Durvalumab or placebo plus gemcitabine and cisplatin in participants with advanced biliary tract cancer (TOPAZ-1): updated overall survival from a randomised phase 3 study.

BACKGROUND: In the preplanned interim analysis of the TOPAZ-1 study, durvalumab plus gemcitabine-cisplatin significantly improved overall survival versus placebo plus gemcitabine-cisplatin in participants with advanced biliary tract cancer. We aimed to report updated overall survival and safety data from TOPAZ-1 with additional follow-up and data maturity beyond the interim analysis. METHODS: TOPAZ-1 was a phase 3, randomised, double-masked, placebo-controlled, global study done at 105 sites in 17 countries. Participants aged 18 years or older with unresectable, locally advanced, or metastatic biliary tract cancer were randomly assigned (1:1) to durvalumab plus gemcitabine-cisplatin or placebo plus gemcitabine-cisplatin using a computer-generated randomisation scheme, stratified by disease status and primary tumour location. Participants received durvalumab (1500 mg) or placebo on day 1 of each cycle every 3 weeks for up to eight cycles, plus gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) intravenously on days 1 and 8 of each cycle every 3 weeks for up to eight cycles, followed by durvalumab (1500 mg) or placebo monotherapy every 4 weeks until disease progression or other discontinuation criteria were met. Investigators and participants were masked to study treatment. The primary endpoint was overall survival. TOPAZ-1 met its primary endpoint at the preplanned interim analysis, and the study is active but no longer recruiting participants. Updated overall survival and safety data from TOPAZ-1, with additional follow-up (data cutoff Feb 25, 2022) and data maturity beyond the interim analysis, are reported here. Efficacy was assessed in the full analysis set (all randomly assigned participants). Safety was assessed in the safety analysis set (all participants who received at least one dose of study treatment). The TOPAZ-1 study is registered with ClinicalTrials.gov, NCT03875235. FINDINGS: From April 16, 2019, to Dec 11, 2020, 914 participants were enrolled, 685 of whom were randomly assigned (341 to the durvalumab plus gemcitabine-cisplatin group and 344 to the placebo plus gemcitabine-cisplatin group). 345 (50%) participants were male and 340 (50%) were female. Median follow-up at the updated data cutoff was 23·4 months (95% CI 20·6-25·2) in the durvalumab plus gemcitabine-cisplatin group and 22·4 months (21·4-23·8) in the placebo plus gemcitabine-cisplatin group. At the updated data cutoff, 248 (73%) participants in the durvalumab plus gemcitabine-cisplatin group and 279 (81%) participants in the placebo plus gemcitabine-cisplatin group had died (median overall survival 12·9 months [95% CI 11·6-14·1] vs 11·3 months [10·1-12·5]; hazard ratio 0·76 [95% CI 0·64-0·91]). Kaplan-Meier-estimated 24-month overall survival rates were 23·6% (95% CI 18·7-28·9) in the durvalumab plus gemcitabine-cisplatin group and 11·5% (7·6-16·2) in the placebo plus gemcitabine-cisplatin group. Maximum grade 3 or 4 adverse events occurred in 250 (74%) of 338 participants in the durvalumab plus gemcitabine-cisplatin group and 257 (75%) of 342 in the placebo plus gemcitabine-cisplatin group. The most common maximum grade 3 or 4 treatment-related adverse events were decreased neutrophil count (70 [21%] vs 86 [25%]), anaemia (64 [19%] vs 64 [19%]), and neutropenia (63 [19%] vs 68 [20%]). INTERPRETATION: Durvalumab plus gemcitabine-cisplatin showed robust and sustained overall survival benefit with no new safety signals. Findings continue to support the regimen as a standard of care for people with untreated, advanced biliary tract cancer. FUNDING: AstraZeneca.

Durvalumab versus placebo with chemoradiotherapy for locally advanced cervical cancer (CALLA): a randomised, double-blind, phase 3 trial.

BACKGROUND: Concurrent chemoradiotherapy has been the standard of care for locally advanced cervical cancer for over 20 years; however, 30-40% of treated patients have recurrence or progression within 5 years. Immune checkpoint inhibition has improved outcomes for patients with PD-L1 positive metastatic or recurrent cervical cancer. We assessed the benefit of adding durvalumab, a PD-L1 antibody, with and following chemoradiotherapy for locally advanced cervical cancer. METHODS: The CALLA randomised, double-blind, phase 3 trial included 105 hospitals across 15 countries. Patients aged at least 18 years with previously untreated locally advanced cervical cancer (adenocarcinoma, squamous, or adenosquamous; International Federation of Gynaecology and Obstetrics [FIGO] 2009 stage IB2-IIB lymph node positive, stage ≥III any lymph node status) and WHO or Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) through an interactive web response system using a permuted block size of 4 to receive durvalumab (1500 mg intravenously once every 4 weeks) or placebo with and following chemoradiotherapy, for up to 24 cycles. Chemoradiotherapy included 45 Gy external beam radiotherapy at 5 fractions per week concurrent with intravenous cisplatin (40 mg/m2) or carboplatin (area under the concentration-time curve 2) once weekly for 5 weeks, followed by image-guided brachytherapy (high-dose rate, 27·5-30 Gy or low-dose/pulse-dose rate, 35-40 Gy). Randomisation was stratified by disease stage status (FIGO stage and node status) and geographical region. Chemoradiotherapy quality was continuously reviewed. The primary endpoint was progression-free survival, assessed by the investigator using Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03830866. FINDINGS: Between Feb 15, 2019, and Dec 10, 2020, 770 women were randomly assigned (385 to durvalumab and 385 to placebo; median age 49 years [IQR 41-57]). Median follow-up was 18·5 months (IQR 13·2-21·5) in the durvalumab group and 18·4 months (13·2-23·7) in the placebo group. At data cutoff, median progression-free survival had not been reached (95% CI not reached-not reached) for either group (HR 0·84; 95% CI 0·65-1·08; p=0·17); 12-month progression-free survival was 76·0% (71·3-80·0) with durvalumab and 73·3% (68·4-77·5) with placebo. The most frequently reported grade 3-4 adverse events in both groups were anaemia (76 [20%] of 385 in the durvalumab group vs 56 [15%] of 384 in the placebo group) and decreased white blood cells (39 [10%] vs 49 [13%]). Serious adverse events occurred for 106 (28%) patients who received durvalumab and 89 (23%) patients who received placebo. There were five treatment-related deaths in the durvalumab group (one case each of urinary tract infection, blood loss anaemia, and pulmonary embolism related to chemoradiotherapy only; one case of endocrine disorder related to durvalumab only; and one case of sepsis related to both durvalumab and chemoradiotherapy). There was one treatment-related death in the placebo group (pneumonia related to chemoradiotherapy). INTERPRETATION: Durvalumab concurrent with chemoradiotherapy was well tolerated in participants with locally advanced cervical cancer, however it did not significantly improve progression-free survival in a biomarker unselected, all-comers population. Concurrent durvalumab plus chemoradiotherapy warrants further exploration in patients with high tumoral PD-L1 expression. Rigorous monitoring ensured high chemoradiotherapy compliance with advanced technology and allowed patients to receive optimal care. FUNDING: AstraZeneca.

Pembrolizumab Plus Olaparib for Patients With Previously Treated and Biomarker-Unselected Metastatic Castration-Resistant Prostate Cancer: The Randomized, Open-Label, Phase III KEYLYNK-010 Trial.

PURPOSE: There is an unmet need for therapeutic options that prolong survival for patients with heavily pretreated, metastatic castration-resistant prostate cancer (mCRPC). The phase III, open-label KEYLYNK-010 study evaluated pembrolizumab plus olaparib versus a next-generation hormonal agent (NHA) for biomarker-unselected, previously treated mCRPC. METHODS: Eligible participants had mCRPC that progressed on or after abiraterone or enzalutamide (but not both) and docetaxel. Participants were randomly assigned (2:1) to pembrolizumab plus olaparib or NHA (abiraterone or enzalutamide). The dual primary end points were radiographic progression-free survival (rPFS) by blinded independent central review per Prostate Cancer Working Group-modified RECIST 1.1 and overall survival (OS). Time to first subsequent therapy (TFST) was a key secondary end point. Safety and objective response rate (ORR) were secondary end points. RESULTS: Between May 30, 2019, and July 16, 2021, 529 participants were randomly assigned to pembrolizumab plus olaparib and 264 to NHA. At final rPFS analysis, median rPFS was 4.4 months (95% CI, 4.2 to 6.0) with pembrolizumab plus olaparib and 4.2 months (95% CI, 4.0 to 6.1) with NHA (hazard ratio [HR], 1.02 [95% CI, 0.82 to 1.25]; P = .55). At final OS analysis, median OS was 15.8 months (95% CI, 14.6 to 17.0) and 14.6 months (95% CI, 12.6 to 17.3), respectively (HR, 0.94 [95% CI, 0.77 to 1.14]; P = .26). At final TFST analysis, median TFST was 7.2 months (95% CI, 6.7 to 8.1) versus 5.7 months (95% CI, 5.0 to 7.1), respectively (HR, 0.86 [95% CI, 0.71 to 1.03]). ORR was higher with pembrolizumab plus olaparib versus NHA (16.8% v 5.9%). Grade ≥3 treatment-related adverse events occurred in 34.6% and 9.0% of participants, respectively. CONCLUSION: Pembrolizumab plus olaparib did not significantly improve rPFS or OS versus NHA in participants with biomarker-unselected, heavily pretreated mCRPC. The study was stopped for futility. No new safety signals occurred.

Dosimetric impact of interfraction catheter movement and organ motion on MRI/CT guided HDR interstitial brachytherapy for gynecologic cancer.

PURPOSE: To determine the dosimetric impact of catheter movement for MRI/CT image guided high dose rate (HDR) interstitial brachytherapy (ISBT) for gynecologic cancers. MATERIALS AND METHODS: Ten patients were treated with HDR ISBT. The CTV and organs at risk were contoured using a postimplant MRI and CT. 5 fractions were delivered twice daily on 3 consecutive days. The first fraction was delivered on day 1 (d1), fraction 2-3 on d2 and fraction 4-5 on d3. MRI/CT was acquired prior to the second and fourth fractions. Four scenarios were modeled. (1) The d1 plan was applied to the d2 and d3 CT, using the updated catheter positions. (2) Replanning was performed for d2 and d3. (3) We applied the dwell positions/times from the d2 replan over the d3 CT and compared with a d3 CT replan. (4) Based on daily MRI, target volumes were recontoured and replanned. Dosimetry was analyzed for each plan and compared to the d1 dose distribution. RESULTS: (1) When using the d1 plan on the d2 and d3 CT with the updated catheter positions, the mean CTV D90 was reduced from 93.4% on d1 to 89.3% (p=0.08) on d2 and to 87.7% (p=0.005) on d3. (2) Replanning on d2 and d3 compensated for catheter movement, mean CTV D90 of 95.4% on d2 and 94.6% (p=0.36) on d3. (3) When compared to the replan of d2 applied on the d3 CT vs the d3 replan, there was no significant difference in coverage, mean CTV D90 of 90.9% (p=0.09). (4) Reoptimization based on daily MRI, significantly improved the CTV coverage for each day. The mean D2cc for the rectum was significantly higher with model 1 vs model 3 59.1±4.7 vs 60.9±4.8 (p=0.04) Gy EQD2. There were no significant differences in D2cc of bladder and sigmoid between models. CONCLUSIONS: Interfraction dosimetric changes significantly decreased the CTV coverage of the third day. Rather than replanning on each day, replanning on the day 2 CT before the second or third fraction would give an optimal solution that would compensate for interfraction catheter displacement.