Phase I and Randomized Phase II Study of Ruxolitinib With Frontline Neoadjuvant Therapy in Advanced Ovarian Cancer: An NRG Oncology Group Study.

Landen CN ，Buckanovich RJ ，Sill MW ，Mannel RS ，Walker JL ，DiSilvestro PA ，Mathews CA ，Mutch DG ，Hernandez ML ，Martin LP ，Bishop E ，Gill SE ，Gordinier ME ，Burger RA ，Aghajanian C ，Liu JF ，Moore KN ，Bookman MA ... -  《-》

Objective responses to first-line neoadjuvant carboplatin-paclitaxel regimens for ovarian, fallopian tube, or primary peritoneal carcinoma (ICON8): post-hoc exploratory analysis of a randomised, phase 3 trial.

Platinum-based neoadjuvant chemotherapy followed by delayed primary surgery (DPS) is an established strategy for women with newly diagnosed, advanced-stage epithelial ovarian cancer. Although this therapeutic approach has been validated in randomised, phase 3 trials, evaluation of response to neoadjuvant chemotherapy using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST), and cancer antigen 125 (CA125) has not been reported. We describe RECIST and Gynecologic Cancer InterGroup (GCIG) CA125 responses in patients receiving platinum-based neoadjuvant chemotherapy followed by DPS in the ICON8 trial. ICON8 was an international, multicentre, randomised, phase 3 trial done across 117 hospitals in the UK, Australia, New Zealand, Mexico, South Korea, and Ireland. The trial included women aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-2, life expectancy of more than 12 weeks, and newly diagnosed International Federation of Gynecology and Obstetrics (FIGO; 1988) stage IC-IIA high-grade serous, clear cell, or any poorly differentiated or grade 3 histological subtype, or any FIGO (1988) stage IIB-IV epithelial cancer of the ovary, fallopian tube, or primary peritoneum. Patients were randomly assigned (1:1:1) to receive intravenous carboplatin (area under the curve [AUC]5 or AUC6) and intravenous paclitaxel (175 mg/m2 by body surface area) on day 1 of every 21-day cycle (control group; group 1); intravenous carboplatin (AUC5 or AUC6) on day 1 and intravenous dose-fractionated paclitaxel (80 mg/m2 by body surface area) on days 1, 8, and 15 of every 21-day cycle (group 2); or intravenous dose-fractionated carboplatin (AUC2) and intravenous dose-fractionated paclitaxel (80 mg/m2 by body surface area) on days 1, 8, and 15 of every 21-day cycle (group 3). The maximum number of cycles of chemotherapy permitted was six. Randomisation was done with a minimisation method, and patients were stratified according to GCIG group, disease stage, and timing and outcome of cytoreductive surgery. Patients and clinicians were not masked to group allocation. The scheduling of surgery and use of neoadjuvant chemotherapy were determined by local multidisciplinary case review. In this post-hoc exploratory analysis of ICON8, progression-free survival was analysed using the landmark method and defined as the time interval between the date of pre-surgical planning radiological tumour assessment to the date of investigator-assessed clinical or radiological progression or death, whichever occurred first. This definition is different from the intention-to-treat primary progression-free survival analysis of ICON8, which defined progression-free survival as the time from randomisation to the date of first clinical or radiological progression or death, whichever occurred first. We also compared the extent of surgical cytoreduction with RECIST and GCIG CA125 responses. This post-hoc exploratory analysis includes only women recruited to ICON8 who were planned for neoadjuvant chemotherapy followed by DPS and had RECIST and/or GCIG CA125-evaluable disease. ICON8 is closed for enrolment and follow-up, and registered with ClinicalTrials.gov, NCT01654146. Between June 6, 2011, and Nov 28, 2014, 1566 women were enrolled in ICON8, of whom 779 (50%) were planned for neoadjuvant chemotherapy followed by DPS. Median follow-up was 29·5 months (IQR 15·6-54·3) for the neoadjuvant chemotherapy followed by DPS population. Of 564 women who had RECIST-evaluable disease at trial entry, 348 (62%) had a complete or partial response. Of 727 women who were evaluable by GCIG CA125 criteria at the time of diagnosis, 610 (84%) had a CA125 response. Median progression-free survival was 14·4 months (95% CI 9·2-28·0; 297 events) for patients with a RECIST complete or partial response and 13·3 months (8·1-20·1; 171 events) for those with RECIST stable disease. Median progression-free survival for women with a GCIG CA125 response was 13·8 months (95% CI 8·8-23·4; 544 events) and 9·7 months (5·8-14·5; 111 events) for those without a GCIG CA125 response. Complete cytoreduction (R0) was achieved in 187 (56%) of 335 women with a RECIST complete or partial response and 73 (42%) of 172 women with RECIST stable disease. Complete cytoreduction was achieved in 290 (50%) of 576 women with a GCIG CA125 response and 30 (30%) of 101 women without a GCIG CA125 response. The RECIST-defined radiological response rate was lower than that frequently quoted to patients in the clinic. RECIST and GCIG CA125 responses to neoadjuvant chemotherapy for epithelial ovarian cancer should not be used as individual predictive markers to stratify patients who are likely to benefit from DPS, but instead used in conjunction with the patient's clinical capacity to undergo cytoreductive surgery. A patient should not be denied surgery based solely on the lack of a RECIST or GCIG CA125 response. Cancer Research UK, UK Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, and Cancer Australia.

Morgan RD ，McNeish IA ，Cook AD ，James EC ，Lord R ，Dark G ，Glasspool RM ，Krell J ，Parkinson C ，Poole CJ ，Hall M ，Gallardo-Rincón D ，Lockley M ，Essapen S ，Summers J ，Anand A ，Zachariah A ，Williams S ，Jones R ，Scatchard K ，Walther A ，Kim JW ，Sundar S ，Jayson GC ，Ledermann JA ，Clamp AR ... -  《-》

Impact of residual disease as a prognostic factor for survival in women with advanced epithelial ovarian cancer after primary surgery.

Ovarian cancer is the seventh most common cancer among women and a leading cause of death from gynaecological malignancies. Epithelial ovarian cancer is the most common type, accounting for around 90% of all ovarian cancers. This specific type of ovarian cancer starts in the surface layer covering the ovary or lining of the fallopian tube. Surgery is performed either before chemotherapy (upfront or primary debulking surgery (PDS)) or in the middle of a course of treatment with chemotherapy (neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS)), with the aim of removing all visible tumour and achieving no macroscopic residual disease (NMRD). The aim of this review is to investigate the prognostic impact of size of residual disease nodules (RD) in women who received upfront or interval cytoreductive surgery for advanced (stage III and IV) epithelial ovarian cancer (EOC). To assess the prognostic impact of residual disease after primary surgery on survival outcomes for advanced (stage III and IV) epithelial ovarian cancer. In separate analyses, primary surgery included both upfront primary debulking surgery (PDS) followed by adjuvant chemotherapy and neoadjuvant chemotherapy followed by interval debulking surgery (IDS). Each residual disease threshold is considered as a separate prognostic factor. We searched CENTRAL (2021, Issue 8), MEDLINE via Ovid (to 30 August 2021) and Embase via Ovid (to 30 August 2021). We included survival data from studies of at least 100 women with advanced EOC after primary surgery. Residual disease was assessed as a prognostic factor in multivariate prognostic models. We excluded studies that reported fewer than 100 women, women with concurrent malignancies or studies that only reported unadjusted results. Women were included into two distinct groups: those who received PDS followed by platinum-based chemotherapy and those who received IDS, analysed separately. We included studies that reported all RD thresholds after surgery, but the main thresholds of interest were microscopic RD (labelled NMRD), RD 0.1 cm to 1 cm (small-volume residual disease (SVRD)) and RD > 1 cm (large-volume residual disease (LVRD)). Two review authors independently abstracted data and assessed risk of bias. Where possible, we synthesised the data in meta-analysis. To assess the adequacy of adjustment factors used in multivariate Cox models, we used the 'adjustment for other prognostic factors' and 'statistical analysis and reporting' domains of the quality in prognosis studies (QUIPS) tool. We also made judgements about the certainty of the evidence for each outcome in the main comparisons, using GRADE. We examined differences between FIGO stages III and IV for different thresholds of RD after primary surgery. We considered factors such as age, grade, length of follow-up, type and experience of surgeon, and type of surgery in the interpretation of any heterogeneity. We also performed sensitivity analyses that distinguished between studies that included NMRD in RD categories of < 1 cm and those that did not. This was applicable to comparisons involving RD < 1 cm with the exception of RD < 1 cm versus NMRD. We evaluated women undergoing PDS and IDS in separate analyses. We found 46 studies reporting multivariate prognostic analyses, including RD as a prognostic factor, which met our inclusion criteria: 22,376 women who underwent PDS and 3697 who underwent IDS, all with varying levels of RD. While we identified a range of different RD thresholds, we mainly report on comparisons that are the focus of a key area of clinical uncertainty (involving NMRD, SVRD and LVRD). The comparison involving any visible disease (RD > 0 cm) and NMRD was also important. SVRD versus NMRD in a PDS setting In PDS studies, most showed an increased risk of death in all RD groups when those with macroscopic RD (MRD) were compared to NMRD. Women who had SVRD after PDS had more than twice the risk of death compared to women with NMRD (hazard ratio (HR) 2.03, 95% confidence interval (CI) 1.80 to 2.29; I2 = 50%; 17 studies; 9404 participants; moderate-certainty). The analysis of progression-free survival found that women who had SVRD after PDS had nearly twice the risk of death compared to women with NMRD (HR 1.88, 95% CI 1.63 to 2.16; I2 = 63%; 10 studies; 6596 participants; moderate-certainty). LVRD versus SVRD in a PDS setting When we compared LVRD versus SVRD following surgery, the estimates were attenuated compared to NMRD comparisons. All analyses showed an overall survival benefit in women who had RD < 1 cm after surgery (HR 1.22, 95% CI 1.13 to 1.32; I2 = 0%; 5 studies; 6000 participants; moderate-certainty). The results were robust to analyses of progression-free survival. SVRD and LVRD versus NMRD in an IDS setting The one study that defined the categories as NMRD, SVRD and LVRD showed that women who had SVRD and LVRD after IDS had more than twice the risk of death compared to women who had NMRD (HR 2.09, 95% CI 1.20 to 3.66; 310 participants; I2 = 56%, and HR 2.23, 95% CI 1.49 to 3.34; 343 participants; I2 = 35%; very low-certainty, for SVRD versus NMRD and LVRD versus NMRD, respectively). LVRD versus SVRD + NMRD in an IDS setting Meta-analysis found that women who had LVRD had a greater risk of death and disease progression compared to women who had either SVRD or NMRD (HR 1.60, 95% CI 1.21 to 2.11; 6 studies; 1572 participants; I2 = 58% for overall survival and HR 1.76, 95% CI 1.23 to 2.52; 1145 participants; I2 = 60% for progression-free survival; very low-certainty). However, this result is biased as in all but one study it was not possible to distinguish NMRD within the < 1 cm thresholds. Only one study separated NMRD from SVRD; all others included NMRD in the SVRD group, which may create bias when comparing with LVRD, making interpretation challenging. MRD versus NMRD in an IDS setting Women who had any amount of MRD after IDS had more than twice the risk of death compared to women with NMRD (HR 2.11, 95% CI 1.35 to 3.29, I2 = 81%; 906 participants; very low-certainty). In a PDS setting, there is moderate-certainty evidence that the amount of RD after primary surgery is a prognostic factor for overall and progression-free survival in women with advanced ovarian cancer. We separated our analysis into three distinct categories for the survival outcome including NMRD, SVRD and LVRD. After IDS, there may be only two categories required, although this is based on very low-certainty evidence, as all but one study included NMRD in the SVRD category. The one study that separated NMRD from SVRD showed no improved survival outcome in the SVRD category, compared to LVRD. Further low-certainty evidence also supported restricting to two categories, where women who had any amount of MRD after IDS had a significantly greater risk of death compared to women with NMRD. Therefore, the evidence presented in this review cannot conclude that using three categories applies in an IDS setting (very low-certainty evidence), as was supported for PDS (which has convincing moderate-certainty evidence).

Bryant A ，Hiu S ，Kunonga PT ，Gajjar K ，Craig D ，Vale L ，Winter-Roach BA ，Elattar A ，Naik R ... -  《Cochrane Database of Systematic Reviews》

Efficacy and safety of nanoparticle albumin-bound paclitaxel plus carboplatin as neoadjuvant chemotherapy for stages III-IV, unresectable ovarian cancer: a single-arm, open-label, phase Ib/II study.

Neoadjuvant chemotherapy may be considered for patients with ovarian cancer (OC) whose tumors are deemed unlikely to be completely cytoreduced to no gross residual disease (R0) or who are poor surgical candidates. This Ib/II study was designed to assess the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus carboplatin as neoadjuvant chemotherapy for stages III-IV, unresectable OC. Eligible patients with stage III-IV, unresectable OC were enrolled in this phase Ib/II study. All patients received neoadjuvant nab-paclitaxel (260 mg/m2, day 1, every 3 weeks) plus carboplatin (AUC 5, day 1, every 3 weeks) for 3 cycles before surgery, followed by 3-6 cycles of adjuvant chemotherapy. The phase Ib primary endpoint was safety; the phase II primary endpoint was the R0 resection rate. Secondary endpoints were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety (for all populations). Sixty-two patients were enrolled and were given neoadjuvant therapy treated between October 2019 and December 2020, of whom 9 were in the phase Ib portion and 53 in the phase II portion. A total of 53 patients underwent surgery with an R0 resection rate of 73.6% (95% CI, 59.7-84.7%). With a median follow-up of 17.5 (range 0.7-36.7) months, for all patients, the best ORR was 83.9% (95% CI, 71.7-92.4%) with 47 partial responses, the median PFS was 18.6 (95% CI, 13.8-23.3%) months, and median OS was not reached. During the neoadjuvant chemotherapy, treatment-related adverse events (TRAEs) of any grade occurred in 91.9% (57/62) of all patients. The most common hematologic TRAEs were neutropenia (55/62, 88.7%), and non-hematologic toxicity was alopecia (36/62, 58.1%). Forty-nine patients (79.0%) experienced at least one grade 3-4 TRAEs, with the most common was neutropenia (44/62, 71.0%). Besides, delays in neoadjuvant chemotherapy and surgery due to AEs were observed in 9 (1 in phase Ib; 8 in phase II) and 7 (phase II) patients, respectively. The study demonstrated an encouraging efficacy and manageable safety profile of neoadjuvant chemotherapy nab-paclitaxel plus carboplatin in stage III-IV, unresectable OC. In addition, AEs resulting in chemotherapy and surgery delays should be cautiously considered in this clinical setting. ClinicalTrials.gov, ChiCTR1900026893. Registered at 25 October 2019.

Yin L ，Jiang W ，Liu S ，Fu Y ，Zhou L ，Pei X ，Ye S ，Shen W ，Yang H ，Shan B ... -  《BMC Medicine》

Primary lung tumour stereotactic body radiotherapy followed by concurrent mediastinal chemoradiotherapy and adjuvant immunotherapy for locally advanced non-small-cell lung cancer: a multicentre, single-arm, phase 2 trial.

Patients with locally advanced non-small-cell lung cancer (NSCLC) who undergo concurrent chemotherapy and radiotherapy often experience synergistic toxicity, and local regional control rates remain poor. We assessed the activity and safety outcomes of primary tumour stereotactic body radiotherapy (SBRT) followed by conventional chemoradiotherapy to the lymph nodes and consolidation immunotherapy in patients with unresectable locally advanced NSCLC. In this multicentre, single-arm, phase 2 trial, patients aged 18 years and older were enrolled at eight regional cancer centres in North Carolina and South Carolina, USA. Patients were eligible if they had stage II-III, unresectable, locally advanced NSCLC (any histology), with peripheral or central primary tumours that were 7 cm or smaller, excluding central tumours within 2 cm of involved nodal disease, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients who had previously received systemic therapy or radiotherapy were excluded. Participants received SBRT to the primary tumour (50-54 Gy in three to five fractions) followed by standard radiotherapy (planned up to 60 Gy in 30 2 Gy fractions) to the involved lymph nodes with concurrent platinum doublet chemotherapy (either paclitaxel 50 mg/m2 intravenously plus carboplatin area under the curve 2 mg/mL per min every 7 days for a total of six 1-week cycles or etoposide 50 mg/m2 intravenously on days 1-5 and days 29-33 plus cisplatin 50 mg/m2 intravenously on days 1, 8, 29, and 36 for two cycles of 4 weeks). An amendment to the protocol (Dec 11, 2017) permitted the administration of consolidation durvalumab at the discretion of the treating investigator. An additional protocol amendment on Jan 13, 2021, directed patients without disease progression after chemoradiotherapy to receive consolidation durvalumab (10 mg/kg intravenously on day 1 and day 15 of a 4-week cycle for up to 12 cycles or 1500 mg intravenously on day 1 of a 4-week cycle for up to 12 cycles). The primary endpoint was 1-year progression-free survival (per Response Evaluation Criteria in Solid Tumours version 1.1), assessed in all participants who received at least one fraction of SBRT and had radiological follow-up data up to 1 year. A 1-year progression-free survival rate of greater than 60% was required to reject the null hypothesis and show significant improvement in 1-year progression-free survival. One-sided exact binomial tests were used to compare the primary endpoint versus the historical control 1-year progression-free survival rate used to determine the sample size. Safety was assessed in all patients who received at least one fraction of SBRT. This study is registered with ClinicalTrials.gov, NCT03141359, and is closed to accrual. Between May 11, 2017, and June 27, 2022, 61 patients were enrolled and received at least one dose of fractionated SBRT, of whom 59 were evaluable for the primary endpoint. Median age was 67 years (IQR 61-72), 28 (46%) of 61 were female, 33 (54%) were male, 51 (84%) were White, seven (11%) were Black, and three (5%) were of other or unknown race. Of the 61 patients enrolled, 47 received at least one dose of consolidation durvalumab. As of data cutoff (July 12, 2023), median follow-up was 29·5 months (IQR 14·9-47·1). 1-year progression-free survival was 62·7% (90% CI 51·2-73·2; one-sided p=0·39, compared with the historical control rate), with 37 of 59 evaluable participants progression free and alive 1 year after enrolment (n=14 progressed, n=8 died). The most common grade 3-4 treatment-related adverse events were decreased neutrophil count (nine [15%] of 61 patients), decreased white blood cell count (five [8%]), and anaemia (four [7%]). Treatment-related serious adverse events occurred in 11 (18%) of 61 patients, which included lung infection (three [5%]), pneumonitis (two [3%]), decreased neutrophil count (two [3%]), febrile neutropenia (two [3%]), and dyspnoea, hypoxia, respiratory failure, sinus tachycardia, bronchial infection, and acute kidney injury (each in one [2%] patient). Treatment-related deaths occurred in four (7%) of 61 patients (one each of respiratory failure, respiratory failure and dyspnoea, lung infection, and pneumonitis). Although this study did not meet the primary endpoint, activity and safety profiles of primary lung tumour SBRT followed by concurrent mediastinal chemoradiotherapy were favourable compared with other modern trials treating locally advanced NSCLC with chemoradiotherapy. These findings serve as the basis for the ongoing randomised phase 3 study NRG Oncology LU008 (NCT05624996). AstraZeneca and Atrium Health Levine Cancer Institute.

Heinzerling JH ，Mileham KF ，Robinson MM ，Symanowski JT ，Induru RR ，Brouse GM ，Corso CD ，Prabhu RS ，Haggstrom DE ，Moeller BJ ，Bobo WE ，Fasola CE ，Thakkar VV ，Pal SE ，Gregory JM ，Norek SL ，Begic XJ ，Kesarwala AH ，Burri SH ，Simone CB 2nd ... -  《-》