Background: Maintenance immunotherapy (IO) is commonly utilized in metastatic NSCLC patients (pts) who did not progress after initial treatment with platinum doublet and IO. Upon progression, docetaxel with or without ramucirumab remains the treatment of choice, which is associated with poor response and high toxicity. We explored the option of rechallenge of original chemotherapy agents in this patient population. Methods: We queried MD Anderson Cancer Center GEMINI database to perform a retrospective review in pts who received chemotherapy (chemo) rechallenge with or without IO after progression on or after IO maintenance from 03/2016 – 12/2022 at MD Anderson Cancer Center. We assessed clinical response and progression free survival (PFS) with initial triplet treatment and rechallenge with chemotherapy. Clinical response was defined as clinical benefit based on clinician’s radiographic and clinical assessment. PFS was defined as the time interval free of disease progression. Demographics and results were summarized with descriptive statistics. Results: 20 patients received chemo rechallenge with or without IO after progression on IO maintenance. Upon chemo rechallenge, 7 pts received pemetrexed; 10 pts (50%) received carboplatin and pemetrexed; 19 pt received chemo rechallenge with IO. Median duration of initial IO maintenance was 9.4 months. Median duration of chemo rechallenge was 5.2 months. 10 (50%) pts discontinued chemo due to progression after receiving chemo rechallenge; 2 (10%) pts discontinued chemo rechallenge due to toxicities; 3 (15%) pts remained on therapy at the data cutoff of 2/10/2023. Median PFS with initial triplet was 14.3 months. Median PFS with chemo rechallenge was 7.4 months, longer than the histological control of 3-5 months from docetaxel +/- ramucirumab. Conclusions: Our single center retrospective review demonstrated that chemo rechallenge after progression on IO maintenance post front-line chemo-IO therapy had good tolerability and reasonable PFS, which may offer a reasonable alternative option to docetaxel+/-ramucirumab. Future studies are needed to confirm this result using docetaxel +/- ramucirumab as a control.