Non-squamous Cancers of the Larynx.

PURPOSE OF REVIEW: Although non-squamous tumors of the larynx are really rare, they may not always be viewed from the same perspective in the multidisciplinary treatment approach once the diagnosis is made. In this review, non-squamous tumors of the larynx and current approaches in treatment will be discussed. RECENT FINDINGS: When the studies and meta-analyses presented in the last 5 years are evaluated, it is seen that these tumors usually show non-specific symptoms. Due to their submucosal location, the stage of the disease at the time of diagnosis is often advanced. In the literature, treatment may vary in these particular cases. The majority of non-squamous tumors of the larynx includes minor salivary gland tumors, neuroendocrine carcinomas, sarcomas, cartilage tumors, and malignant melanomas. Once treating a patient with these diagnoses, it should be kept in mind that the histopathological subtype is almost as important as the stage of the tumor.

A rare FGF5 candidate variant (rs112475347) for predisposition to nonsquamous, nonsmall-cell lung cancer.

A unique approach with rare resources was used to identify candidate variants predisposing to familial nonsquamous nonsmall-cell lung cancers (NSNSCLC). We analyzed sequence data from NSNSCLC-affected cousin pairs belonging to high-risk lung cancer pedigrees identified in a genealogy of Utah linked to statewide cancer records to identify rare, shared candidate predisposition variants. Variants were tested for association with lung cancer risk in UK Biobank. Evidence for linkage with lung cancer was also reviewed in families from the Genetic Epidemiology of Lung Cancer Consortium. Protein prediction modeling compared the mutation with reference. We sequenced NSNSCLC-affected cousin pairs from eight high-risk lung cancer pedigrees and identified 66 rare candidate variants shared in the cousin pairs. One variant in the FGF5 gene also showed significant association with lung cancer in UKBiobank. This variant was observed in 3/163 additional sampled Utah lung cancer cases, 2 of whom were related in another independent pedigree. Modeling of the predicted protein predicted a second binding site for SO4 that may indicate binding differences. This unique study identified multiple candidate predisposition variants for NSNSCLC, including a rare variant in FGF5 that was significantly associated with lung cancer risk and that segregated with lung cancer in the two pedigrees in which it was observed. FGF5 is an oncogenic factor in several human cancers, and the mutation found here (W81C) changes the binding ability of heparan sulfate to FGF5, which might lead to its deregulation. These results support FGF5 as a potential NSNSCLC predisposition gene and present additional candidate predisposition variants.

Retrospective study of the efficacy and safety of docetaxel/carboplatin combination therapy as postoperative adjuvant chemotherapy for nonsquamous cell carcinoma of the cervix.

OBJECTIVE: Optimal adjuvant chemotherapy for nonsquamous cervical carcinoma has not yet been established. This study investigated the efficacy and safety of docetaxel/carboplatin (DC) for early-stage nonsquamous cell cervical carcinoma after radical hysterectomy (RH). METHODS: We evaluated 157 patients with stage IB-IIB nonsquamous cervical carcinoma with intermediate risk and high risk treated at our institution with DC after type II or III RH from 2007 to 2021. Patients received docetaxel (60-70 mg/m2) and carboplatin (area under the curve 5-6) every 3 weeks for six cycles. The primary endpoint was 2 year recurrence-free survival (RFS) and the secondary endpoint was adverse events (AEs). RESULTS: There were 106 intermediate-risk and 51 high-risk patients. The high-risk patients included 11 with positive parametrial involvement, 20 with pelvic lymph node metastases, and 20 with both parametrial involvement and pelvic lymph node metastases. The 2 year RFS rates for intermediate-risk, high-risk, and positive pelvic lymph nodes were 94.8% (95% confidence interval [CI], 87.9-97.8), 80.1% (95% CI, 64.1-89.5), and 74.5% (95% CI, 55.4-86.4), respectively. Sixteen patients had recurrence, including local recurrence (n = 6), distant metastasis (n = 9), and local and distant metastasis (n = 1). Hematologic toxicity was the most frequent AE, especially leukopenia and neutropenia. Nausea and constipation were the most frequent nonhematologic toxicities. CONCLUSION: DC therapy at our institution showed good 2 year RFS, and postoperative adjuvant therapy with DC therapy is suggested as a useful strategy for patients with nonsquamous cervical carcinoma.

[Response characteristics of tislelizumab combined with chemotherapy in first-line treatment of locally advanced or metastatic non-squamous non-small cell lung cancer].

Objective: To investigate the response characteristics of patients with locally advanced/metastatic non-squamous non-small cell lung cancer (nsq-NSCLC) treated with tislelizumab in combination with chemotherapy in the first line. Methods: Patients with nsq-NSCLC who achieved complete or partial remission after treatment with tislelizumab in combination with chemotherapy or chemotherapy alone in the RATIONALE 304 study, as assessed by an independent review board, were selected to analyze the response characteristics and safety profile of the responders. Time to response (TTR) was defined as the time from randomization to the achievement of first objective response. Depth of response (DpR) was defined as the maximum percentage of tumor shrinkage compared with the sum of the baseline target lesion length diameters. Results: As of January 23, 2020, 128 patients treated with tislelizumab in combination with chemotherapy achieved objective tumor response (responders), representing 57.4%(128/223) of the intention-to-treat population, with a TTR of 5.1 to 33.3 weeks and a median TTR of 7.9 weeks. Of the responders (128), 50.8%(65) achieved first remission at the first efficacy assessment (week 6), 31.3%(40) at the second efficacy assessment (week 12), and 18.0%(23) at the third and subsequent tumor assessments. The percentages of responders who achieved a depth of tumor response of 30% to <50%, 50% to <70% and 70% to 100% were 45.3%(58/128), 28.1%(36/128) and 26.6%(34/128), respectively, with median progression-free survival (PFS) of 9.0 months (95% CI: 7.7 to 9.9 months), 11.5 months (95% CI: 7.7 months to not reached) and not reached (95% CI: 11.8 months to not estimable), respectively. Tislelizumab plus chemotherapy were generally well tolerated in responders with similar safety profile to the overall safety population. Conclusion: Among responders to tislelizumab in combination with chemotherapy for nsq-NSCLC, 82.0%(105/128) achieves response within the first two tumor assessments (12 weeks) and 18.0%(23/128) achieves response at later (18 to 33 weeks) assessments, and there is a trend toward prolonged PFS in responders with deeper tumor response.

Predictive value of EGFR mutation in non-small-cell lung cancer patients treated with platinum doublet postoperative chemotherapy.

The mutation status of tumor tissue DNA (n = 389) of resected stage II-III non-squamous non-small-cell lung cancer (Ns-NSCLC) was analyzed using targeted deep sequencing as an exploratory biomarker study (JIPANG-TR) for the JIPANG study, a randomized phase III study of pemetrexed/cisplatin (Pem/Cis) vs vinorelbine/cisplatin (Vnr/Cis). The TP53 mutation, common EGFR mutations (exon 19 deletion and L858R), and KRAS mutations were frequently detected. The frequency of the EGFR mutation was significant among female patients. Patients with an EGFR mutation-positive status had a significantly shorter recurrence-free survival (RFS) time (24 mo vs not reached) (HR, 1.64; 95% CI, 1.22-2.21; P = .0011 for EGFR mutation status). Multivariable analysis identified both the pathological stage and EGFR mutation status as independent prognostic factors for RFS (HR, 1.78; 95% CI, 1.30-2.44; P = .0003 for disease stage; and HR, 1.57; 95% CI, 1.15-2.16; P = .0050 for EGFR mutation status). This study demonstrated that the EGFR mutation has either a poor prognostic or predictive impact on a poor response to postoperative chemotherapy with platinum doublet chemotherapy for stage II-III Ns-NSCLC patients. This result supports a role for mandatory molecular diagnosis of early-stage Ns-NSCLC for precision oncology and signifies the importance of adjuvant for the 3rd generation tyrosine kinase inhibitor rather than platinum-based chemotherapy. This study is registered with the UMIN Clinical Trial Registry (UMIN 000012237).

Prevention of Pemetrexed-Induced Rash Using Low-Dose Corticosteroids: A Phase II Study.

BACKGROUND: Rash eruptions are a common side-effect of pemetrexed, for which the administration of 8 mg/day of dexamethasone for 3 days from the day preceding pemetrexed administration is recommended. This study aimed to prospectively assess the effectiveness of prophylactic administration of low-dose dexamethasone for pemetrexed-induced rashes. METHODS: This single-arm, phase II study recruited patients with non-squamous non-small cell lung cancer and malignant pleural mesothelioma scheduled to receive chemotherapy including pemetrexed. Patients received 2 mg of dexamethasone daily from days 2 to 6 after chemotherapy with pemetrexed. The primary endpoint was the 3-week incidence of rash eruptions. RESULTS: Twenty-five patients were enrolled between September 2017 and May 2019. The incidence of rash after 3 weeks was 16.7%. Rashes erupted mainly on the upper half of the body, such as the chest and neck, and were of grades 1 and 2 in 2 patients each. No rashes of grade 3 or higher were observed, and there were no adverse events associated with additional corticosteroids. CONCLUSION: Prophylactic administration of low-dose dexamethasone for 5 days from the day after pemetrexed administration resulted in a milder incidence and severity of rash. These findings may provide a standard preventative strategy for pemetrexed-induced rashes. (Trial identifier: UMIN000025666).

Effectiveness of PD-(L)1 inhibitors alone or in combination with platinum-doublet chemotherapy in first-line (1L) non-squamous non-small-cell lung cancer (Nsq-NSCLC) with PD-L1-high expression using real-world data.

BACKGROUND: Anti-programmed cell death protein (death-ligand) 1 [PD-(L)1] therapy alone [cancer immunotherapy (CIT)-mono] or combined with platinum-based chemotherapy (CIT-chemo) is used as the first-line treatment for patients with metastatic non-small-cell lung cancer (NSCLC). Our study compared clinical outcomes with CIT-mono versus CIT-chemo in the specific clinical scenario of non-squamous (Nsq)-NSCLC with a high PD-L1 expression of ≥50% [tumor proportion score (TPS) or tumor cells (TC)]. METHODS: This was a retrospective cohort study using a real-world de-identified database. Patients with metastatic Nsq-NSCLC with high PD-L1 expression initiating first-line CIT-mono or CIT-chemo between 24 October 2016 and 28 February 2019 were followed up until 28 February 2020. We compared overall survival (OS) and real-world progression-free survival (rwPFS) using the Kaplan-Meier methodology. Hazard ratios (HRs) were adjusted (aHR) for differences in baseline key prognostic characteristics using the inverse probability of treatment weighting methodology. RESULTS: Patients with PD-L1-high Nsq-NSCLC treated with CIT-mono (n = 351) were older and less often presented with de novo stage IV disease than patients treated with CIT-chemo (n = 169). With a median follow-up of 19.9 months for CIT-chemo versus 23.5 months for CIT-mono, median OS and rwPFS did not differ between the two groups [median OS: CIT-chemo, 21.0 months versus CIT-mono, 22.1 months, aHR = 1.03, 95% confidence interval (CI) 0.77-1.39, P = 0.83; median rwPFS: CIT-chemo, 10.8 months versus CIT-mono, 11.5 months, aHR = 1.04, 95% CI 0.78-1.37, P = 0.81]. CIT-chemo showed significant and meaningful improvement in OS and rwPFS versus CIT-mono only in the never-smoker subgroup, albeit among a small sample of patients (n = 50; OS HR = 0.25, 95% CI 0.07-0.83, interaction P = 0.02; rwPFS HR = 0.40, 95% CI 0.17-0.95, interaction P = 0.04). CONCLUSION: Except in the subgroup of never-smoker patients, sparing the chemotherapy in first-line CIT treatment does not appear to impact survival outcomes in Nsq-NSCLC patients with high PD-L1 expression.

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).

Efficacy and safety of maintenance immune checkpoint inhibitors with or without pemetrexed in advanced non-squamous non-small cell lung cancer: a retrospective study.

BACKGROUND: Advanced non-squamous non-small cell lung cancer (NS-NSCLC) patients without driver gene mutations are usually treated with immune checkpoint inhibitors (ICIs) plus pemetrexed as maintenance therapy after first-line ICIs plus 4-6 cycles of pemetrexed/platinum. Some patients in the real world receive ICIs monotherapy as maintenance therapy. No clinical study has compared the efficacy and safety of ICIs with or without pemetrexed as maintenance therapy. METHODS: We performed a retrospective study analyzing clinical data of patients with NS-NSCLC who were diagnosed in Zhejiang Cancer Hospital from September 2018 to May 2021 and received maintenance therapy after 4-6 cycles of ICIs plus pemetrexed/platinum. Patients were divided into ICIs plus pemetrexed group and ICIs monotherapy group. Progression Free Survival 1 (PFS1) and PFS2, defined as the interval from the date of initial treatment and maintenance therapy to the date of systemic progression/death or the last follow-up, respectively. RESULTS: A total of 120 patients received ICIs with or without pemetrexed as maintenance therapy. Eighty-two patients received ICIs plus pemetrexed as maintenance therapy, and 38 patients received ICIs monotherapy. There were no statistically significant difference in median PFS1 between the ICIs monotherapy group and ICIs plus pemetrexed group (12.00 months vs. 12.07 months, P = 0.979). Among patients with PD-L1 TPS < 1%, the median PFS1 was worse with ICIs monotherapy (9.50 months vs. 14.20 months, P = 0.039). Among patients with PD-L1 TPS ≥50% or 1-49%, the median PFS1 in both groups was not statistically significant (P = 0.866, P = 0.589, respectively). Results for median PFS2 were similar to median PFS1, with statistically significantly different only in patients with PD-L1 TPS < 1% (P = 0.008). The 2-year survival rates of the two groups were similar (66.7% vs. 69.5%, P = 0.812). The incidence of fatigue was significantly higher in the ICIs plus pemetrexed group (P = 0.023). CONCLUSIONS: ICIs with or without pemetrexed can be used as maintenance therapy after first-line ICIs plus 4-6 cycles of pemetrexed/platinum in patients with advanced NS-NSCLC based on PD-L1 expression.

Indirect comparison of sintilimab and other PD-L1 inhibitors for first-line treatment of non-squamous non-small-cell lung cancer.

Objective: To evaluate sintilimab compared with other PD-L1 inhibitors in combination with platinum-based doublet chemotherapy as the first-line treatment of non-squamous non-small-cell lung cancer. Methods: A frequentist meta-analysis was used to compare outcomes, including progression-free survival, overall survival, objective response rate, time to response and safety profile. Results: The sintilimab combination arm had progression-free survival comparable to that of the pembrolizumab combination arm (hazard ratio [HR] = 1.00; 95% CI: 0.71, 1.41), the atezolizumab combination arm (HR: 0.81; 95% CI: 0.59, 1.10), the tislelizumab combination arm (HR: 0.75; 95% CI: 0.48, 1.16), the camrelizumab combination arm (HR: 0.80; 95% CI: 0.54, 1.20) and the nivolumab combination arm (HR: 0.72; 95% CI: 0.51, 1.02). Any grade or grade ≥3 adverse event was comparable between PD-L1 inhibitors. Conclusion: Sintilimab showed a comparable efficacy and safety profile when compared with other PD-L1 inhibitors combined with platinum-based doublet chemotherapy as the first-line treatment of locally advanced or metastatic non-squamous non-small-cell lung cancer.

Lung cancer is the most diagnosed cancer and the leading cause of cancer-related mortality in China. Non-small-cell lung cancer (NSCLC) accounts for 85% of all lung cancers, of which non-squamous NSCLC (nsqNSCLC) is the most frequent histologically, comprising 70% of NSCLC. Six different PD-L1 inhibitors (sintilimab, pembrolizumab, camrelizumab, atezolizumab, tislelizumab and nivolumab) in combination with chemotherapy have been approved as the first-line treatment of advanced/metastatic nsqNSCLC patients in China. Since there is no direct evidence of comparable efficacy and safety due to a lack of head-to-head trials among the PD-L1 inhibitors, an indirect comparison was conducted to evaluate sintilimab compared with other PD-L1 inhibitors in combination with platinum-based doublet chemotherapy. The results showed that sintilimab combined with platinum-based doublet chemotherapy showed progression-free survival, overall survival, objective response rate, time to response and safety profile comparable to other PD-L1 inhibitors in combination with platinum-based doublet chemotherapy as the first-line treatment of locally advanced or metastatic nsqNSCLC patients.

Generalizability of ORIENT-11 trial results to a US standard-of-care cohort with advanced non-small-cell lung cancer.

Aim: This retrospective study estimated efficacy and safety of sintilimab + pemetrexed + platinum (SPP) versus placebo + pemetrexed + platinum (PPP) in untreated locally advanced/metastatic, nonsquamous non-small-cell lung cancer (NSCLC), after adjusting each ORIENT-11 trial patient's contribution to ORIENT-11 data based on characteristics of a target US population. Materials & methods: The target US population (n = 557) was selected from a real-world deidentified advanced NSCLC database based on key ORIENT-11 eligibility criteria. Inverse probability weights for ORIENT-11 patients (n = 397) relative to US patients were calculated. Efficacy and safety of SPP versus PPP were adjusted by inverse probability weights. Results: After adjustment, progression-free survival remained superior for SPP. Other efficacy and safety outcomes were consistent. Conclusion: These results provide evidence on how the effects observed with SPP in ORIENT-11 could translate to a US population with untreated locally advanced/metastatic nonsquamous NSCLC.

Sintilimab is an immunotherapy drug that was successfully developed and tested in China for untreated locally advanced/metastatic nonsquamous non-small-cell lung cancer. To assess if results from the Chinese ORIENT-11 trial are applicable to the US population, this study used US real-world patient data to adjust the ORIENT-11 trial analysis. After adjustment, progression-free survival benefit observed in ORIENT-11 with the addition of sintilimab to standard chemotherapy remained superior, and other efficacy and safety end points were consistent. This finding may help inform clinical decisions about the applicability of ORIENT-11 trial results to US patients with untreated locally advanced/metastatic nonsquamous NSCLC. In addition, this study offers another way real-world evidence can be applied to help complement clinical trial evidence and optimize treatment decisions.

The efficacy and toxicity of maintenance therapy with bevacizumab plus pemetrexed versus bevacizumab/pemetrexed alone for stage IIIB/IV nonsquamous non-small cell lung cancer: A meta-analysis of randomized controlled trials.

WHAT IS KNOWN AND OBJECTIVE: Whether maintenance therapy with bevacizumab (Bev) + pemetrexed (Pem) can achieve greater clinical benefits than Bev or Pem alone for stage IIIB/IV nonsquamous non-small cell lung cancer (NSCLC) remains unclear. We assessed the antitumour effect and toxicity of maintenance Bev+Pem versus maintenance with single-agent Bev/Pem in this meta-analysis. METHODS: Appropriate randomized controlled trials (RCTs) were screened using electronic databases (Google Scholar, PubMed, Embase, Scopus, ScienceDirect, Ovid MEDLINE, Cochrane and Web of Science). The endpoints were progression-free survival (PFS), overall survival (OS) and adverse events (AEs). RESULTS AND DISCUSSION: We included six RCTs that contained 2,447 patients receiving induction therapy with platinum-based combination therapies. The maintenance therapy Bev+Pem group had prolonged PFS (HR = 0.74, 95% CI 0.69-0.80, p < 0.00001) and OS (HR = 0.91, 95% CI 0.83-0.99, p = 0.02) compared with the Bev/Pem group. Moreover, we further analysed the PFS rate (PFSR) and OS rate (OSR) and found that the Bev+Pem group exhibited improved PFSR-0.5y, PFSR-1y, PFSR-1.5y, PFSR-2y and OS-2y, with preferable trends in OS-1y, OS-3y and OS-4y compared with the Bev/Pem single-agent maintenance therapy. In addition, subgroup analyses indicated that the Bev+Pem group had greater PFS and OS among patients aged <65 years, patients with an Eastern Cooperative Oncology Group (ECOG) score of 0, and patients who never smoked. Regarding adverse events (AEs), the Bev+Pem group exhibited an increased occurrence of anaemia, fatigue, thrombocytopenia and anorexia. WHAT IS NEW AND CONCLUSION: For stage IIIB/IV nonsquamous NSCLC patients, maintenance therapy with Bev+Pem offers an increased survival outcome (PFS, OS) compared with monotherapy. However, the increased incidence of AEs should not be neglected.

Tumor mutation burden as a biomarker for lung cancer patients treated with pemetrexed and cisplatin (the JIPANG-TR).

The JIPANG study is a randomized phase III study of pemetrexed/cisplatin (Pem/Cis) versus vinorelbine/cisplatin (Vnr/Cis) for completely resected stage II-IIIA non-squamous non-small cell lung cancer (Ns-NSCLC). This study did not meet the primary endpoint (recurrence-free survival, RFS) but Pem/Cis had a similar efficacy to Vnr/Cis with a better tolerability. Tumor mutation burden (TMB) is thought to have a predictive value of immune checkpoint inhibitors. However, the relevance of TMB to cytotoxic chemotherapy remains unknown. This exploratory study investigates the relationship between tumor mutation profiles and clinical outcome of Pem/Cis. Formalin-fixed, paraffin-embedded tumor tissues (n = 389) were obtained from the patients. Mutation status of tissue DNA was analyzed by targeted deep sequencing. Epidermal growth factor receptor (EGFR) mutations were detected frequently in Ns-NSCLC (139/374). Patients without any EGFR mutations experienced longer RFS in the Pem/Cis arm versus Vnr/Cis arms. Pem/Cis in patients with high TMB (≥12-16 mut/Mb) tended to have improved survival. In patients with wild-type EGFR, TMB ≥ 12 mut/Mb was significantly associated with improved RFS with Pem/Cis versus Vnr/Cis (not reached vs 52.5 months; hazard ratio (HR) 0.477). It could be proposed that TMB was predictive of RFS benefit with Pem/Cis versus Vnr/Cis in Ns-NSCLC. Further investigation is required to determine whether TMB combined with EGFR mutation status could be used as a predictive biomarker.

Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189.

BACKGROUND: In the phase III KEYNOTE-189 study (NCT02578680), pembrolizumab plus pemetrexed and platinum-based chemotherapy (pemetrexed-platinum) significantly improved overall survival (OS) and progression-free survival (PFS) in patients with previously untreated metastatic nonsquamous non-small-cell lung cancer (NSCLC) versus placebo plus pemetrexed-platinum. We report updated efficacy outcomes from the protocol-specified final analysis, including outcomes in patients who crossed over to pembrolizumab from pemetrexed-platinum and in patients who completed 35 cycles (∼2 years) of pembrolizumab. PATIENTS AND METHODS: Eligible patients were randomized 2 : 1 to receive pembrolizumab 200 mg (n = 410) or placebo (n = 206) every 3 weeks (for up to 35 cycles, ∼2 years) plus four cycles of pemetrexed (500 mg/m2) and investigators' choice of cisplatin (75 mg/m2) or carboplatin (area under the curve 5 mg·min/ml) every 3 weeks, followed by pemetrexed until progression. Patients assigned to placebo plus pemetrexed-platinum could cross over to pembrolizumab upon progression if eligibility criteria were met. The primary endpoints were OS and PFS. RESULTS: After a median follow-up of 31.0 months, pembrolizumab plus pemetrexed-platinum continued to improve OS [hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.46-0.69] and PFS (HR, 0.49; 95% CI, 0.41-0.59) over placebo plus pemetrexed-platinum regardless of programmed death-ligand 1 expression. Objective response rate (ORR) (48.3% versus 19.9%) and time to second/subsequent tumor progression on next-line treatment (PFS2; HR, 0.50; 95% CI, 0.41-0.61) were improved in patients who received pembrolizumab plus pemetrexed-platinum. Eighty-four patients (40.8%) from the placebo plus pemetrexed-platinum group crossed over to pembrolizumab on-study. Grade 3-5 adverse events occurred in 72.1% of patients receiving pembrolizumab plus pemetrexed-platinum and 66.8% of patients receiving placebo plus pemetrexed-platinum. Fifty-six patients completed 35 cycles (∼2 years) of pembrolizumab; ORR was 85.7% and 53 (94.6%) were alive at data cut-off. CONCLUSIONS: Pembrolizumab plus pemetrexed-platinum continued to show improved efficacy outcomes compared with placebo plus pemetrexed-platinum, with manageable toxicity. These findings support first-line pembrolizumab plus pemetrexed-platinum in patients with previously untreated metastatic nonsquamous NSCLC.

Anti-transcriptional intermediary factor 1-γ antibody-positive dermatomyositis induced by nivolumab for lung adenocarcinoma: A case report.

Immune checkpoint inhibitors can induce immune-related adverse events (irAEs) in different organs. Dermatomyositis is a rare form of systemic irAE. Although dermatomyositis-specific antibodies, especially anti-transcriptional intermediary factor 1-γ (anti-TIF1-γ) antibodies, have been detected in a few cases of immune checkpoint inhibitor-associated dermatomyositis, their titers before immunotherapy have not been examined. We hereby report the first irAE case of dermatomyositis accompanied by seroconversion of anti-TIF1-γ antibody following nivolumab treatment for advanced lung adenocarcinoma. A 64-year-old Japanese male with an advanced lung adenocarcinoma (cT4N2M1a stage IVA) received nivolumab as third-line therapy. Skin rashes appeared two days later, and were treated with a topical steroid as just drug eruptions. 7 weeks later, he was emergently admitted because of high serum creatine kinase level. Clinical examination showed deteriorated rashes along with slightly weakened proximal muscles. Muscle biopsy revealed myopathic changes consistent with dermatomyositis. Anti-TIF1-γ antibody was positive, which was found to be within normal range before nivolumab administration. He was diagnosed with dermatomyositis and treated with systemic corticosteroids, tacrolimus, and intravenous immunoglobulin. However, these drugs showed limited effectiveness against the progression of muscle weakness. He died of respiratory failure due to lung cancer and muscle weakness progression 6 months after the admission. In conclusion, our case demonstrates that the development of dermatomyositis was causally related to immune activation by nivolumab. Given the potential exacerbation of autoimmune paraneoplastic disorders in cancer patients receiving immunotherapy, clinicians should be aware of early manifestations of systemic irAEs that require prompt diagnosis and intervention.

Docetaxel and carboplatin chemotherapy for treating patients with stage IVB or recurrent non-squamous cell carcinoma of the uterine cervix: a phase II study.

BACKGROUND: This phase II study evaluated the efficacy and safety of docetaxel/carboplatin chemotherapy for treating patients with stage IVB or recurrent non-squamous cell carcinoma of the uterine cervix. METHODS: A total of 50 patients with International Federation of Gynecology and Obstetrics stage IVB or recurrent non-squamous cell carcinoma of the uterine cervix were enrolled and administered docetaxel at a dose of 60 mg/m2, followed by carboplatin at a dose based on the area under the receiver operating characteristic curve of 6. The treatments were repeated every 21 days until disease progression or unacceptable adverse events. Except for two patients, 48 were eligible for evaluation. Another patient withdrew consent before treatment; adverse events were evaluated in 47. RESULTS: The response rate was 47.9% with 5 patients achieving complete response, 18 partial response, 14 stable disease, and 6 progressive disease. The disease control rate was 77.1%. With a median follow-up duration of 368 days, the median progression-free survival and overall survival were 6.1 months (95% CI 5.5-8.6) and 15.8 months (95% CI 18.2-28.3), respectively. The most frequent grade 3 and grade 4 hematological toxicity was neutropenia, with 38 patients (81%) having grade 4 and 4 (9%) having grade 3 neutropenia. The non-hematological toxicities were mainly grade 1 or 2 in severity. CONCLUSION: Docetaxel/carboplatin chemotherapy was effective, with a higher disease control rate and well-tolerated chemotherapeutic regimen for patients with stage IVB or recurrent non-squamous cell carcinoma of the uterine cervix.

Phase II study of the combination of S-1 with bevacizumab for patients with previously treated advanced non-squamous non-small-cell lung cancer.

BACKGROUND: We assessed the efficacy and safety of bevacizumab and S-1 chemotherapy for patients with previously treated advanced non-squamous non-small-cell lung cancer (NSCLC). METHODS: This was a prospective single-arm study, including patients with non-squamous NSCLC who had received at least one chemotherapy regimen along with a platinum-based regimen. Bevacizumab 15 mg/kg was intravenously administered every 3 weeks, and S-1 40 mg/m2 was orally administered twice daily from day 1 (evening) through day 15 (morning). The treatment continued for 3 weeks/cycle until disease progression or until unacceptable toxicities occurred. During the lead-in part, six patients were evaluated for dose-limiting toxicity (DLT) rate. In phase II, the primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: In the lead-in part, we evaluated the safety in the first six patients and observed no DLT. In phase II, a total of 46 patients were enrolled from September 2012 to December 2018. The median follow-up duration was 13.7 months [95% confidence interval (CI) 1.4-72.0]. The ORR was 28.3%. The median PFS and OS were 4.3 (95% CI 2.9-5.9) and 15.0 months (95% CI 9.8-30.3), respectively. The most common adverse events were hypertension (65.2%), diarrhea (47.8%), mucositis oral (45.7%), and proteinuria (43.5%), and the most common grade 3 adverse events were hypertension (23.9%) and proteinuria (6.5%). Grade 4/5 adverse events were not observed. CONCLUSION: Bevacizumab and S-1 combination chemotherapy showed high activity and were well tolerated in patients with previously treated advanced non-squamous NSCLC.

The Impact of Histological Subtype on Survival Outcome of Patients with Stage IIB-IVA Cervical Cancer Who Received Definitive Radiotherapy.

The impact of histologic subtype on definitive radiotherapy for patients with locally advanced cervical cancer remains unclear. The aim of this retrospective analysis was to assess clinicopathological findings and clinical outcome by histological type in patients with stage IIB-IVA cervical cancer. Ninety-two patients with stage IIB-IVA [International Federation of Gynecology and Obstetrics (FIGO) 2008] cervical cancer, who underwent definitive radiotherapy between 2013 to 2018, were identified as eligible for this study. The clinical information of the eligible patients was obtained from medical records of our hospital. Seventy-eight patients underwent concurrent chemoradiotherapy, and the remaining 14 patients received radiotherapy alone. Of 92 patients, 83 had squamous cell carcinoma (SCC) and 9 had non-SCC histology. Progression-free survival (PFS) rate of patients with non-SCC was significantly worse than of those with SCC (2-year PFS: 62.0% vs. 12.5%, p = 0.0020), but overall survival (OS) rate did not statistically differ between the two subtypes (2-year OS: 82.4% vs. 62.5%, p = 0.2157). Pelvic failure-free (PFF) rate of patients with non-SCC histology was significantly worse than of those with non-SCC (2-year PFF; 88.2% vs. 25.0%, p < 0.0001). In univariate analysis, non-SCC histology was associated with PFS rate, although there was no association with OS rate. In multivariate analysis, non-SCC histology and lymph node metastasis were independent prognostic factors for shorter PFS. In patients with stage IIB-IVA cervical cancer who underwent definitive radiotherapy, patients with non-SCC showed significantly worse PFS rate than those with SCC.

Better survival in impaired renal function patients with metastatic non-small cell lung cancer treated by cisplatin-pemetrexed.

PURPOSE: Cisplatin-pemetrexed is the first-line chemotherapy for advanced, metastatic non-squamous non-small cell lung cancer (NSCLC), but the risk of kidney toxicity limits the therapeutic schedule. We performed a retrospective study of patient survival at 1 year and glomerular filtration rate (GFR) outcomes in cisplatin-pemetrexed-treated NSCLC patients. METHODS: Patients (P) treated for NSCLC between 2008 and 2014 were divided into two groups according to GFR at diagnosis: G1 (GFR ≥ 90 mL/min/1.73 m2) and G2 (GFR between 60 and 89 mL/min/1.73 m2). GFR were compared in the two groups at 3 and 12 months. The following statistical methods were used: multivariate generalized estimating equation model for GFR outcome, Kaplan-Meier method for patient survival rate, and Cox model for analysing survival criteria. RESULTS: A total of 112 patients were included in the study (G1 = 87 P, G2 = 25 P). At 12 months, mean GFR significantly decreased by 28.4 mL/min/1.73 m2 (- 22.3%, p = 0.001) in G1 and. 13.8 mL/min/1.73 m2 (- 17.2%, p = 0.001) in G2. Median patient survival was 9.6 months (1.1-52.4) in G1 and 19.7 months (3.7-56.9) in G2. A better overall survival was significantly correlated with GFR between 60 and 89 mL/min/1.73 m2 at diagnosis (p = 0.04), and higher cumulated doses of pemetrexed (p = 0.003) and cisplatin (p = 0.001). CONCLUSION: The better survival rate in G2 and its correlation with pemetrexed and cisplatin treatments suggest that, until other therapeutic choices become available, a cautious increase in dosage could be investigated as a way to improve poor prognoses.

Surgical outcomes of early-stage primary vaginal nonsquamous cell carcinoma.

OBJECTIVE: Definitive radiation therapy (RT), using external beam RT and/or brachytherapy, is a standard treatment option for primary vaginal carcinoma. However, this treatment has poor prognosis when applied to vaginal nonsquamous cell carcinoma (non-SCC). We aimed to clarify treatment outcome and surgical safety in early-stage primary vaginal non-SCC. METHODS: After receiving approval from the institutional review board, we retrospectively reviewed the clinical records and pathological samples of patients treated at our hospital between 1991 and 2018. Among 49 patients with primary vaginal carcinoma, 12 with histologically confirmed early-stage primary vaginal non-SCC were included in this study. RESULTS: In total, 40% of patients with primary vaginal carcinoma treated at our hospital had primary vaginal non-SCC. The average observation time was 34 months (median 53.3 months). Three patients had local recurrence: 2 in pelvic lymph nodes and 1 in the vagina. Furthermore, 2 patients died of their disease. Five-year local control rate of stage I and stage II non-SCC was 75% and 100%, respectively. Disease-specific survival rate of stage I and stage II non-SCC was 81.8% and 100%, respectively. No major morbidity was observed. Three patients required allogeneic blood transfusion, whereas 1 underwent autotransfusion. None of the 12 patients were discharged with self-catheterization. CONCLUSION: Five-year local control and disease-specific survival rates of patients surgically treated for vaginal non-SCC were favorable. Therefore, surgery could be a safe and reasonable option for early-stage primary vaginal non-SCC.