Platinum-containing Chemotherapy Regimens Research Articles

Real-world outcomes on platinum-containing chemotherapy for EGFR-mutated advanced nonsquamous NSCLC with prior exposure to EGFR tyrosine kinase inhibitors.

Front-line therapy with an EGFR tyrosine kinase inhibitor (TKI) is the standard of care for treating patients with advanced nonsquamous NSCLC with the common sensitizing EGFR exon 19 deletion and exon 21 L858R point mutations. However, EGFR TKI resistance inevitably develops. The optimal subsequent therapy remains to be identified, although platinum-containing chemotherapy regimens are often administered. Our objectives were to describe baseline characteristics, survival, and subsequent treatment patterns for patients with advanced nonsquamous NSCLC with EGFR exon 19 deletion or L858R mutation who received a platinum-based combination regimen after front-line EGFR TKI therapy. This retrospective study used a nationwide electronic health record-derived deidentified database to select adult patients with advanced nonsquamous NSCLC, evidence of EGFR exon 19 deletion or L858R mutation, and ECOG performance status of 0-2 who initiated platinum-containing chemotherapy, with or without concomitant immunotherapy, from 1-January-2011 to 30-June-2020 following receipt of any EGFR TKI as first-line therapy or, alternatively, a first- or second-generation EGFR TKI (erlotinib, afatinib, gefitinib, dacomitinib) as first-line therapy followed by the third-generation EGFR TKI osimertinib as second-line therapy. Data cut-off was 30-June-2022. The Kaplan-Meier method was used to estimate overall survival (OS) after initiation of pemetrexed-platinum (n=119) or any platinum-based combination regimen (platinum cohort; n=311). The two cohorts included two-thirds women (65%-66%) and 57%-58% nonsmokers; median ages were 66 and 65 years in pemetrexed-platinum and platinum cohorts, respectively. Median OS was 10.3 months (95% CI, 8.1-13.9) from pemetrexed-platinum initiation and 12.4 months (95% CI, 10.2-15.2) from platinum initiation; 12-month survival rates were 48% and 51%, respectively; 260 patients (84%) had died by the end of the study. The suboptimal survival outcomes recorded in this study demonstrate the unmet need to identify more effective subsequent treatment regimens for patients with EGFR-mutated advanced nonsquamous NSCLC after EGFR TKI resistance develops.

Outcomes of pediatric extracranial germ cell tumors: A single center experience in a developing country.

The purpose of this study was to analyze the outcomes of extracranial GCT in children in a developing country and to assess prognostic factors. The data on 141 children (<18years old) with extracranial GCT, confirmed histopathologically, collected over the past 9years (from February 2013 to June 2022) were retrospectively studied. The patients underwent the same therapy with platinum-containing chemotherapy regimens. In the malignant GCT group, OS and EFS were 81.0 ± 4% and 73 ± 5%, respectively. OS and EFS in the teratoma group were 90 ± 5% and 85 ± 6%. In univariate analysis, parameters like stage of disease, tumor localization, AFP level ≥10,000ng/mL, serum AFP kinetics and resection status were found to be statistically significant prognostic factors. In the multivariate analysis, the significant adverse factors were the resection status, initial AFP level ≥10,000ng/mL and serum AFP kinetics slow down (p = .000). Good survival rates can be achieved in developing countries with adequate compliance with treatment protocols. The analysis demonstrates high efficacy of platinum-containing chemotherapy regimens. In our opinion, the protocol used in high-income countries can be implemented in low-income countries with the financial support from the government. The qualification of specialists is also important.

Progress in systemic therapy for advanced-stage urothelial carcinoma.

Despite recent advances, advanced-stage urothelial carcinoma (aUC) remains incurable, with 5-year survival rates of approximately 10%. Platinum-based chemotherapy has a major role as first-line therapy for most patients with aUC. The approval of the anti-PD-L1 antibody avelumab as maintenance therapy for patients without initial disease progression on platinum-based chemotherapy is an important development that has improved the survival outcomes of patients with this disease. Otherwise, the use of first-line immune-checkpoint inhibitors (ICIs) targeting PD-1 or PD-L1 has been restricted to patients who are ineligible for platinum-containing chemotherapy regimens. Other important developments include the FDA-accelerated approval of first-line enfortumab vedotin plus pembrolizumab for patients ineligible to receive cisplatin and the availability of FGFR inhibitors, enfortumab vedotin and sacituzumab govitecan for subsequent lines of therapy. Several research questions remain unaddressed including the lack of adequate biomarkers, how to assign priority to the different treatment options for individual patients and which agents can be effective as monotherapies. The future is promising with the emergence of modalities such as antibody-drug conjugate-like drugs, next-generation ICIs, bispecific antibodies and cellular therapies. In this Review, we summarize the evolution of systemic therapy for patients with aUC and provide insights into the unmet needs.

BRCA Mutation Status in Triple-Negative Breast Cancer Patients Treated with Neoadjuvant Chemotherapy: A Pivotal Role for Treatment Decision-Making.

Simple SummaryIn this retrospective observational study, we evaluated data from patients with triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy (NACT) in order to better define the impact of germline BRCA1/2 (gBRCA1/2) mutation status on outcomes in this patient population. Our results show that patients with BRCA1/2 mutation had a higher pathologic complete response (pCR) rate than non-mutated patients; nevertheless, the benefit was confirmed only in the subset of patients who received a platinum-based NACT. Furthermore, pCR was associated with improved Event Free Survival (EFS) and Overall Survival (OS), regardless of BRCA1/2 mutation status and type of NACT received. Long-term follow-up analyses are needed to further define the impact of gBRCA mutation status in patients with early-TNBC.Triple-negative breast cancer (TNBC) is characterized by earlier recurrence and shorter survival compared with other types of breast cancer. Moreover, approximately 15 to 25% of all TNBC patients harbor germline BRCA (gBRCA) 1/2 mutations, which confer a more aggressive phenotype. However, TNBC seems to be particularly sensitive to chemotherapy, the so-called ‘triple negative paradox’. Therefore, Neoadjuvant chemotherapy (NACT) is currently considered the preferred approach for early-stage TNBC. BRCA status has also been studied as a predictive biomarker of response to platinum compounds. Although several randomized trials investigated the addition of carboplatin to standard NACT in early-stage TNBC, the role of BRCA status remains unclear. In this retrospective analysis, we evaluated data from 136 consecutive patients with Stage I-III TNBC who received standard NACT with or without the addition of carboplatin, in order to define clinical features and outcomes in BRCA 1/2 mutation carriers and non-carrier controls. Between January 2013 and February 2021, 67 (51.3%) out of 136 patients received a standard anthracyclines/taxane regimen and 69 (50.7%) patients received a platinum-containing chemotherapy regimen. Deleterious germline BRCA1 or BRCA2 mutations were identified in 39 (28.7%) patients. Overall, patients with deleterious gBRCA1/2 mutation have significantly higher pCR rate than non-carrier patients (23 [59%] of 39 vs. 33 [34%] of 97; p = 0.008). The benefit of harboring a gBRCA mutation was confirmed only in the subset of patients who received a platinum-based NACT (17 [65.4%] of 26 vs. 13 [30.2%] of 43; p = 0.005) while no differences were found in the platinum-free subgroup. Patients who achieved pCR after NACT had significantly better EFS (OR 4.5; 95% CI 1.9–10.7; p = 0.001) and OS (OR 3.3; 95% CI 1.3–8.9; p = 0.01) than patients who did not, regardless of BRCA1/2 mutation status and type of NACT received. Our results based on real-world evidence show that TNBC patients with the gBRCA1/2 mutation who received platinum-based NACT have a higher pCR rate than non-carrier patients, supporting the use of this chemotherapy regimen in this patient population. Long-term follow-up analyses are needed to further define the role of gBRCA mutation status on clinical outcomes in patients with early-TNBC.

Hepatocellular-Cholangiocarcinoma Collision Tumors: An Update of Current Management Practices.

Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare form of primary hepatic collision tumor, with an incidence ranging from 0.4 to 14.2%. Given the diagnostic challenges and lack of randomized trials, standardized treatment has yet to be established. We aim to review the literature to summarize the diagnosis, molecular characteristics, current treatment modalities, and challenges for cHCC-CC. A literature review was performed using PubMed. We included studies investigating and describing cHCC-CC, focusing on surgical, medical, and radiologic treatments. Overall prognosis is poor, with a 5-year survival rate under 30%. Minor or major hepatectomy with R0 resection is the only curative treatment; however, recurrence is likely (as high as 50% within 5years). The role of liver transplantation is also highly debated given the biliary nature of these tumors, with cHCC-CC as a relative contraindication for liver transplantation. Although gemcitabine-based treatments had higher progression-free survival over sorafenib, there is no standard chemotherapy regimen. Treatment with gemcitabine and platinum demonstrates improved disease control rates compared to gemcitabine in conjunction with 5-fluorouracil (78.4% verse 38.5% respectively). Additionally, platinum-containing chemotherapy regimens exhibit a higher overall response rate than non-platinum regimens (21.4% verse 7.0% respectively). These molecular-directed therapies have prolonged survival for HCC, but further investigation needs to be done to assess their utility in patients with cHCC-CC. cHCC-CC is a rare and complex subset of primary hepatic neoplasms with a dismal prognosis and unstandardized treatment options. Further trials need to be performed to investigate systemic chemotherapy and immunotherapy options for patients with unresectable disease.

Enfortumab Vedotin (Padcev)

&#x0D; CADTH recommends that Padcev should be reimbursed by public drug plans for the treatment of advanced or metastatic urothelial cancer (UC) if certain conditions are met.&#x0D; Padcev should only be covered to treat adult patients with UC who have already received treatment with a platinum-containing chemotherapy regimen, and a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor for advanced or metastatic disease.&#x0D; Padcev should only be reimbursed if prescribed as monotherapy by a clinician who has experience treating patients with advanced UC and if the price of Padcev is reduced.&#x0D;

Effects of Shenmai injection combined with platinum-containing first-line chemotherapy on quality of life, immune function and prognosis of patients with nonsmall cell lung cancer: A protocol for systematic review and meta-analysis.

Background:Lung cancer is the leading cause of death among cancer patients worldwide. Close to 85% of lung cancer pathology types are nonsmall cell lung cancer (NSCLC). With advances in medicine, the survival rate of early-stage NSCLC has improved. Nevertheless, about 70% of patients are diagnosed at an advanced stage, and chemotherapy is the primary treatment option. Chemotherapy causes toxic side effects such as bone marrow suppression, gastrointestinal reactions, and damage to vital organs, which are difficult for patients to tolerate. Many published literatures have reported that Shenmai injection (SMI) combined with platinum-containing first-line chemotherapy regimen for NSCLC can improve the recent efficacy, reduce toxic side effects and improve the quality of life. However, most of the studies were small samples and lacked persuasive power, while controversies existed among individual studies. Therefore, this study used meta-analysis to further evaluate the effects of SMI combined with platinum-containing first-line chemotherapy on the quality of life, immune function and prognosis of patients with NSCLC.Methods:Wanfang, Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure, the Chongqing VIP Chinese Science and Technology Periodical Database, PubMed, Embase, and Web of Science databases were searched. The search was scheduled from the establishment of the database to September 2021. All randomized controlled trials comparing SMI in combination with platinum-containing first-line chemotherapy to platinum-containing first-line chemotherapy alone for the treatment of NSCLC were searched and evaluated for inclusion. Two investigators independently performed study selection, data extraction and synthesis. The Cochrane Risk of Bias tool was used to assess the risk of bias in the randomized controlled trials. Stata 16.0 software was used for meta-analysis.Results:The results of this meta-analysis will be submitted to a peer-reviewed journal for publication.Conclusion:This study comprehensively evaluated the effects of SMI combined with platinum-containing first-line chemotherapy on quality of life, immune function and prognosis in patients with NSCLC to provide an evidence-based basis for clinical practice.Ethics and dissemination:The private information from individuals will not be published. This systematic review should also not damage participants’ rights. Ethical approval was not available. The results may be published in a peer-reviewed journal or disseminated in relevant conferences.OSF Registration number: DOI 10.17605/OSF.IO/AMKDC

Abemaciclib in Combination With Pembrolizumab for Stage IV KRAS-Mutant or Squamous NSCLC: A Phase 1b Study

IntroductionAbemaciclib is an oral, selective small-molecule CDK 4 and 6 inhibitor. In preclinical models, abemaciclib synergized with programmed cell death protein-1 blockade to enhance antitumor efficacy. Here, we report the safety and anticancer activity of abemaciclib plus pembrolizumab in two cohorts with NSCLC. MethodsThis nonrandomized, open-label, phase 1b study included patients with previously untreated programmed death-ligand 1–positive, KRAS-mutant nonsquamous metastatic NSCLC (cohort A); squamous NSCLC after one previous platinum-containing chemotherapy regimen for metastatic disease (cohort B); and two breast cancer cohorts (disclosed separately). Patients received 150 mg abemaciclib every 12 hours plus 200 mg pembrolizumab intravenously on day 1 every 21 days. The primary objective was safety; secondary objectives included objective response rate, disease control rate, progression-free survival, and overall survival. Clinical Trial Number: NCT02779751. ResultsEach cohort enrolled 25 patients. Grades greater than or equal to 3 treatment-emergent adverse events in cohorts A and B were reported by 20 (80%) and 19 patients (76%), respectively. Six patients in cohort A (24.0%) and two patients in cohort B (8.0%) had a confirmed partial response; disease control rate was 56% and 64%, respectively. Median progression-free survival was 7.6 months (95% confidence interval [CI]: 1.6–not estimable) and 3.3 months (95% CI: 1.4–5.2); median overall survival was 27.8 months (95% CI: 9.9–not estimable) and 6.0 months (95% CI: 3.7–13.1) in cohorts A and B, respectively. ConclusionsThe combination of abemaciclib and pembrolizumab in stage IV NSCLC resulted in greater toxicity compared with that previously reported for each individual treatment. Risk-benefit profile does not warrant further evaluation of the combination in this population.

Pharmacoeconomic aspects of oral vinorelbine application: a budget impact analysis considering the new registered price

Objective: comparative assessment of the economic effect of oral vinorelbine when used as indicated, taking into consideration the new registered price.Material and methods. A clinical-economic study was performed to compare active platinum-containing chemotherapy regimens of the first line for stage IV non-small-cell lung cancer with oral vinorelbine and pemetrexed as well as first-line chemotherapy regimens for metastatic breast cancer presented with oral vinorelbine and ixabepilone alone. A systematic search for information in medical databases was carried out, the cost estimate was made out in accordance with the recommendations of The Center for Healthcare Quality Assessment and Control of the Ministry of Health of the Russian Federation. The direct medical costs were estimated, formed on the basis of the dosage, frequency and dosage regimen of the compared drugs, based on the data of the State Register of maximum selling prices, clinical guidelines for the studied nosologies, and instructions for medical use. The comparison of the economic effect of the studied drugs was carried out in pairs using the cost minimization method with a sensitivity analysis. Further, the calculations of the amounts of reimbursement of medical care provided were made using each of the compared drugs. An economic assessment of the economic effect of oral vinorelbine was carried out taking into consideration the change in the price of the drug and a budget impact analysis with a sensitivity analysis.Results. It was determined that the use of oral vinorelbine provides financial savings for a medical organization at the amount of 246,042.34 rubles per 6 cycles of chemotherapy for each patient with stage IV non-small-cell lung cancer compared with the use of pemetrexed, and 558,659.32 rubles per year – for the treatment of each patient with metastatic breast cancer compared with ixabepilone. The results of the budget impact analysis showed that the indication of oral vinorelbine saved 3,287,470.56 rubles for the budget fund considering the change in the cost of 1 mg of the drug for a hypothetical population of patients with stage IV non-small-cell lung cancer in 1000 people. This would create the possibility of therapy for additional 15 patients with this diagnosis. The indication of oral vinorelbine in first-line chemotherapy of metastatic breast cancer for a similar target population would save 18,355,043.96 rubles for the budget fund, which makes it possible to treat 15 more patients with this diagnosis.Conclusion. The use of oral vinorelbine is associated with the saving of financial resources of a medical organization. In addition, the reimbursement for medical care provided from the compulsory medical insurance funds when using regimens with oral vinorelbine is primarily lower than for comparison drugs. Thus, the use of regimens with oral vinorelbine is more beneficial for the payer (the Federal Compulsory Health Insurance Fund) and for the medical organization. The change in the cost of the drug is associated with an increase in the availability of medical care for patients with stage IV non-small-cell lung cancer and patients with metastatic breast cancer.

Approaches to immune checkpoint inhibitor (ICI) maintenance therapy in metastatic urothelial cancer (mUC): A qualitative analysis of oncology providers in the United States.

407 Background: Avelumab first-line (1L) maintenance therapy for patients (pts) with advanced/mUC that has not progressed with platinum-containing chemotherapy was recently approved in the US based on improved overall survival seen in the JAVELIN Bladder 100 trial. However, provider perspectives regarding 1L maintenance therapy in mUC have not been reported. Methods: We performed a qualitative interview study with US oncologists and oncology nurses treating pts with mUC in academic and community practices. Telephone interviews were conducted in August 2020 using a semi-structured discussion guide to explore decision-making processes about treatment for pts with mUC and perspectives about ICI maintenance therapy in the 1L setting. The latter was defined as either 1) ICI for pts who achieve disease control with platinum-containing chemotherapy (Regimen A) or 2) ICI + chemotherapy followed by ICI (Regimen B). Thematic analysis identified key determinants and clinical considerations associated with ICI maintenance therapy in mUC. Results: Results for 18 oncologists (mean age 51.3 yrs [SD 9]; 11% female; 55% with &gt;15 yrs in practice; 39% academic) and 18 oncology nurses (mean age 43.8 yrs [SD 11.1]; 94% female; 34% with &gt;15 yrs in practice; 50% academic) are reported. Cisplatin- and carboplatin-based chemotherapy regimens were the most commonly administered 1L treatments, with ICI monotherapy reserved only for frail (i.e., comorbid and/or elderly) pts. All oncologists recommended 4-6 cycles of 1L chemotherapy. Providers reported different perspectives about the maintenance approaches. Those who expressed a preference for Regimen A (oncologists, 66.6%; nurses, 71.4%) cited potentially less toxicity as a key factor driving their choice. Providers who preferred Regimen B cited the perceived potential for deeper and more durable responses based on previous experience with this maintenance approach in other tumors as a driver of their choice. For Regimen A, providers universally did not recommend a treatment break between chemotherapy and ICI maintenance because of concerns about progression. Frequency of administration was not cited as a driver of treatment decisions for either maintenance approach; instead, providers prioritized survival and tolerability. Responses were generally consistent between oncologists and nurses. Conclusions: Overall, providers adhered to new guidelines for 1L treatment of mUC (NCCN and ESMO) and expressed receptivity toward Regimen A. Although few providers had experience with this new regimen, most preferred it vs ICI + chemotherapy followed by ICI in 1L mUC. Our findings highlight the need to increase provider awareness of Regimen A, i.e., avelumab maintenance in pts with response or stable disease with 1L chemotherapy as a standard of care in advanced/mUC, which has Level I evidence.

Persistent Overall Response on Early PET/CT Scans during Salvage Therapy for Relapsed or Refractory DLBCL Predicts for Disease Specific Survival

Persistent Overall Response on Early PET/CT Scans during Salvage Therapy for Relapsed or Refractory DLBCL Predicts for Disease Specific Survival

Platinum-containing regimens for triple-negative metastatic breast cancer.

In a previous Cochrane Review, we found that for women with metastatic breast cancer unselected for triple-negative disease, there is little or no survival benefit and excess toxicity from platinum-based regimens. In subgroup analyses, however, we found preliminary low-quality evidence of a survival benefit from platinum-based regimens for women with metastatic triple-negative breast cancer (mTNBC). This review updates the evidence from the mTNBC subgroup analyses in the previous Cochrane Review. To assess the effects of platinum-containing chemotherapy regimens with regimens not containing platinum in the management of women with mTNBC. We obtained relevant studies published prior to 2015 and their extracted results from the mTNBC subgroup analysis in the previous Cochrane Review. We searched the Cochrane Breast Cancer Group's Specialised Register, CENTRAL, MEDLINE, Embase, the World Health Organization's International Clinical Trials Registry Platform and ClinicalTrials.gov between 2015 and 27 September 2019. We identified further potentially relevant studies from previous trial reports, systematic reviews, and meta-analyses. Randomised trials comparing platinum-containing chemotherapy regimens with regimens not containing platinum in women with mTNBC. Individual trials could compare one or more platinum-based regimens to one or more non-platinum regimens; hence there could be more 'treatment-comparisons' (i.e. platinum regimen versus non-platinum regimen comparison) than trials. Trial participants may have been purposely selected for mTNBC or inadvertently selected as a subgroup. At least two independent reviewers assessed studies for eligibility and quality, and extracted all relevant data from each study. We derived hazard ratios (HRs) for time-to-event outcomes, where possible, and used fixed-effect models for meta-analyses. We analysed objective tumour response rates (OTRRs) and toxicities as binary (dichotomous) outcomes with risk ratios (RRs) used as measures of effects. We extracted quality of life data, if available. We used GRADE to rate the quality of evidence for time-to-event and tumour response outcomes. This review includes 13 treatment-comparisons involving 1349 women from 10 studies. Twelve of the 13 treatment-comparisons were included in one or more meta-analyses. Of the 13 treatment-comparisons, six and eight had published or provided time-to-event data on overall survival (OS) or progression-free survival/time to progression (PFS/TTP), respectively, that could be included in meta-analyses. Ten treatment-comparisons published or provided OTRR data that could be included in meta-analyses. Eight of the 13 treatment-comparisons were from studies that selected participants on the basis of mTNBC status, while the other five treatment-comparisons were from studies that reported mTNBC results as part of subgroup analyses. Analysis of six treatment-comparisons indicated that platinum-containing regimens may have provided a small survival benefit to mTNBC patients (HR 0.85, 95% CI 0.73 to 1.00; 958 women; moderate-quality evidence) with no evidence of heterogeneity (P = 0.41; I2 = 1%). Data from eight treatment-comparisons showed that platinum regimens may improve PFS/TTP (HR 0.77, 95% CI 0.68 to 0.88; 1077 women; very low-quality evidence). There was marked evidence of heterogeneity (P < 0.0001; I2 = 80%). There was also low-quality evidence of better tumour response for platinum recipients (RR 1.40, 95% CI 1.22 to 1.59; 1205 women) with some evidence of heterogeneity (P = 0.01; I2 = 58%). The observed heterogeneity for the PFS/TTP and OTRR outcomes may reflect between-study differences and general difficulties in assessing tumour response, as well as the varying potencies of the comparators. Compared with women receiving non-platinum regimens: rates of grade 3 and 4 nausea/vomiting were higher for platinum recipients (RR 4.77, 95% CI 1.93 to 11.81; 655 women; low-quality evidence) and rates of grade 3 and 4 anaemia were higher for platinum recipients (RR 3.80, 95% CI 2.25 to 6.42; 843 women; low-quality evidence). In general, however, relatively few intervention-comparisons could be included in meta-analyses for adverse events. None of the studies reported quality of life. For women with mTNBC, there was moderate-quality evidence of a small survival benefit from platinum-based regimens compared to non-platinum regimens. This finding is consistent with findings of a PFS/TTP benefit and improved tumour response from platinum-based regimens. These potential benefits, however, should be weighed against previously identified excess toxicities from platinum-based regimens, particularly regimens containing cisplatin. Further randomised trials of platinum-based regimens among women with mTNBC are required.

Combination Treatment With Paclitaxel, Carboplatin, and Cetuximab (PCE) as First-Line Treatment in Patients With Recurrent and/or Metastatic Nasopharyngeal Carcinoma.

Background: Platinum-containing doublet chemotherapy regimens are generally considered the standard first-line systemic therapy for recurrent or metastatic (R/M) nasopharyngeal cancer (NPC). Gemcitabine (GEM) plus cisplatin (CDDP) has become a standard therapy based on a phase 3 study in several countries, yet this regimen sometimes affects quality of life due to nausea or appetite loss. Here, we present the manageable toxicity and promising activity of paclitaxel + carboplatin + cetuximab (PCE) therapy for R/M NPC.Materials and Methods: We conducted a retrospective review of patients with R/M NPC who were treated with PCE from 2013 to 2019 at the National Cancer Center East, Kashiwa, Japan. PCE consisted of PTX 100 mg/m2 on days 1 and 8; CBDCA area under the blood concentration–time curve (AUC) 2.5 on days 1 and 8, repeated every 3 weeks; and cetuximab at an initial dose of 400 mg/m2, followed by 250 mg/m2 weekly, as reported in the paper.Results: Fourteen patients were identified, consisting of 10 males and 4 females with a median age 59.6 years (range, 43–74). Among the 12 of 14 patients assessed for efficacy, overall response rate was 58.3%, with 2 complete responses and 5 partial responses. On median follow-up of 23.8 months, median overall survival was not reached with observed death events of 2. Median PFS was 4.1 months (95% CI, 2.6–5.6 months). Two patients experienced disease progression during cetuximab maintenance and restarted PCE treatment, then achieved partial response again. The most common grade 3 or 4 adverse events were neutropenia (21.4%) and skin reaction (14.3%). No treatment-related death was observed.Conclusion: Although the number of study population was small, our results suggest that PCE is feasible and potentially effective for R/M NPC, with a 58.3% response rate and 4.1-month PFS. Further prospective evaluation is warranted.

A phase Ib study of abemaciclib in combination with pembrolizumab for patients (pts) with stage IV Kirsten rat sarcoma mutant (KRAS-mut) or squamous non-small cell lung cancer (NSCLC) (NCT02779751): Interim results.

9562 Background: Abemaciclib is an orally administered, selective small molecule cyclin-dependent kinase 4 and 6 inhibitor. In preclinical models, abemaciclib induced intratumor immune inflammation and synergized with PD-1 blockade to enhance antitumor efficacy in anti-PD-L1 refractory disease. Here, we report the safety and antitumor activity of abemaciclib plus the approved NSCLC treatment pembrolizumab in 2 cohorts for pts with nonsquamous and squamous NSCLC. Methods: Eligible pts for this nonrandomized, open-label, multicohort, phase 1b study were either chemotherapy-naive with ≥ 1% tumor cell (TC) PD-L1 staining, KRAS-mut nonsquamous NSCLC (Cohort A) or had a squamous subtype and received ≤ 1 prior platinum-containing chemotherapy regimen (Cohort B) for metastatic NSCLC. Primary endpoint was safety; secondary objectives included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: Twenty-five pts with NSCLC were enrolled in each cohort. Most pts (68%) in Cohort B had received 1 prior line of chemotherapy. Safety profiles observed in both cohorts were largely consistent with previous reports for abemaciclib and pembrolizumab monotherapy. Grades 3/4 AEs in Cohorts A and B, respectively, included ALT increase (6 pts [24%]/ 0 pts), diarrhea (3 pts [12%]/ 0 pts), neutropenia (3 pts [12%]/ 0 pts), and pneumonitis (3 pts [12%]/ 1 pt [4%]). Six pts in Cohort A (24%) and 2 pts in Cohort B (8%) had a confirmed partial response for a disease control rate (CR+PR+SD) of 52% and 64%, respectively. In Cohort A, the ORR in pts with strong (≥50% TC) PD-L1 staining (n = 13) was 31% vs. 17% in pts with weak (1-49% TC) PD-L1 expression (n = 12). Median PFS and OS were 7.6 months (95% CI: 1.6, NR) and 22.0 months (95% CI: 9.9, NR) in Cohort A and 3.3 months (95% CI: 1.4, 5.2) and 6.0 months (95% CI: 3.7, 13.1) in Cohort B, respectively. Conclusions: Abemaciclib plus pembrolizumab resulted in a numerical higher rate of transaminase elevations and pneumonitis. Antitumor activity was remarkable in the KRAS-mut nonsquamous NSCLC but not noticeably higher as compared to historical data for pembrolizumab monotherapy. Clinical trial information: NCT02779751 .

511P - Phase II trial of carboplatin, nab-paclitaxel and bevacizumab for advanced non-squamous non-small cell lung cancer (CARNAVAL study; TORG1424/OLCSG1402)

BackgroundNanoparticle albumin-bound paclitaxel (nab-PTX) + carboplatin (Cb) therapy is one of the standard platinum-containing chemotherapy regimens for patients with advanced non-small cell lung cancer (NSCLC). Adding the anti-vascular endothelial growth factor antibody bevacizumab (BEV) to chemotherapy is an effective treatment option for non-squamous NSCLC. Because the efficacy and safety of the Cb + nab-PTX + BEV triplet regimen has not yet been assessed, we conducted a multicenter, open-label, phase I/II trial of Cb + nab-PTX + BEV therapy for patients with NSCLC. The phase II trial was based on the drug dose and schedule determined in the phase I trial. MethodsIn this phase II trial, the required number of patients was calculated to be 49 cases with α = 0.05 (one-sided) and β = 0.1 assuming a threshold response rate of 30% and an expected response rate of 50%. The patients were to receive 4–6 cycles of Cb (area under the curve = 6) + nab-PTX (100 mg/m2 on days 1, 8 and 15) + BEV (15 mg/kg on day 1) followed by a maintenance dose of nab-PTX + BEV every 3 weeks until disease progression. The primary endpoint was the overall response rate (ORR), and the secondary endpoints included overall survival (OS), progression free survival (PFS) time and toxicity. ResultsThe trial was terminated early because of slow patient accrual. Finally, 47 cases were registered, and the main analysis was performed in 46 cases, excluding one case who was unqualified. The median age of the patients was 66 years. The transition percentage to maintenance therapy was 58.7%. The ORR based on central judgment was 56.5% (26/46 cases) with a 95% confidence interval (CI) of 42.2–70.8%, and the primary endpoint was met. The median PFS and OS were 7.79 months and 18.9 months, respectively. The main toxicity was myelosuppression, with grade 3–4 neutropenia (72.0%), anemia (28.0%), thrombocytopenia (14.0%) and febrile neutropenia (2.0%). The grade 3–4 sensory and motor neuropathy commonly seen with paclitaxel was 0%. All adverse events were manageable, and there was no treatment-related death. ConclusionsCb + nab-PTX + BEV therapy is a favorable and well-tolerated treatment for patients with advanced non-squamous NSCLC. Clinical trial identificationUMIN000014560. Legal entity responsible for the studyTORG/OLCSG. FundingTaiho Pharmaceutical CO., LTD. DisclosureT. Kubo: Honoraria (self): Taiho pharmaceutical; Honoraria (self): Chugai pharmaceutical; Honoraria (self): BMS. A. Bessho: Honoraria (self): Taiho pharmaceutical; Honoraria (self): Chugai pharmaceutical. A. Morita: Honoraria (self): Chugai pharmaceutical. T. Yokoyama: Honoraria (self): Taiho pharmaceutical; Honoraria (self): Chugai pharmaceutical. K. Kaira: Honoraria (self): Taiho pharmaceutical; Honoraria (self): BMS. T. Harada: Honoraria (self): Taiho pharmaceutical. T. Shimokawa: Research grant / Funding (institution): Taiho pharmaceutical; Research grant / Funding (institution): Chugai pharmaceutical; Research grant / Funding (institution): BMS. K. Kiura: Research grant / Funding (institution): Chugai pharmaceutical; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Taiho pharmaceutical. H. Okamoto: Research grant / Funding (institution): Taiho pharmaceutical; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Chugai pharmaceutical. All other authors have declared no conflicts of interest.

Platinum-Based Chemotherapy Plus Cetuximab in Patients With Recurrent or Metastatic Nasopharyngeal Cancer

Platinum-containing doublet chemotherapy regimens are generally considered the standard first-line systemic therapy for recurrent or metastatic (R/M) nasopharyngeal caner (NPC). Gemcitabine (GEM)+Cisplatin (CDDP) demonstrated significant improvement of both progression-free survival and overall survival over 5FU+CDDP for R/M NPC in a phase 3 study, leading to standard of care as first-line therapy for R/M NPC. Although the results of a phase 2 study of cetuximab (Cmab) in combination with carboplatin in patients with heavily pretreated NPC was reported, there was no available data for platinum-based chemotherapy plus Cmab as first-line therapy for R/M NPC. The objective of the currents study was to evaluate safety and efficacy of platinum-based chemotherapy plus Cmab in patients with R/M NPC. We conducted a retrospective review of patients with recurrent or metastatic NPC who were treated with platinum-based chemotherapy plus cetuximab during 2013 to 2017 at our institute. Treatment consisted of CDDP or carboplatin+5FU+Cmab(PFE) or paclitaxel+carboplatin+Cmab(PCE). Eleven patients were identified; patient characteristics were median age, 54.7 years (36-75); male /female 8/3; PS 0/1/2, 6/5/0; histology WHOI/II/III/ unknown, 2/3/3/3; number of prior chemotherapies 0/1/2/3 2/2/1; treatment regimen: PFE/PCE: 3/8. Of the 10 patients assessable for efficacy, 1 patient (10%) achieved complete response (CR), 3 patients (30%) with partial responses (PR), 5 patients (50%) with stable disease (SD), and 1 patient (10%) with progressive diseases (PD), in best response. Overall response rate (ORR) was 40% in all patients. The median progression-free survival (PFS) were 5.6 overall, 6.5 for patients treated with PFE, 5.4 months for patients treated with PCE, respectively. The median overall survival (OS) were 25.3 overall, 25.3 for patients treated with PFE, 25.8 months for patients treated with PCE, respectively. A patient who achieved CR has continued to receive Cmab maintenance for 42.3 months. Most common adverse events(AEs) were acne-like rash (81.8%), skin cracks (72.7%), and bone marrow suppression (54.5%). Most common grade 3 AEs were acne-like rash (1 patient) and althralgia (1 patient). Grade 4 AEs were infusion reaction (1 patient) and allergy due to carboplatin (1 patient). No treatment-related death was observed. Platinum-based chemotherapy plus Cmab demonstrated promising efficacy with ORR 40%, median PFS 5.6 months and OS of 25.3 months, with acceptable toxicities. Cmab in combination with gemcitabine plus CDDP, warrants further investigations.

SWI/SNF aberrations sensitize pancreatic cancer cells to DNA crosslinking agents.

While gemcitabine has been the mainstay therapy for advanced pancreatic cancer, newer combination regimens (e.g. FOLFIRINOX) have extended patient survival, though carry greater toxicity. Biomarkers are needed to better stratify patients for appropriate therapy. Previously, we reported that one-third of pancreatic cancers harbor deletions or deleterious mutations in key subunits of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex. The SWI/SNF complex mobilizes nucleosomes on DNA, and plays a key role in modulating DNA transcription and repair. Thus, we hypothesized that pancreatic cancers with SWI/SNF aberrations might exhibit compromised DNA repair, and show increased sensitivity to DNA damaging agents. Here, we studied human pancreatic cancer cell lines with deficient (or else exogenously reconstituted) SWI/SNF subunits, as well as normal pancreatic epithelial cells following SWI/SNF subunit knockdown. Cells were challenged with DNA damaging agents, including those used in current combination regimens, and then cell viability assayed. We found that pancreatic cells with SWI/SNF dysfunction showed markedly increased sensitivity to DNA damaging agents, and in particular DNA crosslinking agents (cisplatin and oxaliplatin). Assaying clearance of γH2AX confirmed that SWI/SNF dysfunction impaired DNA damage response/repair. Finally, by analyzing pancreatic cancer patient data from The Cancer Genome Atlas, we found that pancreatic cancers with SWI/SNF deficiency (subunit mutation and/or decreased expression) were associated with extended patient survival specifically when treated with platinum containing regimens. Thus, SWI/SNF dysfunction sensitizes pancreatic cancer cells to DNA crosslinking agents, and SWI/SNF mutation status may provide a useful biomarker to predict which patients are likely to benefit from platinum-containing chemotherapy regimens.

Abstract 3809: SWI/SNF aberrations sensitize pancreatic cancer cells to DNA crosslinking agents

Abstract While gemcitabine has been the mainstay therapy for advanced pancreatic cancer, newer combination regimens (e.g. FOLFIRINOX) have extended patient survival, though carry greater toxicity. Biomarkers are needed to better stratify patients for appropriate therapy. Previously, we reported that one-third of pancreatic cancers harbor deletions or deleterious mutations in key subunits of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex. The SWI/SNF complex mobilizes nucleosomes on DNA, and plays a key role in modulating DNA transcription and repair. Thus, we hypothesized that pancreatic cancers with SWI/SNF aberrations might exhibit compromised DNA repair, and show increased sensitivity to DNA damaging agents. Here, we studied pancreatic cancer cell lines with deficient (or else exogenously reconstituted) SWI/SNF subunits, as well as normal pancreatic epithelial cells (HPDE) following SWI/SNF subunit knockdown. Cells were challenged with DNA damaging agents, including those used in current combination regimens, and then cell viability assayed. We found that pancreatic cells with SWI/SNF dysfunction showed markedly increased sensitivity to DNA damaging agents, and in particular DNA crosslinking agents (cisplatin and oxaliplatin). Assaying clearance of γH2AX foci confirmed that SWI/SNF dysfunction impaired DNA damage response/repair. Finally, by analyzing pancreatic cancer patient data (TCGA), we found that pancreatic cancers with SWI/SNF deficiency (subunit mutation and/or decreased expression) showed a strong trend towards extended survival with platinum containing chemo regimens. Thus, SWI/SNF dysfunction sensitizes pancreatic cancer cells to DNA crosslinking agents, and SWI/SNF mutation status may provide a useful biomarker to predict which patients are likely to benefit from platinum-containing chemotherapy regimens. Citation Format: Zhewei Shen, Jean Davidson, Jonathan Pollack. SWI/SNF aberrations sensitize pancreatic cancer cells to DNA crosslinking agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3809. doi:10.1158/1538-7445.AM2017-3809

Platinum-containing regimens for metastatic breast cancer.

Studies have reported high tumour response rates for platinum-containing regimens in the treatment of women with metastatic breast cancer.To identify and review the evidence from randomised trials comparing platinum-containing chemotherapy regimens with regimens not containing platinum in the management of women with metastatic breast cancer.The specialised register maintained by the editorial base of the Cochrane Breast Cancer Group was searched on 2nd May 2003 using the codes for "advanced breast cancer", "chemotherapy". Details of the search strategy applied to create the register, and the procedure used to code references, are described in the Cochrane Breast Cancer Group module on The Cochrane Library.Randomised trials comparing platinum-containing chemotherapy regimens with regimens not containing platinum in women with metastatic breast cancer.Studies were assessed for eligibility and quality, and data (from published trials) were extracted by two independent reviewers. Hazard ratios were derived for time-to-event outcomes, where possible, and a fixed effect model was used for meta-analysis. Response rates were analysed as dichotomous variables. Toxicity and quality of life data (not available) were extracted where present.Thirteen eligible trials were identified, of which 12 had published time-to-event data. The quality of randomisation was generally not described.Data, based on an estimated 987 deaths in 1377 women, was unable to show a statistically significant difference in favour of platinum-containing regimens. The hazard ratio (HR) for overall survival was 1.00 (95% confidence interval (CI) 0.88 to 1.15, p=0.96), with minor heterogeneity. Results were similar when the analysis was limited to trials in women receiving first line chemotherapy. There was no statistically significant difference in favour of platinum-containing regimens for time to progression (overall HR of 1.06 (95% CI 0.95 to 1.19, p=0.31) although there was marked evidence of heterogeneity (p< 0.0001). There was a statistically significant difference in overall response in favour of platinum-containing regimens (OR 1.47; 95% CI 1.23 to 1.76, p=0.0001). However, there was strong statistical evidence of heterogeneity (p < 0.00010) probably reflecting the varying efficacy of the comparator regimens used in the trials. Heterogeneity may also reflect the differences, and difficulties, in assessing response. Women receiving platinum-containing regimens experienced statistically significant greater toxicity levels for leukopenia, hair loss, nausea and vomiting and anaemia compared with those receiving non-platinum regimens.In view of the significant excess toxicity, lack of progression or survival benefit and the availability of less toxic active agents it is difficult to justify the use of platinum-containing regimens, particularly as first line treatment for women with metastatic breast cancer in routine clinical practice. Ongoing trials are examining the possibility of synergy between platins and trastuzamab, a monoclonal antibody treatment. No randomised trials containing oxalplatin were identified for the present review.

Renal Toxicity in Patients Treated with Anti-Pd-1 Targeted Agents for Solid Tumors

Aim Immune checkpoint inhibitors of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) have recently entered in the therapeutic armamentarium of several types of cancer. Besides the survival benefit, the true revolution of these agents is the distinctive toxicity profile. We aim to assess the incidence and relative risk (RR) of renal toxicity (RT) in patients with solid tumors treated with monoclonal antibodies (mAbs) directed against PD-1/PD-L1. Methods By searching the MEDLINE/PubMed, Cochrane Library, and ASCO Meeting abstracts, prospective studies were identified. Combined RRs and 95% confidence intervals (CIs) were calculated using fixed- or random-effects methods. Results Eleven articles were selected for this analysis, with a total of 5,722 patients who were used to evaluate RT. The incidence of anti-PD-1-related RT of all-grades and high-grades was low (1.4% and 0.2%, respectively). However, compared to controls, treatment with PD-1 inhibitors was associated with a significant increased risk of any grade RT (RR = 1.85, 95% CI, 1.07-3.20; p = 0.03) but not high-grade RT (RR = 1.57, 95% CI, 0.56-4.36; p = 0.39). Pembrolizumab significantly increased the risk of any-grade RT (RR = 4.91, p = 0.01) compared to the control arm, and a significant difference was found between nivolumab and pembrolizumab for developing RT of any grade (p = 0.04). Conversely, no differences were identified between the type of prior treatment (prior platinum-containing chemotherapy regimen vs. nonplatinum containing regimen). Conclusions Immune-mediated RT is a rare adverse event that is generally low in severity. Compared to standard therapies, anti-PD-1 mAbs significantly increase the risk of any grade, without conditioning the risk of high-grade RT. The type of PD-1 inhibitor could affect the risk of developing any-grade RT, while prior therapy with platinum-containing regimens does not affect the risk of developing RT.