Investigator's Choice Of Chemotherapy Research Articles

Datopotamab Deruxtecan Versus Chemotherapy in Previously Treated Inoperable/Metastatic Hormone Receptor-Positive Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer: Primary Results From TROPION-Breast01.

The global, phase 3, open-label, randomized TROPION-Breast01 study assessed the trophoblast cell surface antigen 2-directed antibody-drug conjugate datopotamab deruxtecan (Dato-DXd) versus investigator's choice of chemotherapy (ICC) in hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer. Adult patients with inoperable/metastatic HR+/HER2‒ breast cancer, who had disease progression on endocrine therapy, for whom endocrine therapy was unsuitable, and had received one to two previous lines of chemotherapy in the inoperable/metastatic setting, were randomly assigned 1:1 to Dato-DXd (6 mg/kg once every 3 weeks) or ICC (eribulin/vinorelbine/capecitabine/gemcitabine). Dual primary end points were progression-free survival (PFS) by blinded independent central review (BICR) and overall survival (OS). Patients were randomly assigned to Dato-DXd (n = 365) or ICC (n = 367). Dato-DXd significantly reduced the risk of progression or death versus ICC (PFS by BICR hazard ratio [HR], 0.63 [95% CI, 0.52 to 0.76]; P < .0001). Consistent PFS benefit was observed across subgroups. Although OS data were not mature, a trend favoring Dato-DXd was observed (HR, 0.84 [95% CI, 0.62 to 1.14]). The rate of grade ≥3 treatment-related adverse events (TRAEs) with Dato-DXd was lower than ICC (20.8% v 44.7%). The most common TRAEs (any grade; grade ≥3) were nausea (51.1%; 1.4%) and stomatitis (50%; 6.4%) with Dato-DXd and neutropenia (grouped term, 42.5%; 30.8%) with ICC. Patients receiving Dato-DXd had statistically significant and clinically meaningful improvement in PFS and a favorable and manageable safety profile, compared with ICC. Results support Dato-DXd as a novel treatment option for patients with inoperable/metastatic HR+/HER2‒ breast cancer who have received one to two previous lines of chemotherapy in this setting.

436TiP DYNASTY-Breast02: A phase III trial of BNT323/DB-1303 vs investigator's choice chemotherapy in HER2-low, hormone receptor positive, metastatic breast cancer

436TiP DYNASTY-Breast02: A phase III trial of BNT323/DB-1303 vs investigator's choice chemotherapy in HER2-low, hormone receptor positive, metastatic breast cancer

Treatment-related Adverse Events, Including Fatal Toxicities, in Patients With Extensive-stage Small-cell Lung Cancer Receiving Adjuvant Programmed Cell Death 1/Programmed Cell Death Ligand 1 Inhibitors: A Meta-analysis and Trial Sequential Analysis of Randomized Controlled Trials

Background/AimsThe safety profile of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors when associated with chemotherapy for the treatment of patients with extensive-stage small-cell lung cancer is still not fully unraveled. MethodsWe performed a comprehensive searrch of the PubMed, Embase, and Cochrane databases for randomized controlled trials that investigated the addition of PD-1 or PD-L1 inhibitors to standard investigator choice chemotherapy. We used risk -ratios (RRs) with 95% confidence intervals (CIs) for all endpoints. ResultsSix studies and 2,995 patients were included. At the baseline, the median age of the patients varied from 62 to 65 years, 311 (10.4%) had brain metastases, and 1,060 (35.4%) had liver metastases. PD-1/PD-L1 inhibitors were found to reduce fatal toxicities-related mortality (RR: 0.85; 95% CI: 0.80–0.91; p < 0.001; I2 = 49%). The intervention group had a higher incidence of decreased appetite (RR: 1.19; 95% CI: 1.02–1.40; p = 0.03; I2 = 0%), hyponatremia (RR: 1.51; 95% CI: 1.08–2.12; p = 0.02; I2 = 0%), and hypothyroidism (RR: 3.14; 95% CI: 1.10–8.95; p = 0.03; I2 = 81%) of any grade. Regarding adverse events of grade 3–4, there was no association of the addition of PD-1/PD-L1 inhibitors with an increased occurrence of any of the evaluated outcomes. ConclusionIn this systematic review and meta-analysis, the incorporation of PD-1/PD-L1 inhibitors to chemotherapy demonstrated an excellent safety profile and to be a promising prospect for reshaping the established treatment paradigms for patients with extensive-stage small cell lung cancer.

Health-related quality of life with pembrolizumab plus chemotherapy vs placebo plus chemotherapy for advanced triple-negative breast cancer: KEYNOTE-355.

In KEYNOTE-355 (NCT02819518), the addition of pembrolizumab to chemotherapy led to statistically significant improvements in progression-free survival and overall survival in patients with advanced triple-negative breast cancer with tumor programmed cell death ligand 1 (PD-L1) combined positive score of at least 10. We report patient-reported outcomes from KEYNOTE-355. Patients were randomly assigned 2:1 to pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles plus investigator's choice chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine plus carboplatin). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30), Breast Cancer-Specific Quality of Life Questionnaire, and EuroQol 5-Dimension questionnaire visual analog scale were prespecified. Patient-reported outcomes were analyzed for patients who received at least 1 dose of study treatment and completed at least 1 patient-reported outcome assessment. Changes in patient-reported outcome scores from baseline were assessed at week 15 (latest time point at which completion and compliance rates were at least 60% and at least 80%, respectively). Time to deterioration in patient-reported outcomes was defined as time to first onset of at least a 10-point worsening in score from baseline. Patient-reported outcome analyses included 317 patients with tumor PD-L1 combined positive score of at least 10 (pembrolizumab plus chemotherapy: n = 217; placebo plus chemotherapy: n = 100). There were no between-group differences in change from baseline to week 15 in QLQ-C30 global health status/quality of life (QOL; least-squares mean difference = -1.81, 95% confidence interval [CI] = -6.92 to 3.30), emotional functioning (least-squares mean difference = -1.43, 95% CI = -7.03 to 4.16), physical functioning (least-squares mean difference = -1.05, 95% CI = -6.59 to 4.50), or EuroQol 5-Dimension questionnaire visual analog scale (least-squares mean difference = 0.18, 95% CI = -5.04 to 5.39) and no between-group difference in time to deterioration in QLQ-C30 global health status/QOL, emotional functioning, or physical functioning. Together with the efficacy and safety findings, patient-reported outcome results from KEYNOTE-355 support pembrolizumab plus chemotherapy as a standard of care for patients with advanced triple-negative breast cancer with tumor PD-L1 expression (combined positive score ≥10).

Therapeutic Potential of Tisotumab Vedotin in the Treatment of Recurrent or Metastatic Cervical Cancer: A Short Report on the Emerging Data.

Cervical cancer is the fourth most common type of cancer in women worldwide. It is associated with a high death rate, despite the fact that it is a nearly 100% preventable disease because of very effective primary and secondary preventive strategies. Advanced and recurrent disease is uncurable with a high relapse risk and the second-line therapies are limited with modest response rates and short durability. Investigating alternative mechanisms of action is crucial because of the high request for effective new therapies. Tisotumab vedotin (TV) is the first antibody-drug conjugated to target a cell surface-expressed tissue factor, and preliminary data in patients with metastatic and recurrentcervical cancer have been promising. In addition, the trials showed a favorable tolerability profile, with limited incidence of grade 3 or worse adverse events. According to the data of ENGOT-cx6/GOG-3023/innovaTV 204, the US Food and Drug Administration granted expedited approval of TV on September 20, 2021, for womenwith recurrent or metastatic cervical cancer. Actually, two other trials testing TV alone or in combination with other agents are ongoing. ENGOT-cx8/GOG-3024/innovaTV 205 is a Phase Ib/II trial of TV in combination with platinum or bevacizumab or pembrolizumab, in patients with recurrent or metastatic cervical cancer who have not received prior systemic therapy or who have progressed after no more than two prior systemic therapies. ENGOT-cx12/GOG-3057/InnovaTV 301 is a Phase 3 trial of TV vs investigator's choice chemotherapy in patients with advanced or recurrent cervical cancer who had received no more than 2 prior chemotherapy lines. The outcomes of these two trials will potentially confirm and reinforce the use of TV as a new standard of care in advanced or recurrent cervical cancer.

TROPION-Breast02: Datopotamab deruxtecan for locally recurrent inoperable or metastatic triple-negative breast cancer.

Despite recent treatment advances, the prognosis for patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) remains poor. The antibody-drug conjugate datopotamab deruxtecan (Dato-DXd) is composed of a humanized anti-TROP2 IgG1 monoclonal antibody linked to a topoisomerase I inhibitor payload via a stable, cleavable linker. The phase III TROPION-Breast02 trial in patients previously untreated for locally recurrent inoperable or metastatic TNBC, who are not candidates for PD-1/PD-L1 inhibitors is evaluating efficacy and safety of Dato-DXd versus investigator's choice of chemotherapy (ICC). Approximately 600 patients will be randomized 1:1 to Dato-DXd 6mg/kg iv. every 3weeks or ICC (paclitaxel, nab-paclitaxel, carboplatin, capecitabine or eribulin mesylate). Dual primary end points are progression-free survival by blinded independent central review and overall survival.

First-line lenvatinib plus pembrolizumab plus chemotherapy versus chemotherapy in advanced/metastatic gastroesophageal adenocarcinoma (LEAP-015): Safety run-in results.

411 Background: LEAP-015 (NCT04662710) is a randomized, open-label, 2-part, phase 3 study of the safety and efficacy of lenvatinib + pembrolizumab + chemotherapy as a first-line treatment for advanced/metastatic gastroesophageal adenocarcinoma. We report findings from part 1, the safety run-in, of LEAP-015. Methods: Eligible patients had untreated, HER2-negative, locally advanced unresectable or metastatic gastroesophageal adenocarcinoma, measurable disease per RECIST v1.1, and ECOG performance status 0 or 1. In part 1, patients received induction with IV pembrolizumab 400 mg Q6W (×2) + oral lenvatinib 8 mg QD + investigator choice of chemotherapy (capecitabine + oxaliplatin [CAPOX] Q3W ×4 or 5-fluorouracil + leucovorin + oxaliplatin [mFOLFOX6] Q2W ×6) and consolidation with pembrolizumab 400 mg Q6W for ≤16 doses + lenvatinib 20 mg QD; dose-limiting toxicities (DLTs), defined as selected prespecified grade ≥3 adverse events (AEs) or any-grade thromboembolic events, were evaluated for 21 days after the first dose of study intervention. If ≥3 DLTs occurred in either oxaliplatin-containing regimen, then enrollment in part 2 may be delayed to allow for the examination of safety data and to consider design changes. In part 1, the primary end point was safety and tolerability in all patients. Preliminary efficacy was also assessed in part 1. Objective response and disease control rate were assessed per RECIST version 1.1 by blinded independent central review. Results: In part 1, 15 pts received ≥1 dose of lenvatinib + pembrolizumab + chemotherapy. 1 DLT of grade 3 asthenia occurred in the CAPOX cohort and 1 DLT of grade 4 neutropenia occurred in the FOLFOX cohort. Median time from first dose to data cutoff (Oct 13, 2021) was 7 mo (range, 7-9). Treatment-related AEs occurred in 14 patients (93%), with grade 3/4 events in 8 patients (53%). 4 patients (27%) discontinued any drug because of a treatment-related AE, and no patient discontinued all drugs because of a treatment-related AE. No patients died because of a treatment-related AE. No grade ≥3 immune-mediated AEs or infusion reactions occurred. Objective response was reported in 11 of 15 patients (73%; 95% CI, 45-92) who received ≥1 dose of treatment. Disease control rate was reported in 14 of 15 patients (93%; 95% CI, 68-100) who received ≥1 dose of treatment. Conclusions: In the safety run-in of LEAP-015, lenvatinib + pembrolizumab + chemotherapy was associated with a manageable safety profile in the first-line treatment of advanced/metastatic gastroesophageal adenocarcinoma. Preliminary antitumor activity was observed for lenvatinib + pembrolizumab + chemotherapy. Part 2 will evaluate the efficacy and safety of lenvatinib + pembrolizumab + chemotherapy versus chemotherapy in this same patient population and patient accrual is ongoing. Clinical trial information: NCT04662710 .

Early Readout on Overall Survival of Patients With Melanoma Treated With Immunotherapy Using a Novel Imaging Analysis

Existing criteria to estimate the benefit of a therapy in patients with cancer rely almost exclusively on tumor size, an approach that was not designed to estimate survival benefit and is challenged by the unique properties of immunotherapy. More accurate prediction of survival by treatment could enhance treatment decisions. To validate, using radiomics and machine learning, the performance of a signature of quantitative computed tomography (CT) imaging features for estimating overall survival (OS) in patients with advanced melanoma treated with immunotherapy. This prognostic study used radiomics and machine learning to retrospectively analyze CT images obtained at baseline and first follow-up and their associated clinical metadata. Data were prospectively collected in the KEYNOTE-002 (Study of Pembrolizumab [MK-3475] Versus Chemotherapy in Participants With Advanced Melanoma; 2017 analysis) and KEYNOTE-006 (Study to Evaluate the Safety and Efficacy of Two Different Dosing Schedules of Pembrolizumab [MK-3475] Compared to Ipilimumab in Participants With Advanced Melanoma; 2016 analysis) multicenter clinical trials. Participants included 575 patients with a diagnosis of advanced melanoma who were randomly assigned to training and validation sets. Data for the present study were collected from November 20, 2012, to June 3, 2019, and analyzed from July 1, 2019, to September 15, 2021. KEYNOTE-002 featured trial groups testing intravenous pembrolizumab, 2 mg/kg or 10 mg/kg every 2 or every 3 weeks based on randomization, or investigator-choice chemotherapy; KEYNOTE-006 featured trial groups testing intravenous ipilimumab, 3 mg/kg every 3 weeks and intravenous pembrolizumab, 10 mg/kg every 2 or 3 weeks based on randomization. The performance of the signature CT imaging features for estimating OS at the month 6 posttreatment landmark in patients who received pembrolizumab was measured using an area under the time-dependent receiver operating characteristics curve (AUC). A random forest model combined 25 imaging features extracted from tumors segmented on CT images to identify the combination (signature) that best estimated OS with pembrolizumab in 575 patients. The signature combined 4 imaging features, 2 related to tumor size and 2 reflecting changes in tumor imaging phenotype. In the validation set (287 patients treated with pembrolizumab), the signature reached an AUC for estimation of OS status of 0.92 (95% CI, 0.89-0.95). The standard method, Response Evaluation Criteria in Solid Tumors 1.1, achieved an AUC of 0.80 (95% CI, 0.75-0.84) and classified tumor outcomes as partial or complete response (93 of 287 [32.4%]), stable disease (90 of 287 [31.3%]), or progressive disease (104 of 287 [36.2%]). The findings of this prognostic study suggest that the radiomic signature discerned from conventional CT images at baseline and on first follow-up may be used in clinical settings to provide an accurate early readout of future OS probability in patients with melanoma treated with single-agent programmed cell death 1 blockade.

Efficacy of atezolizumab to treat non-small-cell lung cancer: a meta-analysis based on randomized clinical trials.

Purpose: Atezolizumab, an immunoglobulin G1 monoclonal antibody against PD-L1, is accepted to treat advanced non-small-cell lung cancer (NSCLC). Our systematic review aims to evaluate survival efficacy of atezolizumab, overall and in subgroups defined by PD-L1 expression. Materials and Methods: Search the trials on efficacy of atezolizumab in advanced NSCLC based on online electronic databases from their dates of inception up to June 2019, including PubMed, Embase and Cochrane library databases. After rigorous reviewing of quality, the data of the PFS and OS were measured as outcomes. Results: Six trials including seven researches were included. Overall, 4722 subjects involving 2488 patients received atezolizumab and 2234 patients received investigator's choice chemotherapy were retrieved. For the intention-to-treat (ITT) population, the pooled ORs for overall survival (OS) was 0.81 (95 % confidence interval [CI] 0.75-0.87; P<0.00001) and progression-free survival benefit (PFS) was 0.65 (95 % CI 0.59-0.73; P<0.00001), respectively. For the subgroups PD-L1 expression (negative and high), there were benefits both observed in the PFS and OS in two sub-groups with atezolizumab (P 0.05). However, in the low expression of PD-L1 group, the subjects who received atezolizumab achieved PFS (OR 0.70; 95% CI: 0.58-0.84, P=0.0002) advantage but OS advantage (OR 0.91; 95% CI: 0.62-1.33, P=0.62). Conclusion: In low expression of PD-L1 subgroups, a benefit was observed for PFS but OS. However, the status of PD-L1 expression cannot be recommend as prognostic biomarker to support the decision who will benefit from atezolizumab.

Health-related quality of life in patients with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer treated with first-line pembrolizumab versus chemotherapy (KEYNOTE-177): an open-label, randomised, phase 3 trial

In the KEYNOTE-177 study, pembrolizumab monotherapy provided statistically significant and clinically meaningful improvements in progression-free survival versus chemotherapy as first-line treatment in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. To further support the efficacy and safety findings of the KEYNOTE-177 study, results of the health-related quality of life (HRQOL) analyses are reported here. KEYNOTE-177 is an open-label, randomised, phase 3 trial being done at 192 cancer centres in 23 countries, in patients aged 18 years and older with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had not received previous systemic therapy for metastatic disease. Eligible patients were randomly assigned (1:1) centrally by use of interactive voice response or integrated web response technology to receive pembrolizumab 200 mg intravenously every 3 weeks or investigator's choice chemotherapy (mFOLFOX6 [leucovorin, fluorouracil, and oxaliplatin] or FOLFIRI [leucovorin, fluorouracil, and irinotecan] intravenously every 2 weeks with or without intravenous bevacizumab or cetuximab). Patients and investigators were not masked to treatment assignment. The primary endpoints were progression-free survival (previously reported) and overall survival (data to be reported at the time of the final analysis). HRQOL outcomes were evaluated as prespecified exploratory endpoints. The analysis population comprised all randomly assigned patients who received at least one dose of study treatment and completed at least one HRQOL assessment. HRQOL outcomes were mean change from baseline to prespecified week 18 in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and EORTC Quality of Life Questionnaire-Colorectal 29 (EORTC QLQ-CR29) scale and item scores, and in the EuroQoL 5 Dimensions 3 Levels (EQ-5D-3L) visual analogue scale and health utility scores; the proportion of patients with improved, stable, or deteriorated scores from baseline to prespecified week 18 in EORTC QLQ-C30 scales and items; and time to deterioration in EORTC QLQ-C30 global health status/quality of life (GHS/QOL), physical functioning, social functioning, and fatigue scores and EORTC QLQ-CR29 urinary incontinence scores. The threshold for a small and clinically meaningful mean difference in EORTC QLQ-C30 score was 5-8 points. This study is registered with ClinicalTrials.gov, NCT02563002 and is ongoing; recruitment is closed. Between Feb 11, 2016, and Feb 19, 2018, 307 patients were enrolled and randomly assigned to receive pembrolizumab (n=153) or chemotherapy (n=154). The HRQOL analysis population comprised 294 patients (152 receiving pembrolizumab and 142 receiving chemotherapy). As of Feb 19, 2020, median time from randomisation to data cutoff was 32·4 months (IQR 27·7-37·8). Least squares mean (LSM) change from baseline to prespecified week 18 showed a clinically meaningful improvement in EORTC QLQ-C30 GHS/QOL scores with pembrolizumab versus chemotherapy (between-group LSM difference 8·96 [95% CI 4·24-13·69]; two-sided nominal p=0·0002). Median time to deterioration was longer with pembrolizumab versus chemotherapy for GHS/QOL (hazard ratio 0·61 [95% CI 0·38-0·98]; one-sided nominal p=0·019), physical functioning (0·50 [95% CI 0·32-0·81]; one-sided nominal p=0·0016), social functioning (0·53 [95% CI 0·32-0·87]; one-sided nominal p=0·0050), and fatigue scores (0·48 [95% CI 0·33-0·69]; one-sided nominal p<0·0001). Pembrolizumab monotherapy led to clinically meaningful improvements in HRQOL compared with chemotherapy in patients with previously untreated microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. These data, along with the previously reported clinical benefits, support pembrolizumab as a first-line treatment option for this population. Merck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA.

Phase III, randomized trial of mirvetuximab soravtansine versus chemotherapy in patients with platinum-resistant ovarian cancer: primary analysis of FORWARD I

Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate comprising a folate receptor alpha (FRα)-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent. The randomized, open-label, phase III study FORWARD I compared MIRV and investigator's choice chemotherapy in patients with platinum-resistant epithelial ovarian cancer (EOC). Eligible patients with 1-3 prior lines of therapy and whose tumors were positive for FRα expression were randomly assigned, in a 2 : 1 ratio, to receive MIRV (6 mg/kg, adjusted ideal body weight) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary endpoint was progression-free survival [PFS, Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, blinded independent central review] in the intention-to-treat (ITT) population and in the prespecified FRα high population. A total of 366 patients were randomized; 243 received MIRV and 109 received chemotherapy. The primary endpoint, PFS, did not reach statistical significance in either the ITT [hazard ratio (HR), 0.98, P= 0.897] or the FRα high population (HR, 0.69, P= 0.049). Superior outcomes for MIRV over chemotherapy were observed in all secondary endpoints in the FRα high population including improved objective response rate (24% versus 10%), CA-125 responses (53% versus 25%), and patient-reported outcomes (27% versus 13%). Fewer treatment-related grade 3 or higher adverse events (25.1% versus 44.0%), and fewer events leading to dose reduction (19.8% versus 30.3%) and treatment discontinuation (4.5% versus 8.3%) were seen with MIRV compared with chemotherapy. In patients with platinum-resistant EOC, MIRV did not result in a significant improvement in PFS compared with chemotherapy. Secondary endpoints consistently favored MIRV, particularly in patients with high FRα expression. MIRV showed a differentiated and more manageable safety profile than chemotherapy.

KEYNOTE-811 pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction cancer (mG/GEJc): A double-blind, randomized, placebo-controlled phase III study.

TPS463 Background: Combination therapy with the anti-HER2 antibody trastuzumab plus fluoropyrimidine and platinum is the current standard of care for patients with HER2+ mG/GEJc. We hypothesize that combination anti–PD-1 and anti-HER2 therapy will result in T-cell activation, augment antibody-dependent, cell-mediated cytotoxicity, and potentiate antitumor immune response in HER2+ patients. A phase 2 study in HER2+ mG/GEJc demonstrated the safety and preliminary efficacy of trastuzumab/pembrolizumab/chemotherapy; the objective response rate was 87%, and the disease control rate was 100% (Janjigian YY, ASCO GI 2019). KEYNOTE-811 (ClinicalTrials.gov, NCT03615326), a global, multicenter, randomized, placebo-controlled, phase 3 study, is underway. Methods: Key eligibility criteria are age ≥18 years; previously untreated unresectable or metastatic HER2+ (centrally confirmed IHC 3+ or IHC 2+/ISH &gt; 2.0) G/GEJ cancer; life expectancy &gt; 6 months with RECIST v1.1 measurable disease; and adequate organ function and performance status (ECOG PS of 0 or 1). Patients will be randomly assigned 1:1 to receive chemotherapy with pembrolizumab 200 mg intravenously (IV) or placebo with trastuzumab 6 mg/kg (after 8 mg/kg load) every 3 weeks (Q3W) up to 2 years or until intolerable toxicity or disease progression. Investigator-choice chemotherapy will include day 1 cisplatin 80 mg/m2 IV and 5-fluorouracil 800 mg/m2/day IV (days 1-5) or oxaliplatin 130 mg/m2 IV and capecitabine 1000 mg/m2 BID days 1-14 (Q3W). Primary end points are progression-free survival and overall survival. Secondary end points are objective response rate, duration of response, and safety and tolerability. Adverse events are graded per CTCAE v4.0 and will be monitored for 30 or 90 days after treatment. Patients will be followed up for survival. Planned enrollment is approximately 692 patients. Clinical trial information: NCT03615326.

PI3K/AKT/mTOR inhibitors for advanced or recurrent endometrial cancer.

Endometrial cancer is one of the most common gynaecological cancers in developed countries. Treatment of advanced endometrial cancer usually involves radiotherapy, chemotherapy, endocrine therapy or a combination of these. However, survival outcomes are poor in advanced or metastatic disease. Better systemic treatment options are needed to improve survival and safety outcomes for these women. The PI3K/AKT/mTOR pathway is a frequently altered signalling pathway in endometrial cancer. Single-arm studies have reported some encouraging results of the PI3K/AKT/mTOR inhibition in advanced or recurrent endometrial cancer. To assess the efficacy and safety of PI3K/AKT/mTOR inhibitor-containing regimens in women with locally-advanced, metastatic or recurrent endometrial cancer. We searched the Cochrane Central Register of Controlled Trials, MEDLINE and Embase to 16 January 2019; and the World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov in July 2018. We also reviewed reference lists from included studies and endometrial cancer guidelines. We included randomised controlled trials (RCTs) comparing a regimen with a PI3K/AKT/mTOR inhibitor (either alone or in combination with other treatments, such as chemotherapy or hormonal therapy) versus a comparator regimen without a PI3K/AKT/mTOR inhibitor. There were no restrictions on which comparator(s) were included. We extracted data independently, and assessed risks of bias and the certainty of the evidence. The primary outcome measures were progression-free survival and toxicity (grade 3/4 where available). We derived hazard ratios (HRs) for time-to-event outcomes and risk ratios (RRs) for dichotomous outcomes. Secondary outcomes included overall survival, objective tumour response rate, quality of life and treatment-related death. We used GRADEproGDT to assess the certainty of the evidence for the most important outcomes (by first-line and second/third-line therapy for progression-free survival and overall survival). We included two RCTs involving 361 women. One study assessed the effects of the mTOR inhibitor temsirolimus, in combination with carboplatin/paclitaxel versus carboplatin/paclitaxel and bevacizumab in treatment-naïve women with advanced or recurrent endometrial cancer. The second study compared the mTOR inhibitor ridaforolimus alone versus progestin or investigator choice of chemotherapy in women who had received prior treatment for metastatic or recurrent endometrial cancer. We identified five ongoing studies on the effects of PI3K and AKT inhibitors, metformin and dual mTOR inhibitors.For first-line therapy, an mTOR inhibitor-containing regimen may worsen progression-free survival (HR 1.43, 95% CI 1.06 to 1.93; 1 study, 231 participants; low-certainty evidence), while for second/third-line therapy, an mTOR inhibitor probably improves progression-free survival compared to chemotherapy or endocrine therapy (HR 0.53, 95% CI 0.31 to 0.91; 1 study, 95 participants; moderate-certainty evidence). Data on toxicity were available from both studies: administering an mTOR inhibitor regimen may increase the risk of grade 3/4 mucositis (RR 10.42, 95% CI 1.34 to 80.74; 2 studies, 357 participants; low-certainty evidence), but may result in little to no difference in risk of anaemia or interstitial pneumonitis (low-certainty evidence for both toxicities). Overall, event rates were low. For first-line therapy, an mTOR inhibitor-containing regimen may result in little to no difference in overall survival compared to chemotherapy (HR 1.32, 95% CI 0.98 to 1.781 study, 231 participants; low-certainty evidence). The finding was similar for second/third-line therapy (HR 1.06, 95% CI 0.70 to 1.61; 1 study, 130 participants; low-certainty evidence). Administering mTOR inhibitor-containing regimens may result in little to no difference in tumour response compared to chemotherapy or hormonal therapy in first-line or second/third-line therapy (first line: RR 0.93, 95% CI 0.75 to 1.17; 1 study, 231 participants; second/third line: RR 0.22, 95% CI 0.01 to 4.40; 1 study, 61 participants; low-certainty evidence).Neither study collected or reported quality-of-life data. Two RCTs have been reported to date, with low certainty of evidence. In a recurrent disease setting, mTOR inhibitors may result in improved progression-free survival, but we found no clear benefit in overall survival or tumour response rate. We await the publication of at least five ongoing studies investigating the role of PI3K/AKT/mTOR inhibitors in advanced or recurrent endometrial cancer before any conclusions can be drawn on their use.

KEYNOTE-811 pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction cancer (mG/GEJC): A double-blind, randomized, placebo-controlled phase 3 study.

TPS4146 Background: Combination therapy with the anti-HER2 antibody trastuzumab with fluoropyrimidine and platinum is the current standard for patients with HER2+ mG/GEJc. We hypothesize that combination anti–PD-1 and anti-HER2 therapy will result in T-cell activation, augment ADCC, and potentiate antitumor immune response in HER2+ patients. This phase 2 study in HER2+ mG/GEJc demonstrated the safety and preliminary efficacy of trastuzumab/pembrolizumab/chemotherapy; the overall response rate was 87%, and the disease control rate was 100% Janjigian YY, ASCO GI 2019). KEYNOTE 811, a global, multicenter, randomized, placebo-controlled, phase 3 study, is underway. Methods: Key eligibility criteria are age ≥18 years; previously untreated unresectable or metastatic HER2+ (centrally confirmed IHC 3+ or IHC 2+/ISH &gt;2.0) G/GEJ adenocarcinoma; life expectancy &gt;6 months with RECIST v1.1 measurable disease; adequate organ function and performance status. Patients will be randomly assigned 1:1 to receive chemotherapy with pembrolizumab 200 mg IV flat dose or placebo with trastuzumab 6 mg/kg (after 8 mg/kg load) Q3W up to 2 years or until intolerable toxicity or disease progression. Investigator choice chemotherapy will include day 1 cisplatin 80 mg/m2 IV and /5-fluorouracil 800 mg/m2/day IV (days 1-5) or oxaliplatin 130 mg/m2 IV and capecitabine 1000 mg/m2 BID days 1-14 (Q3W). Primary end points are progression-free survival and overall survival. Secondary end points are objective response rate, duration of response, and safety and tolerability. Adverse events are graded per NCI CTCAE v4.0 and will be monitored for 30 or 90 days after treatment. Patients will be followed up for survival. Planned enrollment is approximately 692 patients. Clinical trial information: NCT03615326.

Clinical and Molecular Characteristics Associated with Survival in Advanced Melanoma Treated with Checkpoint Inhibitors.

Background We performed meta-analysis to gather more evidence regarding clinical-molecular subgroups associated with better overall survival (OS) in advanced melanoma treated with checkpoint inhibitors. Materials and Methods We performed a systematic search of PubMed, Scopus, Cochrane Library, and clinical trial.gov. Randomized clinical trials that compared a checkpoint inhibitor (nivolumab or pembrolizumab) with investigator choice chemotherapy or ipilimumab were included in our study. Hazard ratios (HR) and confidence interval (CI) were calculated for progression-free survival (PFS) and OS for each subgroup using generic inverse model along with the random effect method. Results A total of 6 clinical trials were eligible for the meta-analysis. OS was prolonged in wild BRAF subgroup (HR 0.65, 95% CI 0.49-0.85, p 0.002), Programmed cell death subgroup (PD-1+) (HR 0.57, 95% CI 0.41-0.80, p 0.001), and high lactate dehydrogenase (LDH) level subgroup (HR 0.60, 95% CI 0.38-0.95, p 0.03). Similarly, we found increased OS in eastern cooperative oncology group (ECOG) 1, males and age >65 years subgroups. Conclusions Checkpoint inhibitors significantly increased OS in patients with wild BRAF, positive PD-1, and high LDH. However, results should be interpreted keeping in mind associated significant heterogeneity. The results of this study should help in designing future clinical trials.

Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma

AimTo evaluate the protocol-specified final analysis of overall survival (OS) in the KEYNOTE-002 study (NCT01704287) of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory, advanced melanoma. MethodsIn this randomised, phase II study, eligible patients had advanced melanoma with documented progression after two or more ipilimumab doses, previous BRAF or MEK inhibitor or both, if BRAFV600 mutant-positive. Patients were randomised to pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy. Crossover to pembrolizumab was allowed following progression on chemotherapy. The protocol-specified final OS was performed in the intent-to-treat population. Survival was positive if p < 0.01 in one pembrolizumab arm. ResultsA total of 180 patients were randomised to pembrolizumab 2 mg/kg, 181 to pembrolizumab 10 mg/kg and 179 to chemotherapy. At a median follow-up of 28 months (range 24.1–35.5), 368 patients died and 98 (55%) crossed over to pembrolizumab. Pembrolizumab 2 mg/kg (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.67–1.10, p = 0.117) and 10 mg/kg (0.74, 0.57–0.96, p = 0.011) resulted in a non-statistically significant improvement in OS versus chemotherapy; median OS was 13.4 (95% CI 11.0–16.4) and 14.7 (95% CI 11.3–19.5), respectively, versus 11.0 months (95% CI 8.9–13.8), with limited improvement after censoring for crossover. Two-year survival rates were 36% and 38%, versus 30%. Progression-free survival, objective response rate and duration of response improved with pembrolizumab versus chemotherapy, regardless of dose. Grade III–V treatment-related adverse events occurred in 24 (13.5%), 30 (16.8%) and 45 (26.3%) patients, respectively. ConclusionImprovement in OS with pembrolizumab was not statistically significant at either dose versus chemotherapy.

Characterization of potential predictive biomarkers of response to nivolumab in CheckMate 141 in patients with squamous cell carcinoma of the head and neck (SCCHN).

6050 Background: Nivolumab, an anti-programmed death-1 (PD-1) monoclonal antibody, demonstrated longer median overall survival (7.5 vs 5.1 months) and improved response (13.3% vs 5.8%) versus investigator choice chemotherapy (ICC) in patients with recurrent SCCHN after platinum failure in CheckMate 141 (NCT02105636), a randomized, open-label Phase 3 trial. We screened peripheral blood lymphocytes (PBL) to identify biomarkers which may predict response to nivolumab. Methods: Paired baseline (day 1) and on treatment (day 43) PBL samples (n = 36; 24 nivolumab; 12 ICC) were analyzed using multicolor flow cytometry and a non-competing anti-PD-1 antibody. Results were correlated with clinical outcome: responders (complete/partial response) and non-responders (stable or progressive disease). Results: Levels of CD8+ T cells at baseline and on treatment were higher in nivolumab responders compared to non-responders (23% vs 13%; P&lt; 0.05). Interestingly, PD-1+ CD8+ and PD-1+ CTLA-4+ CD8+ effector T cells (likely exhausted T cells) decreased about 2-fold following nivolumab in both responders and non-responders ( P&lt; 0.05), whereas, the decrease in CTLA-4+ CD8+ effector T cells following nivolumab was significant in responders only (8% vs 5%; P&lt; 0.05). Levels of PD-1+ TIM-3+ CD8+ effector cells decreased following nivolumab in non-responders only (11% vs 7%; P&lt; 0.05), a similar non-significant reduction was observed in responders. Levels of PD-1+ Tregs were lower in responders than non-responders at baseline (19% vs 33%; P&lt; 0.01), and following nivolumab (12% vs 20%; P&lt; 0.001). As in T-effector cell populations, PD-1+ Tregs decreased about 1.6-fold after nivolumab in both responders and non-responders ( P&lt; 0.01). Interestingly, baseline Ki67+ Treg levels were lower in non-responders (28% vs 17%; P&lt; 0.05). Conclusions: Response to nivolumab may be associated with higher levels of CD8+ T cells and CTLA-4+ CD8+ effector T cells, and lower PD-1+ CD8+ effector T cells and PD-1+ Tregs at baseline. Targeting both PD-1 and CTLA-4 axes is warranted in SCCHN to overcome suppressive signals in CD8+ effector T cells and in Treg cells expressing both checkpoint receptors. Clinical trial information: NCT02105636.

Phase 3, open-label, randomized study of first-line pembrolizumab (pembro) vs investigator-choice chemotherapy for mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal carcinoma (mCRC): KEYNOTE-177.

TPS3618 Background: About 5% of mCRCs are dMMR, leading to high levels of MSI. CRCs with MSI-H have abundant lymphocyte infiltrates and strong expression of immune checkpoints. In the phase 2 KEYNOTE-016 study, the anti-programmed death 1 (PD-1) antibody pembro provided an ORR of 40% in patients (pts) with progressive dMMR mCRC vs 0% in pts with MMR-proficient mCRC. KEYNOTE-177 (ClinicalTrials.gov, NCT02563002) is an international, randomized, open-label, phase 3 study designed to evaluate the efficacy and safety of pembro vs standard-of-care (SOC) chemotherapy in the first-line setting for dMMR or MSI-H mCRC. Methods: Key eligibility criteria include age ≥ 18 years, locally confirmed dMMR or MSI-H stage IV CRC, measurable disease per RECIST v1.1 by local site assessment, ECOG performance status 0-1, no active autoimmune disease or brain metastases, and no prior therapy for mCRC. Pts are to be randomized 1:1 to receive either pembro 200 mg Q3W or investigator’s choice of SOC chemotherapy, which must be chosen prior to randomization; options include mFOLFOX6 or FOLFIRI alone or in combination with bevacizumab or cetuximab. Treatment is to continue until disease progression, unacceptable toxicity, pt/investigator decision, or completion of 35 cycles (pembro only). Response is to be evaluated Q9W per RECIST v1.1 by central imaging vendor review and per RECIST adapted for immunotherapy response patterns. Pts in the SOC arm who have disease progression and meet crossover criteria may be eligible to receive pembro for up to 17 treatment cycles. Eligible pts may continue pembro beyond initial RECIST-defined progression. AEs are to be assessed throughout treatment and for 30 days thereafter (90 days for serious AEs) and graded per NCI CTCAE v4.0. Pts are to be followed for survival Q9W. Primary end point is PFS per RECIST v1.1 by central imaging vendor review. Secondary end points include ORR per RECIST v1.1 by central imaging vendor review, OS, and safety and tolerability. Other end points include DOR and HRQoL. Planned enrollment in KEYNOTE-177 is 270 pts across 21 countries. Clinical trial information: NCT02563002.

Avelumab, an anti-PD-L1 monoclonal antibody, shows activity in various tumour types

During the past 5 years, immune checkpoint inhibitors have revolutionised the management and treatment of cancer, because they have been associated with striking improvements in clinical outcomes in patients with some tumour types. For example, the use of checkpoint inhibitors has changed the natural history of melanoma with a pronounced increase in patients' survival. 1 Robert C Long GV Brady B et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015; 372: 320-330 Crossref PubMed Scopus (4060) Google Scholar , 2 Ribas A Puzanov I Dummer R et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015; 16: 908-918 Summary Full Text Full Text PDF PubMed Scopus (1230) Google Scholar These agents have also been tested in many other tumour types, such as renal cancer, urothelial cancer, and squamous cell cancer of the head and neck, with promising results and have subsequently gained approval from the regulatory authorities. In non-small-cell lung cancer (NSCLC), survival rates have improved in recent years, both as a result of advances in disease management—including the addition of new-generation agents to the therapeutic armamentarium—and supportive care. Indeed, the development of many active and better-tolerated drugs, such as bevacizumab, pemetrexed, nab-paclitaxel, and, more recently, nintedanib and ramucirumab, has increased the number of available treatment options for patients with NSCLC. Two anti-PD-1 monoclonal antibodies, nivolumab and pembrolizumab, have already been approved for the treatment of NSCLC in the second-line setting or beyond, 3 Borghaei H Paz-Ares L Horn L et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015; 373: 1627-1639 Crossref PubMed Scopus (6826) Google Scholar , 4 Brahmer J Reckamp KL Baas P et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015; 373: 123-135 Crossref PubMed Scopus (6294) Google Scholar , 5 Herbst RS Baas P Kim DW et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016; 387: 1540-1550 Summary Full Text Full Text PDF PubMed Scopus (4591) Google Scholar as has the anti-PD-L1 antibody atezolizumab. 6 Rittmeyer A Barlesi F Waterkamp D et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017; 389: 255-265 Summary Full Text Full Text PDF PubMed Scopus (3203) Google Scholar Additionally, on Oct 24, 2016, pemrbolizumab also gained approval for the first-line treatment of NSCLC in a small subgroup of patients with high expression (>50%) of PD-L1. 7 Reck M Rodriguez-Abreu D Robinson AG et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016; 375: 1823-1833 Crossref PubMed Scopus (6306) Google Scholar Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trialAvelumab has an acceptable toxicity profile up to 20 mg/kg and the maximum tolerated dose was not reached. Based on pharmacokinetics, target occupancy, and immunological analysis, we chose 10 mg/kg every 2 weeks as the dose for further development and phase 3 trials are ongoing. Full-Text PDF Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trialAvelumab showed an acceptable safety profile and antitumour activity in patients with progressive or treatment-resistant NSCLC, providing a rationale for further studies of avelumab in this disease setting. Full-Text PDF Correction to Lancet Oncol 2017; 18: 556–57Kotsakis A, Georgoulias V. Avelumab, an anti-PD-L1 monoclonal antibody, shows activity in various tumour types. Lancet Oncol 2017; 18: 556–57—In this Comment, the term ‘immune-related’ should have read ‘infusion-related’ in two phrases. The two affected sentences should have read as follows: “However, an important finding from these two studies was that the frequency of infusion-related reactions exceeded 20%; infusion-related reactions are uncommon with the other approved immunotherapeutic agents, with an estimated frequency of about 1–2%” and “Once again, ongoing phase 3 trials ( NCT02395172 , NCT02576574 ) might shed light on the frequency, significance, and severity of infusion-related adverse events and how best to manage them.” These corrections have been made to the online version as of July 26, 2017. Full-Text PDF

Characterization of potential predictive biomarkers of response to nivolumab in CheckMate-141 in patients with squamous cell carcinoma of the head and neck (SCCHN).

5 Background: Nivolumab, an anti-programmed death-1 (PD-1) monoclonal antibody, demonstrated longer median overall survival (7.5 vs. 5.1 months) and improved response (13.3% vs. 5.8%) versus investigator choice chemotherapy (ICC) in patients with recurrent SCCHN after platinum failure in CheckMate 141 (NCT02105636), a randomized, open-label Phase 3 trial. We screened peripheral blood lymphocytes (PBL) to identify biomarkers which may predict response to nivolumab. Methods: Paired baseline (day 1) and on treatment (day 43) PBL samples (n=36; 24 nivolumab; 12 ICC) were analyzed using multicolor flow cytometry and a non-competing anti-PD-1 antibody. Results were correlated with clinical outcome: responders (complete/partial response) and non-responders (stable or progressive disease). Results: Levels of CD8+ T cells at baseline and on treatment were higher in nivolumab responders compared to non-responders (23% vs. 13%; p&lt;0.05). Interestingly, PD-1+ CD8+ and PD-1+ CTLA-4+ CD8+ effector T cells (likely exhausted T cells) decreased about 2-fold following nivolumab in both responders and non-responders (p&lt;0.05), whereas, the decrease in CTLA-4+ CD8+ effector T cells following nivolumab was significant in responders only (8% vs. 5%; p&lt;0.05). Levels of PD-1+ TIM-3+ CD8+ effector cells decreased following nivolumab in non-responders only (11% vs. 7%; p&lt;0.05), a similar non-significant reduction was observed in responders. Levels of PD-1+Tregs were lower in responders than non-responders at baseline (19% vs. 33%; p&lt;0.01), and following nivolumab (12% vs. 20%; p&lt;0.001). As in T effector cell populations, PD-1+ Tregs decreased about 1.6-fold after nivolumab in both responders and non-responders (p&lt;0.01). Interestingly, baseline Ki67+ Treg levels were lower in non-responders (28% vs. 17%; p&lt;0.05). Conclusions: Response to nivolumab may be associated with higher levels of CD8+ T cells and CTLA-4+ CD8+ effector T cells, and lower PD-1+ CD8+ effector T cells and PD-1+ Tregs at baseline. Targeting both PD-1 and CTLA-4 axes is warranted in SCCHN to overcome suppressive signals in CD8+ effector T cells and in Treg cells expressing both checkpoint receptors. Clinical trial information: NCT02105636.