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Introduction: EGFR tyrosine kinase inhibitors have been the standard treatment for patients with NSCLC who have sensitive EGFR mutations. This study revealed final analysis survival data, biomarkers, and resistance mechanisms of osimertinib plus bevacizumab or osimertinib monotherapy in previously untreated patients with advanced EGFR-positive nonsquamous NSCLC. Methods: We previously reported the primary results of a randomized, open-label, phase 2 study comparing osimertinib plus bevacizumab with osimertinib monotherapy for this population. In this exploratory analysis using tissue and plasma samples, we evaluated gene profiles at baseline and disease progression or the last dose using targeted deep sequencing. Results: The median progression-free survival (PFS) by the blinded independent central reviewer was 22.1 months for the osimertinib plus bevacizumab arm and 20.2 months for the osimertinib arm (hazard ratio [HR] = 0.864, 95% confidence interval [CI]: 0.549–1.359). The 3-year overall survival was not different between the two arms (osimertinib plus bevacizumab: 57.1%; osimertinib monotherapy: 65.0%; HR 1.271, 95% CI: 0.727–2.223). A total of 94 patients had assessable plasma samples at baseline, and 40 had assessable pretreatment tissue samples. EGFR mutations (76.6%) and TP53 mutations (44.7%) were detected in plasma samples at baseline. In patients with plasma TP53 mutations (n = 42), the median PFS by blinded independent central reviewer was 19.8 months for the osimertinib plus bevacizumab arm and 20.2 months for the osimertinib arm (HR = 1.107, 95% CI: 0.534–2.297). Conclusions: There was also no significant difference in the PFS between the two arms, even in patients with TP53 mutations.

Introduction: Immune checkpoint inhibitors have recently been approved for the treatment of early-stage NSCLC in the perioperative setting on the basis of phase 3 trials. However, the characteristics of such patients who are susceptible to recurrence after adjuvant chemotherapy or who are likely to benefit from postoperative immunotherapy have remained unclear. Methods: This biomarker study (WJOG12219LTR) was designed to evaluate cancer stem cell markers (CD44 and CD133), programmed death-ligand 1 (PD-L1) expression on tumor cells, CD8 expression on tumor-infiltrating lymphocytes, and tumor mutation burden in completely resected stage II to IIIA NSCLC with the use of archived DNA and tissue samples from the prospective WJOG4107 trial. Tumors were classified as inflamed or noninflamed on the basis of the PD-L1 tumor proportion score and CD8+ tumor-infiltrating lymphocyte density. The association between each potential biomarker and relapse-free survival (RFS) during adjuvant chemotherapy was assessed by Kaplan-Meier analysis. Results: A total of 117 patients were included in this study. The median RFS was not reached (95% confidence intervals [CI]: 22.4 mo–not reached; n = 39) and 23.7 months (95% CI: 14.5–43.6; n = 41) in patients with inflamed or noninflamed adenocarcinoma, respectively (log-rank p = 0.02, hazard ratio of 0.52 [95% CI: 0.29–0.93]). Analysis of the combination of tumor inflammation category and TP53 mutation status revealed that inflamed tumors without TP53 mutations were associated with the longest RFS. Conclusions: PD-L1 expression on tumor cells, CD8+ T cell infiltration, and TP53 mutation status may help identify patients with early-stage NSCLC susceptible to recurrence after adjuvant chemotherapy.

Introduction: EGFR gene mutations are drivers of NSCLC. The RELAY double-blind, placebo (PBO)-controlled phase 3 study revealed superior progression-free survival (PFS) for ramucirumab plus erlotinib (RAM + ERL) versus PBO (PBO + ERL) in patients with untreated advanced NSCLC and an EGFR-activating mutation. This exploratory analysis evaluated potential associations between EGFR exon 19 deletion (ex19del) variants and clinical outcomes. Methods: Patients (N = 449) were randomized (1:1) to RAM plus ERL or PBO plus ERL. Plasma samples were collected at baseline, on treatment, and at 30-day post-study treatment discontinuation follow-up. Baseline and treatment-emergent gene alterations were investigated by Guardant360 next-generation sequencing. Patients with a valid baseline plasma sample and ex19del were included (RAM + ERL, n = 62; PBO + ERL, n = 72). Results: The most common ex19del variant was E746_A750del (67.2%); EGFR E746 deletions (E746del) occurred more frequently than L747 deletions (74.6% versus 25.4%, respectively). TP53 mutations were the most frequently co-occurring baseline gene alterations. With treatment arms combined, median PFS was 18.0 months versus 12.5 months for patients with uncommon (non-E746_A750del, n = 44) versus common (E746_A750del, n = 90) ex19del variants (hazard ratio [HR] = 1.657 [95% confidence interval or CI:1.044–2.630]). Median PFS was longer with RAM plus ERL versus PBO plus ERL for patients with the common (15.2 versus 9.9 mo; HR = 0.564 [95% CI: 0.344–0.926]) and E746del (15.4 versus 9.9 mo; HR = 0.587 [95% CI: 0.363–0.951]) variants. Treatment-emergent post-progression EGFR T790M rates were higher in the common versus uncommon and E746del versus L747 deletion subgroups. Conclusions: RAM plus ERL provides benefit and improves treatment outcomes for patients with metastatic NSCLC with EGFR ex19del variants.

Introduction: Osimertinib may be effective in treating central nervous system (CNS) metastasis, but its efficacy in treating radiation therapy (RT)-naive metastasis is unclear. The OCEAN study assessed the efficacy of osimertinib against RT-naive CNS metastasis in patients previously treated (T790M cohort) and untreated patients (first-line cohort) with EGFR mutation. Here, we report the results of the first-line cohort. Methods: Previously untreated patients with RT-naive CNS metastasis and EGFR mutation-positive NSCLC were treated with osimertinib. The brain metastasis response rate (BMRR), progression-free survival (PFS), and overall survival in the first-line cohort were secondary end points. Results: A total of 26 patients were enrolled in the study between September 2019 and July 2020. The median age was 72.0 years with 80.8% female. There were 20 patients who had multiple CNS metastases. BMRR assessed by PAREXEL criteria was 76.9% (90% confidence interval [CI]: 63.3%–90.5%), BMRR assessed by Response Evaluation Criteria in Solid Tumors was 76.9% (95% CI: 54.0%–99.8%), and median PFS of CNS metastasis was 22.0 months (95% CI: 9.7 mo–not reached). The overall response rate was 64.0% (95% CI: 45.2%–82.8%), median PFS was 11.5 months (95% CI: 6.9 mo–not reached), and median survival time was 23.7 months (95% CI: 16.5 mo–not reached). Paronychia and increased creatinine level were the most frequent nonhematological toxicities observed in 13 patients (50%). Grade three and higher adverse events were less than 10%, and there were no treatment-related deaths. Pneumonitis was observed in five patients (19.2%). Conclusions: These results suggest that osimertinib is effective in untreated patients with RT-naive asymptomatic CNS metastasis in a clinical practice first-line setting. Trial registration: UMIN identifier: UMIN000024218. jRCT identifier: jRCTs071180017.

Introduction: Perioperative treatment in NSCLC has gained marked attention with the introduction of immune checkpoint inhibitors. Such a paradigm shift has given us additional opportunities to evaluate potential biomarkers in patients with these curable disease stages. Methods: This study (WJOG12319LTR) was designed as a biomarker study to evaluate whether soluble immune markers were prognostic or predictive on relapse-free survival in patients with stage II to IIIA NSCLC who underwent complete resection and adjuvant chemotherapy with cisplatin plus S-1, which is an oral fluoropyrimidine formulation that consists of tegafur, gimeracil, and oteracil, or S-1 alone in the previous WJOG4107 study. Archived plasma samples were assayed for soluble (s) forms of programmed cell death protein 1 (sPD-1), programmed death-ligand 1(sPD-L1), and CTLA-4 (sCTLA-4) with the highly sensitive HISCL system. Using time-dependent receiver operating characteristic curve analysis, the area under the curves were derived and optimal cutoff values were determined. Using the cutoff values, whether the marker was prognostic or predictive was assessed by survival analysis. Results: A total of 150 patients were included in the study. The time-dependent receiver operating characteristics analysis revealed that the area under the curves for sPD-1, sPD-L1, and sCTLA-4 were 0.54, 0.51, and 0.58, respectively. The survival analysis did not reject that hazard ratios were 1 in terms of the soluble immune marker and the treatment-marker interaction for all three markers. Conclusions: There was no proof that circulating concentrations of sPD-1, sPD-L1, and sCTLA-4 were prognostic or predictive factors of the outcome for adjuvant chemotherapy after complete resection in patients with NSCLC.

Introduction: Docetaxel plus ramucirumab could be a promising treatment for chemo-naive elderly patients with NSCLC, but high incidence of febrile neutropenia (FN) is a critical concern. We thus adopted a routine primary prophylactic pegylated-granulocyte-colony stimulating factor (PEG-G-CSF) to reduce FN and maximize the efficacy of docetaxel plus ramucirumab in elderly patients. Methods: This is a single arm phase 2 trial for chemo-naive elderly patients (aged ≥75 y) with advanced NSCLC. Docetaxel (60 mg/m2, d 1) plus ramucirumab (10 mg/kg, d 1) with PEG-G-CSF (3.6 mg, d 2) was administered every 3 weeks until progression. The primary end point was overall response rate (ORR) (expected ORR: 35%). Results: Between February 2018 and January 2021, 54 patients were enrolled. Median age was 78 (range: 75–86). A total of 21 (38.9%) partial response, 22 (40.7%) stable disease, nine (16.7%) progressive disease, and two (3.7%) not assessable were confirmed, resulting in ORR of 38.9% (90% confidence interval [CI]: 27.7%–51.0%) and disease control rate of 79.6%. Median progression-free survival and overall survival were 5.2 (95% CI: 4.2–6.9) and 12.7 (95% CI: 10.2–18.9) months, respectively. There were one (1.9%) FN, two (3.7%) bleeding grade greater than or equal to 3, and one (1.9%) treatment-related death (pneumonitis). Pneumonitis occurred in five patients (9.3%). Main adverse events grade greater than or equal to 3 were observed: four (7%) thrombocytopenia; three (5.6%) neutropenia; six (11.1%) hyposodium; five (9.3%) infection; five (9.3%) hypertension; four (7.4%) anorexia; and three (5.6%) oral mucositis. Conclusions: Docetaxel plus ramucirumab with PEG-G-CSF revealed efficacy and safety for chemo-naive elderly patients with NSCLC. Primary prophylactic PEG-G-CSF highly prevented FN.

Resistance to ROS1 tyrosine kinase inhibitors is inevitable, but it has been unclear whether crizotinib might be effective after the development of entrectinib resistance. We here present a case of ROS1-rearranged NSCLC that responded to crizotinib after tumor progression due to MET polysomy during entrectinib treatment. This case suggests that crizotinib is an effective option for patients with MET polysomy, even after disease progression on entrectinib.

Introduction: Despite a considerable benefit of adding immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy for patients with extensive-stage SCLC (ES-SCLC), a durable response to ICIs occurs in only a small minority of such patients. Methods: A total of 135 patients with ES-SCLC treated with chemotherapy either alone (chemo-cohort, n = 71) or together with an ICI (ICI combo-cohort, n = 64) was included in this retrospective study. Tumors were classified pathologically as inflamed or noninflamed on the basis of programmed death-ligand 1 expression and CD8+ tumor-infiltrating lymphocyte density. Immune-related gene expression profiling was performed, and predicted neoantigen load was determined by whole-exome sequencing. Results: Among patients in the ICI combo-cohort, median progression-free survival was 10.8 and 5.1 months for those with inflamed (n = 7) or noninflamed (n = 56) tumors, respectively (log-rank test p = 0.002; hazard ratio of 0.26). Among the 89 patients with immune-related gene expression profiling data available, inflamed tumors had a higher T cell-inflamed GEP score than did noninflamed tumors (−0.18 versus −0.58, p < 0.001). The 12-month progression-free survival rate was 16.1% and 0% for patients in the ICI combo-cohort harboring tumors with a high (n = 26) or low (n = 18) frameshift neoantigen load, respectively. A high-frameshift neoantigen load was associated with up-regulation of gene signatures related to antigen presentation and costimulatory signaling. A durable clinical benefit of ICI therapy was observed only in patients with inflamed tumors and a high-frameshift neoantigen load. Conclusions: Expression of programmed death-ligand 1, CD8+ T cell infiltration, and a high-frameshift neoantigen load are associated with clinical benefit of ICI therapy in ES-SCLC. Clinical trial registration: UMIN000041056

Introduction: Although data accumulated in clinical trials have higher accuracy compared with real-world data and are irreplaceably valuable, most previous clinical trial data have been left unused. Methods: The Japan Lung Cancer Society (JLCS) asked six clinical trial groups that conducted randomized clinical trials on curative chemoradiation for locally advanced NSCLC to provide data. After obtaining consent from all six groups, data were collected from August 2019 to June 2021. Results: A total of eight trials, JCOG9812, JCOG0301, NJLCG0601, OLCSG0007, WJTOG0105, WJOG5008L, SPECTRA, and TORG1018, were included. More than 3000 data items were integrated into 408 items by adjusting their definitions and units. The total number of collected cases was 1288: median age (range), 66 (30–93) years; sex (male/female) 1064/224; pathological type (squamous cell carcinoma, adenocarcinoma, other NSCLC, and unknown) 517, 629, 138, and 4; and stage IIIA and B, 536 and 752. The median overall survival was 26.0 months, with 2-, 5-, and 10-year survival rates of 53.7%, 24.8%, and 15.2%, respectively, in all enrollments. The median progression-free survival was 9.6 months, with 2-, 5-, and 10-year progression-free survival rates of 23.6%, 14.0%, and 9.4%, respectively. Part of the information in the database has been made available on the JLCS web page, and the JLCS members were provided the right to propose research using the database. Conclusions: The integration and sharing of clinical trial data for research purposes was made real by the nonprofit, academic organization, the JLCS. This database will lead to innovative researches and contribute to the improvement of lung cancer treatment and future research.

Introduction: Ramucirumab (RAM) plus erlotinib was found to have superior progression-free survival (PFS) versus placebo plus erlotinib in untreated EGFR-mutated metastatic NSCLC in the global phase 3 RELAY study. RELAY+ was an open-label, two-period, single-arm, exploratory study of RAM plus gefitinib (GEF; period 1) and RAM plus osimertinib (period 2) in East Asia (NCT02411448). Methods: Period 1 evaluated RAM (10 mg/kg) plus GEF (250 mg/d) in patients with untreated EGFR-mutated metastatic NSCLC. Period 2 evaluated RAM plus osimertinib (80 mg/d) in patients with disease progression who acquired T790M mutation in period 1. Exploratory end points included 1-year PFS rate (primary), other efficacy parameters, safety, and biomarker analyses of plasma (baseline, on-treatment, follow-up) using next-generation sequencing. Results: From December 2017 to August 2018, a total of 82 patients were enrolled and started treatment (period 1, RAM + GEF). The 1-year PFS rate was 62.9% (95% confidence interval: 50.3–73.1). Treatment-emergent adverse events of grade three or higher were reported with RAM plus GEF in 60 of 82 patients (73.2%; five patients [6.1%] grade four). There were two deaths owing to adverse events that occurred (acute cardiac failure, congestive cardiac failure). T790M rate at disease progression in plasma was 81.0% (13 of 16 patients). Conclusions: RELAY+ was found to have a favorable benefit–risk profile for RAM plus GEF in first-line treatment of East Asian patients with EGFR-mutated NSCLC.

Introduction: In patients with relapsed SCLC, amrubicin (AMR) is the current standard treatment in Japan. Nevertheless, its efficacy is not satisfactory and prognosis is poor. Preclinical study suggested that anthracycline agent might induce immunogenic cell death and work synergistically with immune checkpoint inhibitors. Methods: Patients with relapsed SCLC who relapsed after completion of platinum-containing regimen were registered. Patients were treated with pembrolizumab (200 mg, flat dose on d 1, every 3 wk for 2 y) plus AMR (40 mg/m2 on d 1–3, every 3 wk until progression). Primary end point was overall response rate (ORR). Secondary end points consisted of progression-free survival (PFS), overall survival, and safety. On the basis of the hypothesis that this treatment will improve ORR from 20% to 40% (0.1 of one-sided α and power of 0.8), 25 patients are required (trial identifier: NCT03253068). Results: Between November 2017 and October 2019, a total of 25 patients were enrolled. Most participants (88%) relapsed within 90 days after platinum-containing therapy and all patients were immune checkpoint inhibitor-naive. ORR, the primary end point, was 52.0% (95% confidence interval [CI]: 31.3%–72.2%). Median PFS was 4.0 months (95% CI: 2.8–7.0 mo), and PFS rate at 1 year was 14.4%. Median overall survival was 10.6 months (95% CI: 7.3–21.3 mo). Common adverse events greater than or equal to grade 3 were neutropenia (64%), leukopenia (40%), and febrile neutropenia (16%). No treatment-related deaths occurred. Conclusions: Among patients with relapsed SCLC, pembrolizumab plus AMR was effective and tolerable.

Introduction: The phase 3 RELAY global study (NCT02411448) revealed significant improvement in progression-free survival (PFS) with ramucirumab plus erlotinib (RAM + ERL) compared with placebo plus ERL (PL + ERL) in untreated EGFR-mutated metastatic NSCLC (hazard ratio [HR] = 0.59 [95% confidence interval (CI): 0.46–0.76, p < 0.0001]). This prespecified analysis evaluates efficacy, safety, and postprogression EGFR T790M rates of RELAY patients enrolled in Japan. Methods: Patients were randomized (1:1) to oral ERL (150 mg/d) plus intravenous RAM (10 mg/kg) or PL every 2 weeks. End points included PFS (primary), safety (secondary), and biomarker analyses (exploratory). Plasma samples collected at baseline and poststudy treatment discontinuation were evaluated for EGFR T790M mutations by next-generation sequencing. Results: The Japanese subset included 211 of 449 (47.0%) RELAY patients (RAM + ERL, n = 106; PL + ERL, n = 105). Median PFS was 19.4 versus 11.2 months for RAM + ERL versus PL + ERL treatment (HR = 0.610 [0.431–0.864]) in the Japanese intent-to-treat population, 16.6 versus 12.5 months (HR = 0.701 [0.424–1.159]) in the EGFR exon 19 deletion subgroup, and 19.4 versus 10.9 months (HR = 0.514 [0.317–0.835]) in the EGFR exon 21 L858R subgroup, respectively. Adverse events of grade 3 or above with RAM + ERL included hypertension (24.8%, all grade 3) and dermatitis acneiform (23.8%). Postprogression treatment-emergent T790M rates were similar between arms (RAM + ERL: 47%, 9 of 19 patients; PL + ERL: 50%, 20 of 40 patients). Conclusions: Clinically meaningful efficacy was observed with RAM + ERL versus PL + ERL in the RELAY Japanese subset, with no new safety concerns. Postprogression T790M rates were similar across treatment arms, indicating the addition of RAM did not affect the ERL-associated EGFR T790M rates at disease progression.

Introduction: YS110, a humanized monoclonal antibody with a high affinity to CD26, exhibited promising antitumor activity and was generally well-tolerated in the phase 1 part of a phase 1 and 2 Japanese trial in patients with malignant pleural mesothelioma (MPM). Here we report the results of the phase 2 part of the study. Methods: The patients included were aged 20 years and older, had histologically confirmed MPM, were refractory to or intolerant of existing antineoplastic agents, and were not candidates for standard therapy. YS110 6 mg/kg, determined in the phase 1 dose-determination part, was given in 6-weekly cycles (5 × once-weekly infusions, followed by a 1-wk rest). Results: The study included 31 patients (median age = 68 y, 90.3% men); 64.5% had stage IV MPM, 90.3% had greater than or equal to 20% CD26 expression in tumor tissue, and 38.7% (12 patients) had previously received nivolumab. The 6-month disease control rate was 3.2%. The best overall response was partial response in one patient and stable disease in 14 patients. The median progression-free survival was 2.8 months (both in patients who had and had not previously received nivolumab—groups A and B, respectively). Respective progression-free survival rates at 6 months were 9.1% and 31.6% in groups A and B. The median overall survival was 9.7 months. A total of 30 patients (96.8%) had at least one adverse event. Common treatment-related adverse events were infusion-related reaction (16.1%), hiccups (9.7%), and interstitial lung disease (9.7%). There were no treatment-related deaths. Conclusions: The 6-month disease control rate did not exceed the predefined threshold, but YS110 revealed modest efficacy in response rate as salvage therapy in difficult-to-treat patients with MPM. YS110 was generally well tolerated.

Introduction: We examined the long-term efficacy and safety of nivolumab, a human monoclonal antibody that inhibits interactions between the programmed cell death protein-1 receptor and its ligands (programmed death-ligand 1 and programmed death-ligand 2), in Japanese patients with malignant pleural mesothelioma (MPM). Methods: Japanese patients with previously treated MPM (one or two regimens) were enrolled in a single-arm, phase 2 study and received nivolumab intravenously 240 mg every 2 weeks until progressive disease or unacceptable toxicity. The primary end point was the centrally assessed objective response rate. Other end points included overall survival (OS), progression-free survival (PFS), treatment-related adverse events, and patient-reported outcomes (Lung Cancer Symptom Scale for mesothelioma and EuroQOL visual analog scale). Patient enrollment started on June 16, 2016. Here, we report 3-year follow-up data (cutoff date: November 12, 2019). Results: Thirty-four patients were enrolled. The centrally assessed objective response rate was previously reported (29.4%). The 2- and 3-year OS rates were 35.3% and 23.5%, respectively, and the corresponding PFS rates were 17.0% and 12.7%. Median OS and PFS were 17.3 and 5.9 months, respectively. Eight patients were alive at 3 years of follow-up. Nivolumab was well tolerated and no new safety signals were found. The patient-reported outcomes were maintained without marked deteriorations during the study. Conclusions: Our results reveal clinically relevant long-term efficacy and safety of nivolumab for the treatment of MPM.

Introduction: Despite recent advances in NSCLC treatment, specific data on the elderly population remain limited. In this post hoc subgroup analysis of the East Asia S-1 Trial in Lung Cancer (EAST-LC) trial, we compared S-1 and docetaxel (DTX) in patients aged 70 years old and above with pretreated advanced NSCLC. Methods: Patients were randomly assigned (1:1) to receive S-1 (orally, twice daily on d 1–28 of a 6-wk cycle) or DTX (intravenously, on d 1 of a 3-wk cycle). The initial S-1 dose was 80, 100, or 120 mg/day on the basis of body surface area, and the DTX doses were 60 mg/m2 (Japan) or 75 mg/m2 (outside Japan). The primary end point was overall survival, and secondary end points included progression-free survival, response rate, quality of life (QOL) using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core-30, and safety. Results: Among 189 patients aged 70 years and above assessed as the full analysis set, baseline characteristics were generally similar between treatment arms. The median overall survival was 14.7 (S-1) versus 12.1 months (DTX); the hazard ratio was equal to 0.76, with a 95% confidence interval (CI) of 0.54–1.07. The median progression-free survival was similar in both arms (both 4.1 mo, hazard ratio = 0.84, 95% CI: 0.60–1.18); and the response rate was 12.9% (S-1) and 14.0% (DTX). The adjusted mean QOL score difference (S-1–DTX until wk 48) was 7.41 (95% CI: 0.37–14.46). Safety profiles were generally consistent with those of the overall EAST-LC population. Conclusions: S-1 revealed comparable efficacy, safety, and QOL versus DTX in pretreated elderly patients with advanced NSCLC. Results were consistent with the overall EAST-LC data.

Introduction: Taletrectinib (AB-106/DS-6051b) is an oral, potent selective ROS1 and pan-NTRK tyrosine kinase inhibitor (TKI). Preclinically, taletrectinib has activity against ROS1 G2032R solvent-front mutation. Methods: Patients with ROS1+ NSCLC enrolled into two phase 1 studies conducted in United States (U101, NCT02279433) and Japan (J102, NCT02675491) were analyzed for objective response rate (ORR) by the Response Evaluation Criteria in Solid Tumors version 1.1, progression-free survival, and safety. Results: A total of 22 patients with ROS1+ NSCLC out of the total 61 patients enrolled were analyzed. Taletrectinib was given at the oral dose of 400 mg, 600 mg, 800 mg, and 1200 mg once daily and 400 mg twice daily as part of the dose-escalation schema. Data cutoff was August 19, 2020. Median follow-up time for all 22 patients was 14.9 months (95% confidence interval [CI]: 4.1–33.8). A total of 18 patients with ROS1+ were assessable for response. The confirmed ORR for ROS1 TKI-naive patients (N = 9) was 66.7% (95% CI: 35.4–87.9) with a disease control rate of 100% (70.1–100). The confirmed ORR for crizotinib pretreated patients (N = 6) was 33.3% (95% CI: 9.7–70.0) with a disease control rate of 88.3% (95% CI: 443.6–97.0). The median progression-free survival for ROS1 TKI-naive patients (N = 11) was 29.1 months (95% CI: 2.6–not reached) and 14.2 months (95% CI: 1.5–not reached) for crizotinib-refractory only patients (N = 8). The most common treatment-related adverse events were alanine transaminase elevations (72.7%), aspartate transaminase elevations (72.7%), nausea (50.0%), and diarrhea (50.0%). Grade 3 or higher adverse events were alanine transaminase elevations (18.2%), aspartate transaminase (9.1%), and diarrhea (4.5%). Conclusions: Taletrectinib (AB106/DS6051b) has a meaningful clinical activity in patients with advanced ROS1+ NSCLC who are ROS1 TKI-naive or crizotinib-refractory and a manageable safety profile.