Association of immune-related adverse events with durvalumab efficacy after chemoradiotherapy in patients with unresectable Stage III non-small cell lung cancer.

BACKGROUND: Immune-related adverse events (irAEs) have been found to predict PD-L1 inhibitor efficacy in metastatic NSCLC. However, the relation of irAEs to clinical outcome for nonmetastatic NSCLC has remained unknown. METHODS: In this multicenter prospective study of Stage III NSCLC treated with PACIFIC regimen, the relation of irAEs to PFS was evaluated by 8-week landmark analysis to minimise lead-time bias as well as by multivariable analysis adjusted for baseline factors. irAEs were categorised as mild or nonmild according to whether they were treated with systemic steroid. RESULTS: Median PFS was 16.0 months, not reached, and 9.7 months for patients without (85 cases) or with mild (21 cases) or nonmild (21 cases) irAEs, respectively. Multivariable analysis indicated that nonmild irAEs were associated with poor PFS, with HRs of 3.86 (95% CI, 1.31-11.38) compared with no irAEs and 11.58 (95% CI, 2.11-63.63) compared with mild irAEs. This pattern was consistent after irAE grade, the number of durvalumab doses and immune profiles (PD-L1 score, CD8+ tumour-infiltrating lymphocyte density, and tumour mutation burden) were taken into consideration. CONCLUSIONS: The development of mild irAEs might predict a better survival outcome, whereas immunosuppressive steroid-treated irAEs were associated with a worse outcome, regardless of baseline clinical and immune profiles.

Tracheomediastinal fistula induced by concurrent chemoradiotherapy in small cell lung cancer: A case report and literature review.

Tracheomediastinal fistula is a rare but life-threatening complication of cancer. We report a case of tracheomediastinal fistula induced by concurrent chemoradiotherapy in limited stage small cell lung cancer. Despite the treatment response, the metastatic paratracheal lymph node increased gradually during concurrent chemoradiotherapy, resulting in the occurrence of tracheomediastinal fistula and mediastinitis. Without any surgical intervention, the patient achieved successful recovery from mediastinitis through antibiotic treatment, although the tracheomediastinal fistula remained open. In this report, we also review previous studies of tracheomediastinal and bronchomediastinal fistulas and summarize the clinical features.

Osimertinib readministration for central nervous system metastases in non-small cell lung cancer positive for EGFR activating mutations.

BACKGROUND: Osimertinib shows pronounced efficacy for EGFR mutation-positive non-small cell lung cancer (NSCLC) including associated central nervous system (CNS) metastases. Tumors inevitably develop resistance to the drug, however. Osimertinib is sometimes readministered after completion of standard chemotherapy. To clarify which patients might receive benefit from osimertinib readministration, we have retrospectively assessed its efficacy with a focus on CNS metastases. METHODS: A retrospective analysis of medical records was performed for 21 patients who underwent osimertinib readministration at Kyushu University Hospital between March 2016 and April 2023. CNS metastases were evaluated according to modified Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: Among the 21 enrolled patients, 16 individuals had target lesions on the basis of RECIST. One (6.3%) of these 16 patients achieved a partial response to osimertinib readministration, with the remaining 15 patients showing stable or progressive disease. The median overall progression-free survival (PFS) and median overall survival for all 21 patients were 3.8 and 13.9 months, respectively. The efficacy of osimertinib readministration for CNS metastases was evaluable in eight patients including five individuals with leptomeningeal metastases. The objective response rate for CNS metastases and the improvement rate for leptomeningeal metastases were both 100%. The median PFS with regard to CNS or non-CNS lesions for these eight patients was 24.7 and 10.5 months, respectively. CONCLUSIONS: Osimertinib readministration showed limited efficacy for non-CNS lesions but excellent efficacy for CNS metastases, suggesting that such treatment is an option for EGFR-mutated NSCLC patients with CNS metastases.

Phase II Study of Durvalumab Immediately after Completion of Chemoradiotherapy in Unresectable Stage III Non-small Cell Lung Cancer: TORG1937 (DATE Study).

PURPOSE: Concurrent chemoradiotherapy (CCRT) followed by durvalumab consolidation for up to 12 months is the standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC). However, exactly when to initiate durvalumab therapy after chemoradiation completion remains unknown. We evaluated the efficacy and safety of durvalumab, administered immediately after CCRT completion, for patients with unresectable stage III NSCLC. PATIENTS AND METHODS: This study was a prospective, single-arm, open-label phase II clinical trial. Patients without disease progression after definitive CCRT (two cycles of platinum-based doublet chemotherapy with 60 Gy/30 Fr radiotherapy) received durvalumab (every 2 weeks for up to 12 months) from the next day (up to 5 days) after the final radiation dose. The primary endpoint was the 1-year progression-free survival (PFS) from registration before the start of CCRT. RESULTS: From January 2020 to August 2020, 47 of 50 enrolled patients were evaluable for treatment efficacy and safety. The 1-year PFS from registration was 75.0% [60% confidence interval (CI), 69.0-80.0 and 95% CI, 59.4-85.3]. The objective response rate throughout the study treatment and median PFS from registration were 78.7% and 14.2 months (95% CI, 13.4 to not reached), respectively. Grade 3/4 pneumonitis and febrile neutropenia were each 4.3%. CONCLUSIONS: Our study met the primary endpoint. The incidence of pneumonitis was similar to that of a Japanese subset in the PACIFIC study. Our data support the efficacy and safety of durvalumab administered immediately after the completion of CCRT for patients with unresectable stage III NSCLC.

Effectiveness and Safety of Immune Checkpoint Inhibitors Alone or in Combination With Chemotherapy in Pulmonary Sarcomatoid Carcinoma.

Introduction: Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of lung cancer associated with poor prognosis and resistance to conventional chemotherapy. Immune checkpoint inhibitors (ICIs), alone or in combination with chemotherapy, were found to have clinical benefits in PSC in recent studies. Nevertheless, because these studies included a small number of patients owing to disease rarity, larger studies are needed to evaluate the effectiveness and safety of ICI-based therapy for PSC. Methods: This multicenter retrospective study evaluated patients with ICI-naive advanced or metastatic PSC who were treated with ICI-based therapy at 25 hospitals in Japan. Results: A total of 124 patients were evaluated. The overall response rate, median progression-free survival (PFS), and median overall survival (OS) were 59.0%, 10.5 months, and 32.8 months, respectively. The PFS and OS rates at 24 months were 35.3% and 51.5%, respectively. Programmed death-ligand 1 expression, concomitant chemotherapy, and the treatment line were not significantly associated with PFS or OS. Immune-related adverse events (irAEs) were observed in 70 patients (56.5%), including 30 (24.2%) with grade 3 to 5 events. Patients with mild irAEs (grades 1-2) had longer PFS and OS than did those with severe (grades 3-5) or no irAEs. In a multivariate analysis, any-grade irAEs and the absence of liver metastases were independently associated with PFS, whereas any-grade irAEs and Eastern Cooperative Oncology Group performance status less than or equal to 1 were independently associated with OS. Conclusions: ICI-based therapy was found to have promising effectiveness in patients with advanced or metastatic PSC, regardless of programmed death-ligand 1 expression, concomitant chemotherapy, or treatment line.

Five Cases of Cytokine Release Syndrome in Patients Receiving Cytotoxic Chemotherapy Together With Nivolumab Plus Ipilimumab: A Case Report.

We conducted a phase 3 clinical trial to compare the efficacy of platinum-based combination chemotherapy together with nivolumab plus ipilimumab relative to that of platinum-based combination chemotherapy together with pembrolizumab in previously untreated patients with advanced NSCLC. The trial was terminated prematurely after treatment of 295 patients because of a high proportion of treatment-related deaths, three of which were due to cytokine release syndrome (CRS), in the nivolumab plus ipilimumab treatment arm. In addition, we encountered two cases of CRS that were effectively managed, for a total of five cases (3.4%) among the 148 patients in the nivolumab plus ipilimumab arm. We here provide details of these five cases. Although patient background and timing of CRS onset differed, fever was observed before the emergence of CRS in all five cases. Oncologists should thus be aware that the development of fever during treatment of patients with nivolumab plus ipilimumab may herald the onset of CRS.

Atezolizumab and Platinum Plus Pemetrexed With or Without Bevacizumab for Metastatic Nonsquamous Non-Small Cell Lung Cancer: A Phase 3 Randomized Clinical Trial.

Importance: The combination of an antibody to programmed cell death-1 (PD-1) or to its ligand (PD-L1) with chemotherapy is the standard first-line treatment for metastatic non-small cell lung cancer (NSCLC). Bevacizumab is expected to enhance the efficacy not only of chemotherapy but also of PD-1/PD-L1 antibodies through blockade of vascular endothelial growth factor-mediated immunosuppression, but further data are needed to support this. Objective: To evaluate the efficacy and safety of bevacizumab administered with platinum combination therapy and atezolizumab in patients with advanced nonsquamous NSCLC. Design, Setting, and Participants: An open-label phase 3 randomized clinical trial was conducted at 37 hospitals in Japan. Patients with advanced nonsquamous NSCLC without genetic driver alterations or those with genetic driver alterations who had received treatment with at least 1 approved tyrosine kinase inhibitor were enrolled between January 20, 2019, and August 12, 2020. Interventions: Patients were randomly assigned to receive either atezolizumab plus carboplatin with pemetrexed (APP) or atezolizumab, carboplatin plus pemetrexed, and bevacizumab (APPB). After 4 cycles of induction therapy, maintenance therapy with atezolizumab plus pemetrexed or with atezolizumab, pemetrexed, and bevacizumab was administered until evidence of disease progression, development of unacceptable toxic effects, or the elapse of 2 years from the initiation of protocol treatment. Main Outcomes and Measures: The primary end point was progression-free survival (PFS) as assessed by blinded independent central review (BICR) in the intention-to-treat (ITT) population. Results: A total of 412 patients were enrolled (273 men [66%]; median age, 67.0 [range, 24-89] years) and randomly assigned, with 205 in the APPB group and 206 in the APP group of the ITT population after exclusion of 1 patient for good clinical practice violation. The median BICR-assessed PFS was 9.6 months with APPB vs 7.7 months with APP (stratified hazard ratio [HR], 0.86; 95% CI, 0.70-1.07; 1-sided stratified log-rank test; P = .92). According to prespecified subgroup analysis of BICR-assessed PFS, an improved PFS with APPB vs APP was apparent specifically in driver oncogene-positive patients (median, 9.7 vs 5.8 months; stratified HR, 0.67; 95% CI, 0.46-0.98). Toxic effects related to bevacizumab were increased in the APPB group. Conclusions and Relevance: The findings of this trial did not show superiority of APPB over APP for patients with nonsquamous NSCLC; however, this regimen showed a similar tolerability and improved survival relative to APP in patients with driver oncogenes. Trial Registration: Japan Registry of Clinical Trials Identifier: jRCT2080224500.

Durvalumab Plus Concurrent Radiotherapy for Treatment of Locally Advanced Non-Small Cell Lung Cancer: The DOLPHIN Phase 2 Nonrandomized Controlled Trial.

Importance: Administration of durvalumab after concurrent chemoradiotherapy is the standard treatment of unresectable, locally advanced non-small cell lung cancer (NSCLC); however, 20% to 30% of patients do not receive durvalumab because of adverse events (AEs) during concurrent chemoradiotherapy. In addition, radiotherapy and immunotherapy have a synergistic effect. Objective: To investigate the efficacy and safety of durvalumab immunotherapy plus concurrent radiotherapy followed by maintenance with durvalumab therapy for treatment of locally advanced NSCLC without chemotherapy. Design, Setting, and Participants: The multicenter, single-arm DOLPHIN (Phase II Study of Durvalumab [MEDI4736] Plus Concurrent Radiation Therapy in Advanced Localized NSCLC Patients) nonrandomized controlled trial was performed by 12 institutions in Japan from September 13, 2019, to May 31, 2022. Participants in the primary registration phase included 74 patients with programmed cell death ligand 1 (PD-L1)-positive, unresectable, locally advanced NSCLC. The current analyses were conducted from June 1, 2022, to October 31, 2022. Interventions: Patients received radiotherapy (60 Gy) in combination with concurrent and maintenance durvalumab immunotherapy, 10 mg/kg every 2 weeks, for up to 1 year. Main Outcomes and Measures: The primary end point of the rate of 12-month progression-free survival (PFS), as assessed by an independent central review, was estimated using the Kaplan-Meier method and evaluated with 90% CIs calculated using the Greenwood formula. The key secondary end points were PFS, objective response rate, treatment completion rate, and AEs. Results: Data from 35 patients (median [range] age, 72 [44-83] years; 31 [88.6%] men) were included in the full analysis set of the evaluable population. The 12-month PFS rate was 72.1% (90% CI, 59.1%-85.1%), and the median PFS was 25.6 months (95% CI, 13.1 months to not estimable) at a median follow-up of 22.8 months (range, 4.3-31.8 months). Scheduled radiation therapy was completed in 97.1% of patients. The confirmed objective response rate was 90.9% (95% CI, 75.7%-98.1%), and the treatment completion rate was 57.6% (95% CI, 39.2%-74.5%). Among 34 patients evaluated in the safety analysis set, AEs of grade 3 or 4 occurred in 18 patients (52.9%), and of grade 5 in 2 patients (5.9%). Pneumonitis or radiation pneumonitis of any grade occurred in 23 patients (67.6%), and of grades 3 or 4 in 4 patients (11.8%). Conclusions and Relevance: Findings from this phase 2 nonrandomized controlled trial indicate that durvalumab immunotherapy combined with curative radiotherapy for patients with PD-L1-positive, unresectable, locally advanced NSCLC is a promising treatment with tolerable AEs and is appropriate as a study treatment for phase 3 clinical trials. Trial Registration: Japan Registry of Clinical Trials ID: jRCT2080224763.

Acute myeloid leukemia and myelodysplastic syndrome associated with a combination of immune checkpoint inhibitor and platinum-based chemotherapy.

Therapy related-acute myeloid leukemia (t-AML) and myelodysplastic syndrome (t-MDS) are complications of chemotherapy and/or radiation therapy for malignant diseases. In this report, we describe a patient with advanced lung adenocarcinoma who developed autoimmune hemolytic anemia and MDS associated with a combination of atezolizumab and platinum-based chemotherapy. The patient showed progression from t-MDS to t-AML 20 months after the treatment was initiated. A combination of immune checkpoint inhibitor (ICI) and chemotherapy may increase the risk of developing therapy-related myeloid neoplasms. As the prognosis of t-AML and t-MDS is poorer than that of de novo AML and MDS, proper surveillance, follow-up, and treatment are needed throughout the course of immunotherapy.

Impact of increased plasma levels of calreticulin on prognosis of patients with advanced lung cancer undergoing combination treatment of chemotherapy and immune checkpoint inhibitors.

BACKGROUND: Damage-associated molecular pattern (DAMP)-related immunogenic cell death triggers secondary adaptive immune responses. The relationship between DAMP levels and prognosis in patients with non-small cell lung cancer (NSCLC) who undergo a combination therapy of immune checkpoint inhibitors (ICI) and chemotherapy remains unclear. METHODS: Serial plasma samples were prospectively collected from 45 patients treated with ICI combination therapy for advanced NSCLC. Plasma concentrations of high-mobility group box 1 (HMGB1), calreticulin (CRT), annexin A1, and heat shock protein 70 were measured. Associations between increases in plasma DAMP levels and the efficacy of the ICI combination therapy were evaluated. RESULTS: The maximum fold changes in plasma levels differed across individuals but demonstrated a marked increase, especially for CRT (mean ± SEM, 11.61 ± 46.15). Increased plasma DAMP levels were not clearly associated with clinical responses. There was a significant correlation between the maximum fold change in CRT levels and progression-free survival (PFS; r = 0.49, P < 0.001). Median PFS and overall survival (OS) rates were higher in patients with a ≥ 2-fold increase in plasma CRT levels than in those with a < 2-fold increase (PFS, 14.9 versus 6.0 months, hazard ratio (HR), 0.58; P = 0.17; OS, not reached versus 21.6 months, HR, 0.31, P = 0.02). CONCLUSIONS: Plasma CRT level monitoring has the potential to predict the efficacy of ICI combination therapy and shed light on the mechanisms underlying DAMP-related immunogenic cell death.

Impact of the pretreatment prognostic nutritional index on the survival after first-line immunotherapy in non-small-cell lung cancer patients.

BACKGROUND: Immunotherapy has become a standard-of-care for patients with non-small-cell lung cancer (NSCLC). Although several biomarkers, such as programmed cell death-1, have been shown to be useful in selecting patients likely to benefit from immune checkpoint inhibitors (ICIs), more useful and reliable ones should be investigated. The prognostic nutritional index (PNI) is a marker of the immune and nutritional status of the host, and is derived from serum albumin level and peripheral lymphocyte count. Although several groups reported its prognostic role in patients with NSCLC receiving a single ICI, there exist no reports which have demonstrated its role in the first-line ICI combined with or without chemotherapy. MATERIALS AND METHODS: Two-hundred and eighteen patients with NSCLC were included in the current study and received pembrolizumab alone or chemoimmunotherapy as the first-line therapy. Cutoff value of the pretreatment PNI was set as 42.17. RESULTS: Among 218 patients, 123 (56.4%) had a high PNI (≥42.17), while 95 (43.6%) had a low PNI (<42.17). A significant association was observed between the PNI and both the progression-free survival (PFS; hazard ratio [HR] = 0.67, 95% confidence interval [CI]: 0.51-0.88, p = 0.0021) and overall survival (OS; HR = 0.46, 95% CI: 0.32-0.67, p < 0.0001) in the entire population, respectively. The multivariate analysis identified the pretreatment PNI as an independent prognosticator for the PFS (p = 0.0011) and OS (p < 0.0001), and in patients receiving either pembrolizumab alone or chemoimmunotherapy, the pretreatment PNI remained an independent prognostic factor for the OS (p = 0.0270 and 0.0006, respectively). CONCLUSION: The PNI might help clinicians appropriately identifying patients with better treatment outcomes when receiving first-line ICI therapy.

Pneumonitis associated with pembrolizumab plus chemotherapy for non-squamous non-small cell lung cancer.

Studies elucidating detailed characteristics of pneumonitis in association with chemo-immunotherapy are limited. We aimed to investigate the characteristics of images, prognostic factors, and clinical course of combination therapy associated with pneumonitis. A multicenter, retrospective cohort study of patients with non-squamous non-small cell lung cancer who received a combination of platinum, pemetrexed, and pembrolizumab was conducted. Patients with confirmed pneumonitis established by an independent multidisciplinary team were enrolled. For 53 patients with pneumonitis, radiographic features at diagnosis predominantly comprised an organizing pneumonia pattern (62%, 33/53). Twelve (23%) patients experienced a worsening respiratory status during pneumonitis management, which was associated with a high mortality rate (58%, 7/12) during treatment. Severe grade at pneumonitis diagnosis (p < 0.001), diffuse alveolar damage (DAD) pattern (p = 0.002), and disease extent ≥ 25% in the lungs (p = 0.009) were significantly associated with worsening respiratory status. Furthermore, post-diagnosis survival was significantly worse in severe pneumonitis (p = 0.02) than in mild and in patients with the DAD pattern than in those without (p < 0.0001). We showed detailed clinical course of patients with pneumonitis and reported several important influencing factors. Given the small number of trials on pneumonitis, our findings provide valuable information to guide the development of appropriate management guidelines and improve pneumonitis treatment.

Phase 1 study of DS-1205c combined with gefitinib for EGFR mutation-positive non-small cell lung cancer.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) are effective for the treatment of non-small cell lung cancer (NSCLC) patients with activating mutations of the epidermal growth factor receptor (EGFR), but responses are not durable as tumors develop resistance. DS-1205c is a novel, specific, orally bioavailable, small-molecule AXL receptor TKI. In preclinical studies, DS-1205c restored TKI antitumor activity in a TKI acquired-resistance EGFR-mutant NSCLC tumor xenograft model. METHODS: This first-in-human, multicenter, open-label Phase 1 study (registered at ClinicalTrials.gov: NCT03599518) primarily evaluated the safety and tolerability of combination therapy with DS-1205c and gefitinib in Japanese patients with metastatic or unresectable EGFR-mutant NSCLC and tumor progression during treatment with EGFR-TKIs. Patients (n = 20) received DS-1205c monotherapy (200-1200 mg twice daily [BID]) in a 7-day safety monitoring period before combination DS-1205c/gefitinib (250 mg once daily) in 21-day cycles. RESULTS: The observed common treatment-emergent adverse events (TEAEs) were increased aspartate aminotransferase (35%), increased alanine aminotransferase (30%), rash maculo-papular (30%), and diarrhea (25%). No serious TEAEs were reported. Plasma concentrations and pharmacokinetic parameters of DS-1205a (free form of DS-1205c) were unaffected by concomitant administration of gefitinib. No patient achieved a complete or partial response and 5 patients (25%) had stable disease. CONCLUSION: DS-1205c was generally safe and well tolerated at all dose levels, but the safety profile of ≤800 mg BID was more favorable than 1200 mg BID. The recommended dose for dose-expansion cohorts of DS-1205c in combination therapy with gefitinib was 800 mg BID.

Association of thyroid transcription factor-1 (TTF-1) expression with efficacy of PD-1/PD-L1 inhibitors plus pemetrexed and platinum chemotherapy in advanced non-squamous non-small cell lung cancer.

Background: Thyroid transcription factor-1 (TTF-1) expression in advanced non-squamous non-small cell lung cancer (NSCLC) has been associated with the efficacy of pemetrexed plus platinum chemotherapy. However, the relation between TTF-1 expression and efficacy of the combination of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors plus pemetrexed and platinum chemotherapy, a standard first-line treatment regimen for advanced non-squamous NSCLC, has remained unclear. Methods: We retrospectively evaluated TTF-1 expression in tumor tissue of patients with advanced or recurrent non-squamous NSCLC treated with PD-1/PD-L1 inhibitors plus pemetrexed and platinum chemotherapy in the first-line setting. Clinical characteristics and pathological data for each patient were assessed, and progression-free survival (PFS) was evaluated. Bias due to patient background was minimized by application of inverse probability of treatment weighting (IPTW) analysis. Results: A total of 122 patients, 75 (61.5%) of whom were positive for TTF-1 immunostaining in tumor specimens, was included in this multicenter study. At the time of analysis, 89 (73.0%) patients had experienced progression events and 44 (36.1%) had died [median follow-up 14.6 months (range, 0.53-29.5 months)]. PFS was longer for TTF-1-positive patients than for TTF-1-negative patients [median, 12.2 vs. 6.0 months; hazard ratio (HR) =0.63 (95% CI: 0.37-1.06); log-rank P=0.028]. IPTW-adjusted PFS was significantly longer for TTF-1-positive than for TTF-1-negative patients [HR =0.62 (95% CI: 0.46-0.83); log-rank P=0.024]. Conclusions: TTF-1 expression in advanced non-squamous NSCLC can serve as a basis for prediction of PFS in patients treated with PD-1/PD-L1 inhibitors plus pemetrexed and platinum chemotherapy in the first-line setting.

Forthcoming Phase II Study of Durvalumab (MEDI4736) Plus Chemotherapy for Small Cell Lung Cancer with Brain Metastases.

Background: The standard of care for extensive-stage small cell lung cancer (ES-SCLC) is an immune checkpoint inhibitor (ICI) combined with platinum-etoposide (PE) chemotherapy. At initial diagnosis, about 25% of ES-SCLC patients have brain metastases, which are associated with a poor prognosis. The decision as to whether to treat brain metastases with local therapies such as surgery or radiotherapy before initiation of systemic chemoimmunotherapy is based on symptoms due to the brain lesions and the general condition of the patient. Subset analysis of the CASPIAN study showed that combination therapy with PE plus durvalumab (MEDI4736) is promising for ES-SCLC with brain metastases. However, data required in daily clinical practice, such as intracranial response rate and duration of intracranial response, are insufficient for such patients. Patients and Methods: We have designed a single-arm phase II trial of durvalumab plus PE for patients aged ≥20 years with chemotherapy-naïve ES-SCLC and at least one brain metastasis ≥5 mm in size that has not been previously treated. Patients receive durvalumab intravenously combined with four cycles of PE. Enrollment of 50 patients over 2 years at 25 oncology facilities in Japan is planned. The primary endpoint is intracranial response rate. Conclusion: This is the first prospective study to evaluate the effects of an ICI with PE specifically in ES-SCLC patients with brain metastases. If it demonstrates intracranial efficacy, this regimen will be a potential treatment option for such individuals, and radiation therapy or surgery for brain metastases can be avoided or postponed.

Phase II study of carboplatin/nab-paclitaxel/atezolizumab combination therapy for advanced nonsquamous non-small cell lung cancer patients with impaired renal function: RESTART trial.

BACKGROUND: First-line treatment of nonsquamous non-small cell lung cancer (NSCLC) has undergone a paradigm shift to platinum combination therapy together with immune checkpoint inhibitors (ICIs). However, phase III studies of combinations of cytotoxic chemotherapy and ICIs have included only patients with maintained organ function, not those with renal impairment. METHODS: Cytotoxic chemotherapy-naïve advanced nonsquamous NSCLC patients aged 20 years or older with impaired renal function (creatinine clearance of 15 to 45 mL/min) are prospectively registered in this single-arm phase II study and receive combination therapy with carboplatin, nanoparticle albumin-bound (nab-) paclitaxel, and atezolizumab. Individuals with known genetic driver alterations including those affecting EGFR, ALK, ROS1, BRAF, MET, RET, and NTRK are excluded. We plan to enroll 40 patients over 2 years at 32 oncology facilities in Japan. The primary end point is confirmed objective response rate. DISCUSSION: If the study demonstrates efficacy and safety of carboplatin/nab-paclitaxel/atezolizumab, then this combination regimen may become a treatment option even for nonsquamous NSCLC patients with impaired renal function. TRIAL REGISTRATION: Registered with Japan Registry for Clinical Trials on 25 February 2021 (jRCTs071200102).

A Randomized Comparison of Nivolumab versus Nivolumab + Docetaxel for Previously Treated Advanced or Recurrent ICI-Naïve Non-Small Cell Lung Cancer: TORG1630.

PURPOSE: The addition of cytotoxic chemotherapy to immune-checkpoint inhibitor (ICI) may enhance antitumor effects. We conducted an open-label randomized phase II/III study to evaluate nivolumab + docetaxel combination therapy in comparison with nivolumab monotherapy for previously treated ICI-naïve non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: The primary endpoint of the phase III study was overall survival (OS), and the secondary endpoints included progression-free survival (PFS), overall response rate (ORR), and toxicity. As ICI and platinum-doublet combination chemotherapy was approved in the first-line setting during this study, patient accrual was discontinued. RESULTS: One hundred twenty-eight patients (each arm, n = 64) were included in the full analysis set. The median OS in nivolumab (arm A) and nivolumab + docetaxel (arm B) was 14.7 months (95% CI, 11.4-18.7) and 23.1 months (95% CI, 16.7-NR), respectively. The HR for OS was 0.63 (90% CI, 0.42-0.95; P = 0.0310). The median PFS in arms A and arm B was 3.1 months (95% CI, 2.0-3.9) and 6.7 months (95% CI, 3.8-9.4), respectively. The HR for progression was 0.58 (95% CI, 0.39-0.88; P = 0.0095). The ORR was 14.0% (95% CI, 6.3-25.8) in arm A and 41.8% (95% CI, 28.7-55.9) in arm B. Hematotoxicity and gastrointestinal adverse events were more common in arm B than in arm A. Two treatment-related deaths were observed, including one patient in arm A who died of pneumonitis and one in arm B who died of myocarditis. CONCLUSIONS: Despite a slightly elevated toxicity, the addition of docetaxel to nivolumab has significantly prolonged the OS and PFS of patients with previously treated ICI-naïve NSCLC.

Nivolumab Retreatment in Non-Small Cell Lung Cancer Patients Who Responded to Prior Immune Checkpoint Inhibitors and Had ICI-Free Intervals (WJOG9616L).

PURPOSE: To explore the efficacy of retreatment with immune checkpoint inhibitors (ICI) in patients with advanced non-small cell lung cancer (NSCLC) who responded to prior ICI and had adequate ICI-free interval. PATIENTS AND METHODS: Patients with advanced NSCLC who had achieved complete response (CR), partial response (PR), or stable disease for ≥6 months with prior ICI therapy preceding progression were prospectively enrolled. All patients should have had ICI-free interval ≥60 days before registration. Patients were treated with nivolumab (240 mg) every 2 weeks until progression. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival, and safety (Trial Identifier, UMIN000028561). RESULTS: Sixty-one patients were enrolled during October 2017 to February 2020, with 59 analyzed for efficacy. Regarding prior ICI, 41 patients had CR or PR. Median treatment on ICI and median ICI-free intervals were 8.1 months and 9.2 months, respectively. Twenty patients experienced immune-related adverse events (irAE) that required discontinuation of prior ICI. Nivolumab retreatment demonstrated ORR of 8.5% [95% confidence interval (CI), 2.8-18.7%] and median PFS of 2.6 months (95% CI, 1.6-2.8 months) while 5 responders had 11.1 months of median PFS. In the multivariate analysis, ICI-free interval was the only predictive factor of PFS (HR, 2.02; P = 0.02), while prior efficacy or history of irAE was not. Common adverse events were skin disorders (23%), malaise (20%), and hypoalbuminemia (15%). CONCLUSIONS: Even in patients who initially responded to prior ICI and had ICI-free interval, once resistance occurred, retreatment with nivolumab had limited efficacy.

Exploratory Analysis Comparing Fosnetupitant Versus Fosaprepitant for Prevention of Highly Emetogenic Chemotherapy-Induced Nausea and Vomiting (CINV): A Randomized, Double-Blind, Phase 3 Study (CONSOLE).

INTRODUCTION: We describe the results of an exploratory analysis performed on the first head-to-head study (JapicCTI-194611) comparing two different intravenous (IV) neurokinin 1 (NK1) receptor antagonists, fosnetupitant and fosaprepitant, in combination with palonosetron (PALO) and dexamethasone (DEX) for the prevention of highly emetogenic chemotherapy (HEC)-induced nausea and vomiting (CINV). This analysis was performed to validate the findings of the primary analysis (previously published) utilizing a last observation carried forward (LOCF) approach for missing values for the efficacy endpoint of complete response (no emetic event and no rescue medication), while also evaluating the time periods encompassing the 0-168-hour (h) "extended overall phase" interval. METHODS: Patients scheduled to receive cisplatin-based chemotherapy were randomized 1:1 to fosnetupitant 235 mg or fosaprepitant 150 mg in combination with PALO 0.75 mg and DEX. Complete response rates were calculated and compared (stratified by age category and sex with a Mantel-Haenszel test) during the study's primary overall phase (0-120 h) and during additional time intervals of interest [acute (0-24 h), delayed (24-120 h), extended delayed (> 24-168 h), beyond delayed (120-168 h), and extended overall (0-168 h)]. RESULTS: A total of 785 patients were included (fosnetupitant N = 392, fosaprepitant N = 393). Complete response rates were numerically higher for fosnetupitant versus fosaprepitant for all time intervals and statistically significant for the extended overall phase. Complete response rates for fosnetupitant versus fosaprepitant during the overall, acute, delayed, extended delayed, beyond delayed, and extended overall phases were 75.5% vs. 71.0% (p = 0.1530), 93.9% vs. 92.6% (p = 0.4832), 77.0% vs. 72.8% (p = 0.1682), 74.7% vs. 68.4% (p = 0.0506), 86.7% vs. 81.7% (p = 0.0523), and 73.5% vs. 66.9% (p = 0.0450), respectively. CONCLUSION: In this exploratory analysis, fosnetupitant appeared to be more effective than fosaprepitant in preventing CINV associated with cisplatin-based HEC during the extended 7-day period following chemotherapy. INFOGRAPHIC.

Real-world data on NGS using the Oncomine DxTT for detecting genetic alterations in non-small-cell lung cancer: WJOG13019L.

Considering the increasing number of identified driver oncogene alterations, additional genetic tests are required to determine the treatment for advanced non-small-cell lung cancer (NSCLC). Next-generation sequencing can detect multiple driver oncogenes simultaneously, enabling the analysis of limited amounts of biopsied tissue samples. In this retrospective, multicenter study (UMIN ID000039523), we evaluated real-world clinical data using the Oncomine Dx Target Test Multi-CDx System (Oncomine DxTT) as a companion diagnostic system. Patients with NSCLC who were tested for a panel of 46 genes using the Oncomine DxTT between June 2019 and January 2020 were eligible for enrollment. Patients from 19 institutions affiliated to the West Japan Oncology Group were recruited. The primary endpoint of the study was the success rate of genetic alteration testing in four driver genes (EGFR, ALK, ROS1, and BRAF) using the Oncomine DxTT. In total, 533 patients were enrolled in the study. The success rate of genetic alteration testing for all four genes was 80.1% (95% CI 76.5%-83.4%). Surgical resection was associated with the highest success rate (88.0%), which was significantly higher than that for bronchoscopic biopsy (76.8%, P = .005). Multivariate analysis revealed a significant difference for surgical resection alone (P = .006, 95% CI 1.36-6.18, odds ratio 2.90). Although the success rate of genetic alteration testing immediately after Oncomine DxTT induction was not sufficient in this study, optimizing specimen quantity and quality may improve the use of driver gene testing in clinical settings.