Drastic Response of Re-challenge of EGFR-TKIs Immediately After Nivolumab Therapy in EGFR-TKI–Resistant Patients

EGFR mutations are thought to be a negative predictor for nivolumab in advanced NSCLC.1Borghaei H. Paz-Ares L. Hom L. et al.Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer.N Engl J Med. 2015; 373: 1627-1639Crossref PubMed Scopus (6766) Google Scholar Moreover, a combination of osimertinib and durvalumab, anti–programmed death-ligand 1 (PD-L1), and osimertinib immediately after nivolumab is not acceptable due to increased interstitial lung disease incidence in patients with EGFR-mutant NSCLC.2Ahn M.J. Yang J. Yu H. et al.136O: Osimertinib combined with durvalumab in EGFR-mutant non–small cell lung cancer: results from the TATTON phase 1b trial.J Thorac Oncol. 2016; 11: S115Abstract Full Text Full Text PDF Scopus (210) Google Scholar, 3Kotake M. Murakami H. Kenmotsu H. et al.High incidence of interstitial lung disease following practical use of osimertinib in patients who had undergone immediate prior nivolumab therapy.Ann Oncol. 2017; 28: 669-670Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar However, it remains unclear whether the increased interstitial lung disease incidence is observed when first- or second-generation EGFR-tyrosine kinase inhibitors (TKIs) are administered immediately after nivolumab. A recent phase I study has shown that the addition of nivolumab to erlotinib is well tolerated and exhibits clinical activity in patients with erlotinib-resistant EGFR-mutant NSCLC.4Gettinger S. Hellmann M.D. Chow L.Q. et al.Nivolumab plus erlotinib in patients with EGFR-mutant advanced NSCLC.J Thorac Oncol. 2018; 13: 1363-1372Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar Although little is known about the clinical synergistic effect of EGFR-TKIs and anti–programmed death 1/PD-L1 antibodies, we encountered two cases of drastic response to EGFR-TKIs immediately after nivolumab in patients with NSCLC resistant to EGFR-TKIs. A 39-year-old female Asian never-smoker with stage IV (cT2bN3M1b) pulmonary adenocarcinoma harboring an EGFR del-19 mutation underwent surgical resection of massive cerebral metastasis followed by stereotactic radiosurgery. She received afatinib as first-line therapy in April 2016. After 10 months, the disease progressed with regrowth of the primary tumor harboring an EGFR T790M mutation in February 2017. After 5 months, there was evidence of left lymphadenopathy recurrence. Therefore, therapy with cisplatin and pemetrexed plus bevacizumab was chosen; she was then administered osimertinib re-challenge followed by nivolumab because of repeated recurrence in February 2018. Brain magnetic resonance imaging after 3 months with nivolumab revealed multiple cerebral metastases (Fig 1A). As sixth-line treatment, erlotinib plus bevacizumab was initiated immediately after nivolumab in September 2018. After 1 month, multiple cerebral metastases almost disappeared (Fig. 1B). A 64-year-old female Asian never-smoker with stage IV (cT2aN2M1a) pulmonary adenocarcinoma harboring an EGFR L891Q mutation was administered carboplatin and paclitaxel plus bevacizumab in December 2012. After 10 months, gefitinib was initiated; she then sequentially received carboplatin plus pemetrexed for pulmonary metastasis recurrence. Because of repeated recurrences, she sequentially received afatinib, re-challenge of carboplatin plus pemetrexed, and erlotinib plus bevacizumab. As ninth-line treatment, she received nivolumab in October 2018. As progressive pulmonary metastases appeared (Fig. 1C), she received afatinib re-challenge immediately after nivolumab failure in November 2018. After 14 weeks, her pulmonary metastases almost disappeared (Fig. 1D). To our knowledge, these are the first cases of drastic tumor shrinkage from EGFR-TKIs immediately after nivolumab treatment, regardless of EGFR-TKI resistance. The same factors in both cases included never-smoker status, female sex, the initiation of EGFR-TKIs within 1 month after nivolumab administration, and histories of bevacizumab administration and clinical EGFR-TKI resistance. However, it remains unclear why EGFR-TKI re-challenge could overcome its resistance based on these factors. In our experience, except for our presented cases, two of four patients who received first- or second-generation EGFR-TKIs immediately after nivolumab exhibited partial response and stable disease. A preclinical study suggested that anti–programmed death 1/PD-L1 antibodies are a therapeutic option for EGFR-TKI–resistant NSCLC.5Chen N. Fang W. Zhan J. et al.Upregulation of PD-L1 by EGFR activation mediates the immune escape in EGFR-driven NSCLC: implication for optional immune targeted therapy for NSCLC patients with EGFR mutation.J Thorac Oncol. 2015; 10: 910-923Abstract Full Text Full Text PDF PubMed Scopus (466) Google Scholar However, our cases suggest that EGFR-TKI re-challenge immediately after nivolumab therapy may be tolerable and effective for patients with their resistance.