Writing—review and editing. Consolidation Durvalumab Should Not Be Administered to Patients With Stage III EGFR-Mutant NSCLCJournal of Thoracic OncologyVol. 16Issue 12PreviewOne of the greatest advances in the treatment of locally advanced unresectable NSCLC has been the addition of consolidation durvalumab, an anti–programmed death-ligand 1 (PD-L1) immune checkpoint inhibitor (ICI), after definitive chemoradiotherapy (CRT). Nevertheless, whether the benefits of durvalumab extend to all patients, including those with the classically immune-inert EGFR-mutant NSCLC, continues to generate extensive debate. Full-Text PDF