Comparing the Effectiveness of Afatinib and Osimertinib for Patients With PD-L1-positive EGFR-mutant Non-small Cell Carcinoma.

Background/Aim: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective for treating non-small cell lung cancer (NSCLC) harboring EGFR mutations. However, higher tumor programmed death ligand-1 (PD-L1) expression is associated with a poor response to EGFR-TKIs, and information on the comparison between afatinib and osimertinib in PD-L1-positive EGFR-mutant NSCLC is scarce. Patients and Methods: We retrospectively analyzed data of patients with PD-L1-positive EGFR-mutant NSCLC to compare the effectiveness of afatinib and osimertinib. Results: A total of 177 patients were included in the study. The Cox proportion hazard model was adjusted for age, sex, performance status, EGFR mutation status, PD-L1 expression level, and brain metastasis, revealing that there was no significant difference in risk for progression [hazard ratio (HR)=0.99, 95% confidence interval (CI)=0.64-1.53] or death (HR=0.96, 95% CI=0.54-1.73) between afatinib and osimertinib. Conclusion: In conclusion, the EGFR-TKI treatment duration and overall survival after the treatment with afatinib or osimertinib were similar in patients with PD-L1-positive EGFR-mutant NSCLC in the present study.

Successful application of lorlatinib in a 23-year-old patient with anaplastic lymphoma kinase (ALK)-positive lung cancer and multiple brain metastases.

BACKGROUND: Anaplastic lymphoma kinase (ALK)-positive lung cancer has a better long-term prognosis with ALK-inhibitor than other lung cancers. However, resistance to ALK-inhibitors and the control of metastases in the central nervous system (CNS) remain to be a challenge in the management of ALK-positive lung cancer. CASE: We present the case of a 23-year-old man who developed multiple brain metastases while receiving alectinib treatment for ALK-positive lung cancer. After 3 months of lorlatinib initiation, brain metastases disappeared, and complete response (CR) was maintained. CONCLUSION: While lorlatinib can be used as first line therapy, this drug may be considered as second line or later option for patients with multiple brain metastases if the patient has already been treated with other ALK-inhibitors since lorlatinib is thought to have good CNS penetration. This treatment option should be verified by further research.

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.

Durvalumab after chemoradiotherapy in non-small cell lung cancer with EGFR mutation: A real-world study (HOT2101).

Durvalumab has been administered to patients with unresectable stage III non-small cell lung cancer (NSCLC). However, it remains unclear whether durvalumab benefits these patients with epidermal growth factor receptor (EGFR) mutation. We conducted a retrospective, multicenter study of patients with EGFR mutation who received chemoradiotherapy (CRT) between June 2018 and March 2021. We assessed patient characteristics, efficacy of durvalumab, and durvalumab safety before and after targeted therapy. We collected data on a total of 673 patients, of whom 401 (59.6%) underwent EGFR mutation testing. Fifty-one patients were EGFR positive and 311 were EGFR negative. In the EGFR-positive group, there were higher proportions of females, never-smokers, and patients with adenocarcinoma histology. Of the 51 patients in the positive group and 311 in the negative group who received CRT, 45 (88.2%) and 247 (79.4%) received durvalumab, with median progression-free survival of 23.0 and 24.2 months in the positive and negative groups, respectively (hazard ratio 1.03; 95% confidence interval: 0.64-1.67). The main adverse event was pneumonitis (positive group: 62.2%; 4.4% grade 3; negative group: 62.3%; 6.9% grade 3). No treatment-related deaths were observed. Of the 45 patients in the positive group who received durvalumab, 14 (31.1%) received targeted therapy after durvalumab at the data cutoff. One patient discontinued targeted therapy after developing pneumonitis. In patients with unresectable stage III NSCLC with EGFR mutation, durvalumab after CRT is potentially safe and effective. This may be a suitable treatment sequence for these patients.

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.

First-Line Osimertinib for Previously Untreated Patients With NSCLC and Uncommon EGFR Mutations: The UNICORN Phase 2 Nonrandomized Clinical Trial.

Importance: Non-small cell lung cancer (NSCLC) with uncommon EGFR mutations is a rare subgroup, composing 14% of all EGFR mutations. Objective: To determine the usefulness of osimertinib in previously untreated patients with metastatic NSCLC harboring uncommon EGFR mutations, excluding exon 20 insertion mutations. Design, Setting, and Participants: This multicenter, open-label, single-group, phase 2 nonrandomized clinical trial enrolled patients from April 10, 2020, to May 31, 2022, with a follow-up of 6 months from the date the last patient was enrolled. The study enrolled 42 patients with uncommon EGFR mutations, of whom 40 were eligible. Intervention: Osimertinib, 80 mg once daily, was administered orally to patients. Main Outcomes and Measures: The primary end point was the overall response rate (ORR). The secondary end points were disease control rate (DCR), progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS), duration of response (DoR), and safety of osimertinib. Patients were included in the study on an intention-to-treat basis. Results: Of the 40 eligible patients, 22 were men (55.0%) and the median age was 72 years (range, 39.0-88.0 years). The most common mutations were G719X (20 [50.0%]), S768I (10 [25.0%]), and L861Q (8 [20.0%]). The ORR was 55.0% (90% CI, 40.9%-68.5%) and the DCR was 90.0% (95% CI, 76.3%-97.2%). The median PFS was 9.4 months (95% CI, 3.7-15.2 months) after a median follow-up of 12.7 months (range, 2.7-30.7 months). The median TTF was 9.5 months (95% CI, 5.6-30.3 months), median OS was not reached (NR; 95% CI, 19.3 months to NR), and median DoR was 22.7 months (95% CI, 9.5 months to NR). The ORR for patients with solitary or compound uncommon EGFR mutations was 45.5% (90% CI, 26.9%-65.3%) and 66.7% (90% CI, 43.7%-83.7%), respectively. Median PFS for patients with solitary or compound uncommon EGFR mutations was 5.4 months (95% CI, 3.6-22.7 months) and 9.8 months (95% CI, 5.1 months to NR), respectively. Median OS for patients with solitary or compound uncommon EGFR mutations was 23.0 months (95% CI, 12.3 months to NR) and NR, respectively. Median DoR for patients with solitary or compound uncommon EGFR mutations was 22.7 months (95% CI, 3.6-22.7 months) or NR (95% CI, 5.7 months to NR), respectively. Grade 3 or 4 adverse events were reported by 11 patients (27.5%), and 5 patients (12.5%) developed interstitial lung disease. All adverse events were manageable, and there were no treatment-related deaths. Conclusions and Relevance: Osimertinib showed clinical activity with manageable toxic effects among previously untreated patients with metastatic NSCLC harboring uncommon EGFR mutations other than exon 20 insertion mutations. The results support the use of osimertinib as a treatment option for this patient population. Trial Registration: Japan Registry of Clinical Trials Identifier: jRCTs071200002.

Multicenter, Retrospective Study to Evaluate Necitumumab Plus Cisplatin and Gemcitabine After Immune Checkpoint Inhibitors in Advanced Squamous Cell Lung Cancer in Japan: The NINJA Study.

Introduction: Necitumumab plus gemcitabine and cisplatin (GCN) is a standard therapy for patients with advanced lung squamous cell carcinoma (LSqCC). However, the efficacy and tolerability of GCN in second-line or later treatment for patients previously treated with immune checkpoint inhibitors (ICIs) remain unknown. Methods: This multicenter, retrospective, cohort study assessed the efficacy and tolerability of GCN initiated between November 1, 2019 and March 31, 2022 as second-line to fourth-line treatment in patients with advanced LSqCC who had been pretreated with ICIs. The primary end point was progression-free survival (PFS). Results: A total of 93 patients from 35 institutions in Japan were enrolled. The median PFS, median overall survival (OS), and objective response rate were 4.4 months (95% confidence interval [CI]: 3.8-5.3), 13.3 months (95% CI: 9.6-16.5), and 27.3% (95% CI: 18.3-37.8), respectively. The median PFS, median OS, and objective response rate for second-line, third-line, and fourth-line treatment groups were 4.8 months, 3.8 months, and 4.3 months (p = 0.24); 15.7 months, 11.6 months, and 10.1 months (p = 0.06); and 31.0%, 13.6%, and 37.5% (p = 0.22), respectively. The severity of GCN-related skin disorders was associated with longer PFS (p < 0.05) and OS (p < 0.05). The frequencies of grade ≥3 skin disorders, hypomagnesemia, pneumonitis, and febrile neutropenia were 16.1%, 7.5%, 1.1%, and 4.3%, respectively. There were no treatment-related deaths. Conclusions: GCN for ICI-pretreated patients with LSqCC seems tolerable and offers promising efficacy regardless of treatment line, and ICI pretreatment might enhance GCN efficacy.

Efficacy of paclitaxel-carboplatin with bevacizumab as a late-line therapy for patients with advanced nonsquamous non-small cell lung cancer: A platinum rechallenge.

BACKGROUND: There is no well-established late-line treatment for advanced nonsquamous non-small cell lung cancer (NSCLC). Therefore, we retrospectively determined the efficacy and safety of platinum rechallenge with paclitaxel-carboplatin and bevacizumab in patients with nonsquamous NSCLC as a late-line therapy in a clinical setting. METHODS: Thirty patients with nonsquamous NSCLC who received paclitaxel-carboplatin with bevacizumab therapy as a late-line treatment at Sendai Kousei Hospital (Miyagi, Japan) between December 2011 and December 2021 were enrolled into the study. The efficacy and safety of this treatment were evaluated. The patients were further categorized into responders and nonresponders, and predictive factors of treatment response were estimated. RESULTS: The median progression-free survival (PFS) was 6.3 (range, 4.9-6.8) months, and the median overall survival (OS) was 11.8 (range, 7.2-17.2) months. There were no significant differences in PFS and OS between patients with and those without epidermal growth factor receptor mutations. In the univariate analyses of this study, responders were younger than nonresponders (p = 0.012). No fatal adverse events were reported. CONCLUSIONS: With the increase in the number of treatment options in recent years, the sequence of treatments and overall therapeutic strategy are becoming increasingly important. Thus, platinum rechallenge with paclitaxel-carboplatin and bevacizumab, a late-line treatment for patients with nonsquamous NSCLC, may be an effective therapeutic option.

Phase II trial of daily S-1 combined with weekly irinotecan in previously treated patients with advanced or recurrent squamous cell lung cancer: North Japan lung cancer group 1101.

BACKGROUND: This phase II trial was designed to evaluate the efficacy and safety of S-1 combined with weekly irinotecan as a second- or third-line treatment for patients with advanced or recurrent squamous cell lung cancer. METHODS: Patients with a body surface area <1.25, 1.25-1.50, and >1.50 m2 received oral S-1 on days 1-14 at 80, 100, and 120 mg/day, respectively, and irinotecan on days 1 and 8 at 70 mg/m2 every 3 weeks. The primary endpoint was the overall response rate, and the secondary endpoints were progression-free survival, overall survival, and the incidence and severity of adverse effects. RESULTS: Between September 2011 and December 2014, 30 patients were enrolled in this study. The overall response rate was 6.7% (95% confidence interval [CI]: 0.8%-22.1%), and the disease control rate was 73.3%. The median progression-free survival was 3.0 months (95% CI: 2.5-3.4 months), and the median overall survival was 10.5 months (95% CI: 5.6-13.7 months). Grade 3/4 treatment-related adverse events were reported in ≥10% of the patients, including leukopenia (21%), neutropenia (21%), anemia (17%), anorexia (10%), and hypokalemia (10%). CONCLUSIONS: Although the treatment-related adverse events were manageable, the combination of weekly irinotecan and S-1 did not have the expected effect.

A retrospective study of the efficacy of combined EGFR­TKI plus VEGF inhibitor/cytotoxic therapy vs. EGFR­TKI monotherapy for PD­L1­positive EGFR­mutant non­small cell lung cancer: North Japan Lung Cancer Study Group 2202.

The present multicenter study was performed to compare the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) monotherapy with that of combined EGFR-TKI plus vascular endothelial growth factor receptor (VEGF) inhibitor/cytotoxic therapy in patients with programmed death-ligand 1 (PD-L1)-positive EGFR-mutant non-small cell lung cancer (NSCLC). Data from patients with PD-L1-positive EGFR-mutant NSCLC were collected from 12 institutes. Survival in patients treated with first- and second-generation EGFR-TKIs, osimertinib (third-generation EGFR-TKI), and combined EGFR-TKI plus VEGF inhibitor/cytotoxic therapy was analyzed by multiple regression analysis with adjustments for sex, performance status, EGFR mutation status, PD-L1 expression level, and the presence or absence of brain metastasis using a Cox proportional hazards model. Data from a total of 263 patients were analyzed, including 111 (42.2%) patients who had received monotherapy with a first- or second-generation EGFR-TKI, 132 (50.2%) patients who had received osimertinib monotherapy, and 20 (7.6%) patients who had received combined EGFR-TKI plus VEGF inhibitor/cytotoxic therapy (hereafter referred to as combined therapy). Multiple regression analysis using the Cox proportional hazards model showed that the hazard ratio (95% confidence interval) for progression-free survival was 0.73 (0.54-1.00) in the patients who had received osimertinib monotherapy and 0.47 (0.25-0.90) in patients who had received combined therapy. The hazard ratio for overall survival was 0.98 (0.65-1.48) in the patients who had received osimertinib monotherapy and 0.52 (0.21-1.31) in patients who had received combined therapy. In conclusion, combined therapy was associated with a significant reduction in the risk of progression compared with first- and second-generation EGFR-TKI monotherapy, and therefore, may be promising for the treatment of patients of NSCLC.

Subsequent treatment for locally advanced non-small-cell lung cancer that progressed after definitive chemoradiotherapy and consolidation therapy with durvalumab: a multicenter retrospective analysis (TOPGAN 2021-02).

PURPOSE: For patients with locally advanced non-small-cell lung cancer (LA-NSCLC) that progressed after definitive chemoradiotherapy (CRT) and durvalumab consolidation therapy, no subsequent standard treatment exists. The type of treatment selected for each timing of disease progression and its efficacy have not been investigated. METHODS: We retrospectively enrolled patients with LA-NSCLC or inoperable NSCLC that progressed after definitive CRT and durvalumab consolidation therapy at 15 Japanese institutions. Patients were classified into the following: Early Discontinuation group (disease progression within 6 months after durvalumab initiation), Late Discontinuation group (disease progression from 7 to 12 months after durvalumab initiation), and Accomplishment group (disease progression from 12 months after durvalumab initiation). RESULTS: Altogether, 127 patients were analyzed, including 50 (39.4%), 42 (33.1%) and 35 (27.5%) patients from the Early Discontinuation, Late Discontinuation, and Accomplishment groups, respectively. Subsequent treatments were Platinum plus immune checkpoint inhibitors (ICI) in 18 (14.2%), ICI in 7 (5.5%), Platinum in 59 (46.4%), Non-Platinum in 35 (27.6%), and tyrosine kinase inhibitor in 8 (6.3%) patients. In the Early Discontinuation, Late Discontinuation, and Accomplishment groups, 4 (8.0%), 7 (16.7%), and 7 (20.0%) patients were receiving Platinum plus ICI; 21 (42.0%), 22 (52.4%), and 16 (45.7%) were receiving Platinum, and 20 (40.0%), 8 (19.0%), and 7 (20.0%) were receiving Non-Platinum, respectively. No significant difference in progression-free survival was observed in the timing of disease progression. CONCLUSION: In patients with LA-NSCLC hat progressed after definitive CRT and durvalumab consolidation therapy, subsequent treatment may change depending on the timing of disease progression.

Clinical efficacy of amrubicin in patients with small cell lung cancer relapse after first-line treatment including immune checkpoint inhibitors: A retrospective multicenter study (TOPGAN 2021-01).

BACKGROUND: The therapeutic efficacy of cytotoxic anticancer drugs has been reported to be enhanced after immune checkpoint inhibitors (ICI) in non-small cell lung cancer; however, it is unclear whether the same is applicable for small cell lung cancer (SCLC). We evaluated the efficacy of second-line amrubicin (AMR) following first-line platinum-based chemotherapy and ICI combination therapy (chemo-ICI) in SCLC. PATIENTS AND METHODS: We retrospectively enrolled consecutive patients with SCLC treated with AMR as a second-line following chemo-ICI as first-line between July 2019 and April 2021 from 16 institutions throughout Japan. We investigated the therapeutic effectiveness, safety, and efficacy-enhancing variables of AMR. RESULTS: Overall, 89 patients treated with AMR after first-line chemo-ICI were analyzed. The overall response rate (ORR) was 29.2% (95% confidence intervals [CI], 20.1-39.8) and median PFS (m PFS) was 2.99 months (95% CI, 2.27-3.65). Patients who relapsed more than 90 days after receiving first-line platinum combination therapy (sensitive relapse) exhibited greater ORR (58.3% vs. 24.7%, p = 0.035) and m PFS (5.03 vs. 2.56 months, p = 0.019) than patients who relapsed in <90 days (refractory relapse). Grade 3 or higher adverse events were mainly hematological toxicity. CONCLUSIONS: Our study suggested that the therapeutic effect of AMR was not enhanced after ICI on SCLC. However, AMR may be effective in cases of sensitive relapse after chemo-ICI. There was no increase in severe toxicity associated with AMR after ICI.

Phase II study of durvalumab (MEDI 4736) plus carboplatin and etoposide in elderly patients with extensive stage small cell lung cancer: Study protocol of turtle study (LOGIK 2003).

BACKGROUND: Recently, the addition of antiprogrammed cell death-ligand 1 (PD-L1) monoclonal antibodies, including durvalumab and atezolizumab to platinum-based chemotherapy, has demonstrated clinical benefits in patients with untreated advanced small cell lung cancer (SCLC). However, these clinical trials comprised small populations of elderly patients with SCLC. Therefore, the safety of anti-PD-L1 immunotherapy plus platinum and etoposide in elderly patients remains unclear. METHODS: This prospective, multicenter, single-arm study was designed to evaluate the safety and efficacy of durvalumab plus carboplatin and etoposide in untreated elderly patients (aged > 75) with extensive stage (ES) SCLC. A total of 40 patients were recruited. Patients received up to four cycles of durvalumab 1500 mg and carboplatin at a dose equivalent to an area under the curve of 5 on day 1, and etoposide 80 mg/m2 on days 1 to 3 every 3 weeks as induction treatment, followed by durvalumab maintenance treatment every 4 weeks. The primary endpoint was safety as measured by adverse events according to the Common Terminology Criteria for Adverse Events version 5.0, laboratory analyses, vital signs, and physical examination. Key secondary endpoints were objective response rate, median progression-free survival, 12-month overall survival rate, and the completion rate for four cycles of induction chemotherapy. DISCUSSION: The present study was designed to evaluate the safety of durvalumab plus carboplatin and etoposide in elderly patients with ES-SCLC.

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.

Clinical efficacy of dacomitinib in rechallenge setting for patients with epidermal growth factor receptor mutant non-small cell lung cancer: A multicenter retrospective analysis (TOPGAN2020-02).

BACKGROUND: Dacomitinib is the second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) for mutant non-small cell lung cancer (NSCLC). EGFR-TKIs are often re-administered in Japan after the disease progression prior EGFR-TKI. There is little evidence of dacomitinib in rechallenge setting. This study evaluated clinical outcomes of dacomitinib in rechallenge setting. METHODS: Patients who received dacomitinib for advanced EGFR-mutant NSCLC who had progressed after EGFR-TKI in nine institutions in Japan were included in the analyses. RESULTS: In total, 43 patients were analyzed. The median progression-free survival (PFS) was 4.3 months (95% confidence interval [CI], 2.5-5.6). The overall survival (OS) was 10.5 months (95% CI, 7.4-not reached). The overall response rate was 25.5% (95% CI, 13.1-33.7). Subset analysis indicated that patients with EGFR exon 21 L858R showed longer PFS than those with EGFR exon 19 deletion (5.8 vs. 4.1 months) (p = 0.018). The most common adverse events leading to dose modification were diarrhea, paronychia, rash, and oral mucositis. CONCLUSION: In the real practice in Japan, dacomitinib showed a worthwhile treatment option for NSCLC patients with EGFR mutation after failure of previous EGFR-TKI. The benefit was especially pronounced in patients with the exon 21 mutation.

Bevacizumab plus erlotinib versus erlotinib alone in Japanese patients with advanced, metastatic, EGFR-mutant non-small-cell lung cancer (NEJ026): overall survival analysis of an open-label, randomised, multicentre, phase 3 trial.

BACKGROUND: Bevacizumab is a promising candidate for combination treatment with epidermal growth factor receptor tyrosine-kinase inhibitors (eg, erlotinib), which could improve outcomes for patients with metastatic EGFR-mutant non-small-cell lung cancer (NSCLC). We have previously shown in NEJ026, a phase 3 trial, that the combination of bevacizumab plus erlotinib significantly prolonged progression-free survival compared with erlotinib alone in these patients. In further analyses, we aimed to examine the effects of bevacizumab-erlotinib on overall survival, time from enrolment to progressive disease during second-line treatment or death, and quality of life. METHODS: This open-label, randomised, multicentre, phase 3 trial (NEJ026) was done in 69 hospitals and medical, community-based centres across Japan. Eligible patients had stage IIIB, stage IV, or postoperative recurrent, EGFR-mutant (exon 19 deletion or exon 21 Leu858Arg point mutation) NSCLC, had not previously received systemic chemotherapy, and were randomly assigned (1:1) by a computer-generated randomisation sequence and minimisation to receive either 150 mg oral erlotinib once daily plus 15 mg/kg intravenous bevacizumab once every 21 days, or 150 mg oral erlotinib once daily, until disease progression or intolerable toxicity. Randomisation was stratified according to sex, smoking status, EGFR mutation subtype, and clinical disease stage. All participants, investigators, and study personnel (including those assessing outcomes) were unmasked to treatment allocation. We report the secondary outcomes of overall survival and quality of life (the period from enrolment to confirmation of a minimally important difference on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ]-C30), and the exploratory outcome of time from enrolment to progressive disease during second-line treatment or death. Overall survival and the exploratory outcome were analysed in the modified intention-to-treat population, which comprised all randomly assigned patients who received at least one dose of the study drug and had response evaluations. Quality of life was analysed in patients in the modified intention-to-treat population who had completed the quality of life questionnaires. The trial is registered with the University Hospital Medical Information Network Clinical Trials Registry, UMIN000017069, and the Japan Registry of Clinical Trials, jRCTs031180056, and is currently closed. FINDINGS: Between June 3, 2015, and Aug 31, 2016, 228 patients were enrolled. 112 patients who received bevacizumab-erlotinib and 112 who received erlotinib only were included in the modified intention-to-treat population. At data cutoff (Nov 30, 2019) and a median follow-up of 39·2 months (IQR 23·9-43·5), the median overall survival was 50·7 months (95% CI 37·3-not estimable [NE]) in the bevacizumab-erlotinib group and 46·2 months (38·2-NE) in the erlotinib-only group (hazard ratio [HR] 1·007, 95% CI 0·681-1·490; p=0·97). In analysis of the exploratory outcome, after a median follow-up of 23·9 months (IQR 14·2-39·1), the median time from enrolment to progressive disease during second-line treatment or death was 28·6 months (95% CI 22·1-35·9) in the bevacizumab-erlotinib group and 24·3 months (20·4-29·1) in the erlotinib-only group (HR 0·773, 95% CI 0·562-1·065). The median time between enrolment and confirmation of a minimally important difference on the EORTC QLQ-C30 was 6·0 months (95% CI 5·2-11·3) in the bevacizumab-erlotinib group and 8·3 months (5·7-13·9) in the erlotinib-only group (p=0·47). INTERPRETATION: The addition of bevacizumab to erlotinib did not prolong survival in patients with metastatic EGFR-mutant NSCLC, but both treatment groups had relatively long survival durations. Why the addition of bevacizumab to erlotinib did not affect overall survival is unclear, but it is possible that the beneficial effects of combination therapy were not seen because overall survival was influenced by treatment regimens used after disease progression. FUNDING: Chugai Pharmaceutical.

Gene expression signatures as candidate biomarkers of response to PD-1 blockade in non-small cell lung cancers.

Although anti-PD-1/PD-L1 monotherapy has achieved clinical success in non-small cell lung cancer (NSCLC), definitive predictive biomarkers remain to be elucidated. In this study, we performed whole-transcriptome sequencing of pretreatment tumor tissue samples and pretreatment and on-treatment whole blood samples (WB) samples obtained from a clinically annotated cohort of NSCLC patients (n = 40) treated with nivolumab (anti-PD-1) monotherapy. Using a single-sample gene set enrichment scoring method, we found that the tumors of responders with lung adenocarcinoma (LUAD, n = 20) are inherently immunogenic to promote antitumor immunity, whereas those with lung squamous cell carcinoma (LUSC, n = 18) have a less immunosuppressive tumor microenvironment. These findings suggested that nivolumab may function as a molecular targeted agent in LUAD and as an immunomodulating agent in LUSC. In addition, our study explains why the reliability of PD-L1 expression on tumor cells as a predictive biomarker for the response to nivolumab monotherapy is quite different between LUAD and LUSC.

Association of immune-related pneumonitis with clinical benefit of anti-programmed cell death-1 monotherapy in advanced non-small cell lung cancer.

BACKGROUND: The association between the development of checkpoint inhibitor pneumonitis (CIP) with tumor response and survival has remained unclear so far. The aim of the present study was to evaluate the association between CIP and the clinical efficacy of anti-programmed cell death-1 antibody in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Between January 2016 and August 2019, 203 advanced NSCLC patients were administered with nivolumab or pembrolizumab. Comparisons were made between patients with and without CIP. We evaluated the time-to-treatment failure (TTF), progression-free survival (PFS), and overall survival (OS). RESULTS: CIP was observed in 28 (14%) patients. CIP was associated with a longer PFS (18.9 months [95% confidence interval, CI: 8.7 months-not reached] vs. 3.9 months [95% CI: 3.4-5.1 months, p < 0.01]) and longer OS (27.4 [95% CI: 20.7 months-not reached] vs. 14.8 months [95% CI: 11.2-17.9 months, p = 0.003]). Most patients discontinued the immune checkpoint inhibitor (ICI) treatment when they developed CIP. Seven patients (25%) lived for more than 300 days from treatment discontinuation and did not show any long-term tumor growth after treatment discontinuation. CONCLUSION: CIP was associated with prolonged PFS and OS. Additionally, 25% of CIP patients did not show any tumor growth for long periods after treatment discontinuation. Careful management of CIP can help in obtaining the best clinical efficacy from anti-PD-1 antibody.

Randomized phase II trial of carboplatin + nab-paclitaxel versus cisplatin + gemcitabine for chemotherapy-naïve squamous cell carcinoma: North Japan lung cancer study group 1302.

BACKGROUND: A subset analysis of the CA031 trial showed significant improvement in the overall response rate after administration of carboplatin plus weekly albumin-bound paclitaxel compared to carboplatin plus paclitaxel for squamous cell carcinoma of the lung (SQ). We conducted this phase II study to compare carboplatin plus weekly albumin-bound paclitaxel (CnP) to cisplatin plus gemcitabine (CG), a standard regimen for SQ. METHODS: Chemotherapy-naïve patients with SQ were randomly assigned to receive cisplatin (80 mg/m2) on day 1 plus gemcitabine (1000 mg/m2) on days 1 and 8 every 3 weeks or carboplatin (area under the curve: 6 mg/mL/min) on day 1 plus nab-paclitaxel (75 mg/m2) on days 1, 8, and 15 every 3 weeks. The primary endpoint was overall response rate. The secondary endpoints were progression-free survival, overall survival, disease control rate, and toxicity. RESULTS: Between June 2013 and October 2018, 71 patients were enrolled and assigned to either the CG arm (n = 35) or the CnP arm (n = 36) of the study. The overall response rate was 43% [95% confidence interval (CI) 27.3-58.5] in the CG arm and 47% (95% CI 31.7-62.7) in the CnP arm. Although drug combination efficacies did not differ, there were differences in toxicity: hematologic toxicities (leukopenia, neutropenia, and thrombocytopenia) were found mostly in the CG arm, whereas anemia and sensory neuropathy were more common in the CnP arm. CONCLUSIONS: CnP had similar response as CG despite being a carboplatin-based regimen and toxicities differed between arms. Regarding ORR, CnP was comparable to CG for SQ.

Relationship between Programmed Cell Death Protein Ligand 1 Expression and Immune-related Adverse Events in Non-small-cell Lung Cancer Patients Treated with Pembrolizumab.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) can lead to immune-related adverse events (irAEs). A correlation between the development of irAEs and efficacy has been suggested; however, it is unclear whether there is a relationship between programmed death ligand 1 (PD-L1) expression and the development of these events. METHODS: We performed a retrospective study of advanced or metastatic non-small cell lung cancer (NSCLC) patients who were treated with pembrolizumab monotherapy at our institution between May 2015 and April 2018 (n = 44). Patients were categorized into two groups, specifically those with irAEs (irAE group) or without (non-irAE group), and we evaluated the objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Predictors of irAEs were examined by multivariate analysis. RESULTS: irAEs of any grade occurred in 31 (70.5%) patients. The median PFS was 10.9 months in the irAE group versus 3.7 months in the non-irAE group (P < 0.001). ORR and DCR were also higher in the irAE group than in the non-irAE group. Furthermore, high PD-L1 expression (≥50%) was a predictive factor of irAE based on logistic regression (P = 0.004). CONCLUSIONS: In patients with advanced NSCLC treated with pembrolizumab monotherapy, ORR, DCR, and PFS were significantly better in the irAE group than in the non-irAE group. High PD-L1 expression, at the time of pretreatment, was identified as an independent predictor of irAE development. We believe that more careful management of irAEs for individuals with high PD-L1 expression is needed to improve clinical benefits. Further, PD-L1 expression might be useful for ICI risk management.