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Background: Checkpoint inhibitor therapy has demonstrated overall survival benefit in multiple tumor types. Tumor mutational burden (TMB) is a predictive biomarker for response to immunotherapies. This study evaluated the efficacy of nivolumab+ipilimumab in multiple tumor types based on TMB status evaluated using either tumor tissue (tTMB) or circulating tumor DNA in the blood (bTMB)., Patients and Methods: Patients with metastatic or unresectable solid tumors with high (≥10 mutations per megabase) tTMB (tTMB-H) and/or bTMB (bTMB-H) who were refractory to standard therapies were randomized 2:1 to receive nivolumab+ipilimumab or nivolumab monotherapy in an open-label, phase 2 study (CheckMate 848; NCT03668119). tTMB and bTMB were determined by the Foundation Medicine FoundationOne ® CDx test and bTMB Clinical Trial Assay, respectively. The dual primary endpoints were objective response rate (ORR) in patients with tTMB-H and/or bTMB-H tumors treated with nivolumab+ipilimumab., Results: In total, 201 patients refractory to standard therapies were randomized: 135 had tTMB-H and 125 had bTMB-H; 82 patients had dual tTMB-H/bTMB-H. In patients with tTMB-H, ORR was 38.6% (95% CI 28.4% to 49.6%) with nivolumab+ipilimumab and 29.8% (95% CI 17.3% to 44.9%) with nivolumab monotherapy. In patients with bTMB-H, ORR was 22.5% (95% CI 13.9% to 33.2%) with nivolumab+ipilimumab and 15.6% (95% CI 6.5% to 29.5%) with nivolumab monotherapy. Early and durable responses to treatment with nivolumab+ipilimumab were seen in patients with tTMB-H or bTMB-H. The safety profile of nivolumab+ipilimumab was manageable, with no new safety signals., Conclusions: Patients with metastatic or unresectable solid tumors with TMB-H, as determined by tissue biopsy or by blood sample when tissue biopsy is unavailable, who have no other treatment options, may benefit from nivolumab+ipilimumab., Trial Registration Number: NCT03668119., Competing Interests: Competing interests: AG has received consulting fees from AstraZeneca, Novartis, MSD, and Gilead; has a patent interest with Mylan; has participated in a data safety monitoring board or advisory board for Novartis, AstraZeneca, MSD, and Gilead. AL has received grants from AstraZeneca and Sanofi; consulting fees from Seattle Genetics; honoraria/reimbursement and advisory board fees from AstraZeneca; advisory board fees or continuing medical education from Ability Pharma, Biocad, Clovis Oncology, GSK, Medscape, Merck Serono, MSD, TouchCongress, and Zentalis; support for attending meetings and/or travel from AstraZeneca, Clovis Oncology, GSK, and Roche; and participation on a data safety monitoring board or advisory board for ARIEL4 and TROPHIMMUNE. DSPT has received personal fees for advisory board membership from AstraZeneca, Bayer, Boehringer Ingelheim, Eisai, Genmab, GSK, MSD, and Roche; personal fees as an invited speaker from AstraZeneca, Eisai, GSK, Merck Serono, MSD, Roche, and Takeda; ownership of stocks/shares of Asian Microbiome Library (AMiLi); institutional research grants from AstraZeneca, Bayer, Karyopharm Therapeutics, and Roche; institutional funding as coordinating PI from AstraZeneca, MSD, Eisai, Roche and Bergen Bio; institutional funding as local PI from Roche, GSK, Sutro Pharma, Bayer, Byondis B.V. and Zeria Pharmaceutical; a previous non-renumerated role as Chair of the Asia Pacific Gynecologic Oncology Trials Group (APGOT); a previous non-renumerated role as the Society President of the Gynecologic Cancer Group Singapore; non-renumerated membership of the Board of Directors of the GCIG; research funding from the Pangestu Family Foundation Gynaecological Cancer Research Fund; and product samples from AstraZeneca, Eisai, and MSD (non-financial interest). IL has received consulting fees from Boehringer Ingelheim; honoraria from Agenus, Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Celon, Cullinan Oncology, Jacobio, Janssen, Loxo, Macrogenics, Menarini, MSD, Pfizer, Rhizen, Roche, Sanofi, and Takeda; institutional research funding from Agenus and Roche; and has been reimbursed for travel, accommodations, or expenses from Bristol Myers Squibb. J-PD has participated in advisory boards for Bristol Myers Squibb, Pierre Fabre, and Roche; has been an invited speaker for Merck Serono; has received research grants from Amgen, AstraZeneca, Bristol Myers Squibb, Genentech, MSD, and Transgene. JV has participated in a data safety monitoring board for IO Biotech; has stock options in Genentech-Roche. MB has received consulting fees from AstraZeneca, Bristol Myers Squibb, MSD Oncology, Novartis, and Roche/Genentech; has received fees for participating in speakers’ bureaus for Astra Zeneca, Bristol Myers Squibb, MSD Oncology, and Roche/Genentech. MM has received payment for a speaker for Alfasigma, Amgen, Astex, Bristol Myers Squibb, Eli Lilly, GSK, Incyte, IOnctura, Merck Serono, MSD, Novartis, Pfizer, Pierre Fabre, Sanofi, and SciClone; has received support for attending meetings and/or travel from Alfasigma, Amgen, Astex, Bristol Myers Squibb, Eli Lilly, GSK, Incyte, IOnctura, Merck Serono, MSD, Novartis, Pfizer, Pierre Fabre, Sanofi, and SciClone; has participated on a data safety monitoring board or advisory board for Alfasigma, Amgen, Astex, Bristol Myers Squibb, Eli Lilly, GSK, Incyte, IOnctura, Merck Serono, MSD, Novartis, Pfizer, Pierre Fabre, Sanofi, and SciClone; has stock options in EpiGen and Theravance. MS has received research grants from AbbVie, Amgen, Astellas, AstraZeneca, Bayer, BeiGene, Clovis, Daiichi Sankyo, EISAI, Eli Lilly, Five Prime, Gilead, GSK, Mylan, Novartis, Pfizer, Pharma Mar, Samsung, and Takeda. NS provided consultation or attended advisory boards for Boehringer Ingelheim, Ellipses Pharma, GlaxoSmithKline, Incyte, and Luszana, with all payments to the Netherlands Cancer Institute; has received institutional research grants from AbbVie, Actuate Therapeutics, Amgen, Array, Ascendis Pharma, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, BridgeBio, Bristol Myers Squibb, Cantargia, CellCentric, Cogent Biosciences, Cresecendo Biologics, Cytovation, Deciphera, Dragonfly, Eli Lilly, Exelixis, Genentech, GSK, IDRx, Immunocore, Incyte, InteRNA, Janssen, Kinnate Biopharma, Kling Biotherapeutics, Lixte, Luszana, Merck, MSD, Merus, Molecular Partners, Navire Pharma, Novartis, Numab Therapeutics, Pfizer, Relay Pharmaceuticals, Revolution Medicin, Roche, Sanofi, Seattle Genetics, Taiho, and Takeda. PAA has received research grants from Bristol Myers Squibb, Pfizer, Roche/Genentech, and Sanofi; has received consulting fees from Bayer, Bio-Al Health, Bristol Myers Squibb, Italfarmaco, Lunaphore, Medicenna, Merck Serono, MSD, Nektar, Novartis, Pfizer, Philogen, Pierre-Fabre, Replimune, Roche-Genentech, Sandoz, Sanofi, Sun Pharma, and ValoTx; has received support for attending meetings and/or travel from Bio-AI-Health, MSD, Pfizer, and Replimune; has participated on a data safety monitoring board or advisory board for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Erasca, iTeos, MSD, Nouscom, Novartis, Oncosec, Regeneron, Roche-Genentech, and Seagen. T-EC has received research grants from Amgen, AstraZeneca, Merck Serono, MSD, Pfizer, Roche, and Takeda; consulting fees from Amgen, AstraZeneca, Bristol Myers Squibb, Merck Serono, MSD, Pfizer, Servier, and Takeda; payment as a speaker for Amgen, AstraZeneca, Bristol Myers Squibb, Merck Serono, MSD, Pfizer, Servier, and Takeda; support for attending meetings and/or travel from Amgen, AstraZeneca, Bristol Myers Squibb, Merck Serono, MSD, Pfizer, Servier, and Takeda; has participated on a data safety monitoring board or advisory board for Amgen, AstraZeneca, Bristol Myers Squibb, Merck Serono, MSD, Pfizer, Servier, and Takeda. MP, PD and QD are employed by Bristol Myers Squibb. GK, JB, MP, MT, NH and SVV are employed by and hold stock options in Bristol Myers Squibb., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Docetaxel and irinotecan chemotherapy have shown good efficacy in the treatment of advanced oesophago-gastric cancer. This randomised phase II study evaluated the efficacy and toxicity profile of two non-platinum docetaxel-based doublet regimens in advanced oesophago-gastric cancer., Methods: Chemotherapy-naïve patients with advanced oesophago-gastric cancer were randomised to receive either 3-weekly DI (docetaxel 60 mg m(-2) plus irinotecan 250 mg m(-2) (Day 1)) or 3-weekly DF (docetaxel 85 mg m(-2) (Day 1) followed by 5-fluorouracil 750 mg m(-2) per day as a continuous infusion (Days 1-5))., Results: A total of 85 patients received DI (n=42) or DF (n=43). The primary endpoint was overall response rate (ORR). The ORR and time to progression (TTP) in the evaluable population (n=65) were 37.5% (DI) vs 33.3% (DF), and 4.2 months vs 4.4 months, respectively. In the intent-to-treat population, the observed ORR, TTP and median overall survival were similar between the two groups. Grade 3-4 neutropenia, febrile neutropenia and diarrhoea were more frequent in the DI arm as compared with the DF arm (83.3% vs 69.8%, 40.5% vs 18.6%, and 42.9% vs 16.3%, respectively)., Conclusion: Both docetaxel-based doublet regimens show comparable efficacy; however, the DF regimen was associated with a better toxicity profile and is an alternative treatment option for patients in whom platinum-based regimens are unsuitable., (© 2012 Cancer Research UK)

Platinum/taxane combinations are widely used in patients with carcinoma of unknown primary (CUP), yielding response rates of 30% and median overall survival of 9-11 months in selected patients. Yet these combinations have not been subject to a randomised trial to overcome selection bias, a major problem in CUP. We randomised 92 patients to either paclitaxel/carboplatin (arm A) or the non-platinum non-taxane regimen gemcitabine/vinorelbine (arm B). The primary endpoint was rate of practicability as defined: application of >or=2 cycles of therapy (1) with a maximal delay of 1 week (2) and survival of >or=8 months (3). Practicability was shown in 52.4% (95% CI 36-68%) in arm A and in 42.2% (95% CI 28-58%) in arm B, respectively. The median overall survival, 1-year survival -rate and response rate of patients treated in arm A was 11.0 months, 38, and 23.8%, arm B 7.0 months, 29, and 20%. In conclusion, the paclitaxel/carboplatin regimen showed clinically meaningful activity in this randomised trial (Clinical trial registration number 219, 'Deutsches KrebsStudienRegister', German Cancer Society.)

Purpose: The tumor-activated fluoropyrimidine capecitabine achieves response rates superior to those of bolus 5-fluorouracil/leucovorin (5-FU/LV) as first-line treatment for metastatic colorectal cancer (CRC), with favorable safety and fewer hospitalizations. Capecitabine is also at least as effective as bolus 5-FU/LV in the adjuvant setting, again with a favorable safety profile. Improved outcomes with capecitabine versus bolus 5-FU/LV in the adjuvant setting have been shown in overall trial populations and in patients aged >or= 70 years. Capecitabine/oxaliplatin (XelOx) is a safe and active combination for the first-line treatment of metastatic CRC., Patients and Methods: This post hoc analysis of a large phase II trial compared data from older and younger patients treated with first-line XelOx: oxaliplatin 130 mg/m(2) intravenously on day 1 followed by oral capecitabine 1,000 mg/m(2) twice daily for 14 days every 3 weeks., Results: The median age of the overall population (N = 96) was 64 years (range, 34-79 years), including 52 younger patients (< 65 years of age) and 44 older patients (>or= 65 years of age). Both age groups received a median of 8 cycles (range, 1-26 cycles) of XelOx. The XelOx regimen had similar high activity in both groups, with response rates of 58% (95% CI, 43%-71%) and 52% (95% CI, 37%-68%) in younger and older patients, respectively. In addition, time to disease progression and overall survival were similar in both groups (P > 0.5 for both outcomes). The XelOx regimen also had a favorable safety profile, with no clinically relevant differences between older and younger patients. The overall incidence of adverse events (including grade 3/4), dose reductions, and withdrawals because of adverse events were similar in both groups., Conclusion: In the context of an aging population, XelOx provides a highly effective and tolerable first-line treatment for patients with metastatic CRC.

Purpose: To determine whether addition of the farnesyltransferase inhibitor tipifarnib (Zarnestra, R115777; Johnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium) to standard gemcitabine therapy improves overall survival in advanced pancreatic cancer., Patients and Methods: This randomized, double-blind, placebo-controlled study compared gemcitabine + tipifarnib versus gemcitabine + placebo in patients with advanced pancreatic adenocarcinoma previously untreated with systemic therapy. Tipifarnib was given at 200 mg bid orally continuously; gemcitabine was given at 1,000 mg/m(2) intravenously weekly x 7 for 8 weeks, then weekly x 3 every 4 weeks. The primary end point was overall survival; secondary end points included 6-month and 1-year survival rates, progression-free survival, response rate, safety, and quality of life., Results: Six hundred eighty-eight patients were enrolled. Baseline characteristics were well balanced between the two treatment arms. No statistically significant differences in survival parameters were observed. The median overall survival for the experimental arm was 193 v 182 days for the control arm (P =.75); 6-month and 1-year survival rates were 53% and 27% v 49% and 24% for the control arm, respectively; median progression-free survival was 112 v 109 days for the control arm. Ten drug-related deaths were reported for the experimental arm and seven for the control arm. Neutropenia and thrombocytopenia grade > or = 3 were observed in 40% and 15% in the experimental arm versus 30% and 12% in the control arm. Incidences of nonhematologic adverse events were similar in two groups., Conclusion: The combination of gemcitabine and tipifarnib has an acceptable toxicity profile but does not prolong overall survival in advanced pancreatic cancer compared with single-agent gemcitabine.

The aim of this study was to determine the patient's preference for oral UFT/leucovorin (LV) or intravenous (i.v.) 5-fluorouracil (5-FU)/LV chemotherapy in metastatic colorectal cancer and to compare 5-FU exposure with these two treatment options. A total of 37 previously untreated patients with advanced colorectal cancer were randomised to start treatment with either oral UFT 300 mg/m2/day plus oral LV 90 mg/day for 28 days every 5 weeks or i.v. 5-FU 425 mg/m2/day plus LV 20 mg/m2/day for 5 days every 4 weeks. For the second treatment cycle, patients were crossed-over to the alternative treatment regimen. Prior to the first and after the second therapy cycle, patients were required to complete a therapy preference questionnaire (TPQ). The pharmacokinetics of 5-FU were determined by taking blood samples on days 8, 15 or 22 and 28 for UFT and on days 1 and 5 for i.v. 5-FU. 36 patients were eligible. 84% of the patients preferred oral UFT over i.v. 5-FU. After having experienced both treatment modalities, patients indicated taking the medication at home, less stomatitis and diarrhoea, and pill over injection as the most important reasons for their preference. The area under the plasma concentration curve (AUC) for 5-FU after UFT administration was 113 microM x min on day 8, 114 on day 15 and 98 on day 28; the peak levels (Cmax) were 1.2, 1.3 and 1.0 microM, respectively. The AUC for the 5-FU/LV courses was 3083 microM x min for day 1 and 3809 for day 5 (P=0.002). The Cmax was 170.1 and 196.2 microM (P=0.06) and the clearance 2.6 and 1.9 l/min, respectively (P=0.002). Patients with metastatic colorectal cancer clearly preferred oral over i.v. chemotherapy treatment. This choice was most importantly influenced by convenience and toxicity considerations. Although i.v. bolus 5-FU leads to higher peak 5-FU concentrations and AUC values compared with oral UFT, this pharmacokinetic advantage of i.v. 5-FU seems to translate mainly into higher toxicity as seen in large randomised studies comparing oral UFT/LV with i.v. 5-FU/LV. Oral UFT/LV compares favourably with i.v. 5-FU/LV in terms of toxicity and patient's preference and leads to prolonged 5-FU exposure, which is comparable to continuous i.v. 5-FU treatment.