Previous Platinum-based Chemotherapy Research Articles

Real-World Evidence of Tumor and Patient Characteristics and Survival with Avelumab Maintenance after Chemotherapy for Advanced and Metastatic Urothelial Carcinoma

Introduction: Despite the prospective randomized controlled JAVELIN Bladder 100 trial, no real-world evidence exists regarding tumor characteristics, adverse events (AEs), and survival of avelumab maintenance (AVM)-treated patients with partial/complete response or stable disease after previous platinum-based chemotherapy for advanced/metastatic urothelial carcinoma (mUC). Methods: We relied on our institutional database to identify mUC patients who received AVM between January, 2021 and December, 2023. The main outcomes consisted of overall survival (OS) and progression-free survival (PFS) and were computed by Kaplan-Meier estimates. Stratification was performed according to programmed death ligand 1 (PD-L1) status. Results: Overall, 24 AVM patients were identified at a median age of 71 (interquartile range [IQR]: 67–76) years, of which 67% were males. Of these, 63%, 21%, and 17% received AVM therapy for bladder cancer and upper tract urothelial carcinoma or both, respectively. PD-L1 status was positive in 45% of patients. During AVM treatment, AEs were observed in 33% of patients; however, they were limited to ≤2 grade AEs. At a median follow-up of eight (IQR 4–20) months, 71% of patients had progressed under AVM with median PFS of 6.2 months (confidence interval [CI]: 3.2–18.2). Median OS was 13.4 (CI: 6.9 – not reached [NR]) months. One-year OS after AVM was 52%. In PD-L1-positive patients, median PFS and OS were 6.4 (CI: 2.7 – NR) months and 13.4 (CI: 7.7 months – NR), respectively. Conclusion: AVM is associated with moderate AE rates. Despite similarities in baseline characteristics compared to trial-selected JAVELIN Bladder 100 mUC patients, AVM resulted in longer/similar PFS but significantly shorter OS in real-world setting.

13P Efficacy and biomarker exploration of anlotinib plus penpulimab for extensive-stage small-cell lung cancer who failed previous platinum-based chemotherapy: Results from a phase II perspective trial

13P Efficacy and biomarker exploration of anlotinib plus penpulimab for extensive-stage small-cell lung cancer who failed previous platinum-based chemotherapy: Results from a phase II perspective trial

Serum CA125 level as predictors of the efficacy of olaparib maintenance therapy for platinum-sensitive relapsed ovarian cancer.

Ovarian cancer is a gynecological malignancy with a poor prognosis. For platinum-sensitive relapsed ovarian cancer, maintenance therapy with poly-ADP ribose polymerase (PARP) inhibitors after chemotherapy is considered; however, olaparib treatment does not always lead to sufficient progression-free survival (PFS). This study aimed to identify factors that predict the efficacy of maintenance therapy using olaparib in platinum-sensitive relapsed ovarian cancer. Twenty-seven patients with platinum-sensitive relapsed ovarian cancer, who received initial treatment and showed complete or partial response to prior chemotherapy at our hospital, were included. The primary outcome was the time from the end of previous platinum-based chemotherapy to disease progression (PFS). The Kaplan-Meier method was used to generate time-to-event curves for PFS; multivariate analysis was performed using the Cox proportional hazards regression model. The median PFS was 12 months (95% confidence interval [CI]: 8.3-15.8). Before olaparib administration, the median PFS was 12 months in the <4.1 neutrophil-to-lymphocyte ratio group and 4 months in the ≥4.1 group, with PFS being significantly better in the <4.1 group (log-rank: p = 0.023). When comparing serum cancer antigen 125 (CA125) levels, the median PFS was 13 months in the <18 U/mL group and 6 months in the >18 U/mL group (log-rank: p = 0.022). Multivariate Cox regression analysis revealed that CA125 was the factor affecting PFS (hazard ratio: 4.85; 95% CI: 1.53-15.38). Serum CA125 levels at olaparib initiation in patients with platinum-sensitive relapsed ovarian cancer may predict PFS as an effect of maintenance therapy using olaparib to treat recurrent disease.

A multicenter, open-label phase Ib/II study of cadonilimab (anti PD-1 and CTLA-4 bispecific antibody) monotherapy in previously treated advanced non–small-cell lung cancer (AK104-202 study)

PurposeThis study aimed to evaluate the efficacy and safety of cadonilimab (anti PD-1 and CTLA-4 bispecific antibody) in patients with previously treated metastatic non-small-cell lung cancer (NSCLC). MethodsIn this multicenter, open-label, phase Ib/II study, patients with previously treated NSCLC were enrolled in three different cohorts: Cohort A, patients who had failed previous platinum-based doublet chemotherapy and were immunotherapy naïve; Cohort B, patients who had failed previous platinum-based doublet chemotherapy and had primary resistance to immunotherapy (IO); Cohort C, patients who had failed previous platinum-based doublet chemotherapy and had acquired resistance to IO. Eligible patients were given cadonilimab 6 mg/kg intravenously every 2 weeks. The primary endpoint was the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors version 1.1. ResultsA total of 53 patients were enrolled: including 30 patients in cohort A, 7 in cohort B, and 16 in cohort C. ORR was 10% in cohort A, and there were no responder in cohort B and cohort C. Median overall survival was 19.61 (95% CI 11.30-NE) months, 4.93 (95% CI 1.97-NE) months and 13.16 (95% CI 6.18-NE) months in cohort A, B and C, respectively. Grade 3–4 treatment-related adverse events were reported in 6 (11.3 %) patients, including alanine aminotransferase increased (1.9%), rash (1.9%), chest discomfort (1.9%), hypercalcaemia (1.9%), anaemia (1.9%) and infusion related reaction (1.9%). ConclusionThe study did not meet its primary endpoint. Cadonilimab demonstrated limited efficacy in patients with IO failure, especially in cases of primary resistance. However, cadonilimab might play a role as a second-line immune monotherapy after platinum-based doublet chemotherapy failure and IO naïve, as its efficacy is similar to other immune checkpoint inhibitors after first-line chemotherapy. Cadonilimab was well-tolerated with mild toxicity, making it a potential candidate for the combination strategy.Clinical trial number NCT 04172454.

Platinum-based chemotherapy and PARP inhibitors for patients with a germline BRCA pathogenic variant and advanced breast cancer (LATER-BC): retrospective multicentric analysis of post-progression treatments

IntroductionPatients with breast cancer (BC) harbouring a germinal BRCA pathogenic variant (gBRCA-PV) may have an enhanced sensitivity to platinum-based chemotherapy (PBC) and PARP inhibitors (PARPi). As reported in ovarian cancer, however, sensitivity and resistance to these treatments could partially overlap. In patients with a gBRCA-PV and advanced BC (aBC), it remains unclear whether prior exposure to PARPi/PBC affects tumour response to subsequent PBC/PARPi, respectively. MethodsWe conducted a retrospective, multicentric study to investigate the clinical benefit of post-PBC PARPi and vice versa in patients with a gBRCA-PV and aBC. Patients included had received (neo)adjuvant PBC and then PARPi in advanced setting (group 1), PBC followed by PARPi (group 2) or PARPi followed by PBC (group 3), both in advanced setting. We reported median progression-free survival (mPFS) and disease control rate (DCR) in each group. ResultsA total of 67 patients from six centres were included. PARPi-mPFS in advanced setting was 6.1 months in patients in group 1 (N = 12), while PARPi-DCR was 67%. In group 2 (N = 36), PARPi-mPFS was 3.4 months and PARPi-DCR was 64%. Age < 65 years and platinum-free interval (PFI) > 6 months were associated with longer PARPi-PFS; previous PBC-PFS > 6 months and PBC in first to second line were associated with longer PARPi-DCR. Patients in group 3 (N = 21) reported a PBC-mPFS of 1.8 months and a PBC-DCR of 14%. PARPi-PFS ≥ 9 months and PARPi-FI ≥ 6 months were associated with better PBC-DCR. ConclusionsSensitivity and resistance to PARPi and PBC partially overlap in patients with a gBRCA-PV and aBC. Evidence of PARPi activity emerged in patients who progressed on previous PBC.

Efficacy and safety of KN046, a novel bispecific antibody against PD-L1 and CTLA-4, in patients with non-small cell lung cancer who failed platinum-based chemotherapy: a phase II study

BackgroundThis study aimed to evaluate the efficacy and safety of KN046, a novel recombinant humanised antibody targeting PD-L1 and CTLA-4 in advanced non-small cell lung cancer (NSCLC) patients after failure or intolerance to platinum-based chemotherapy. MethodsIn this multi-centre, open-label phase II clinical trial, patients were enroled after failure or intolerance to platinum-based chemotherapy. KN046 at 3 mg/kg or 5 mg/kg was administered intravenously every 2weeks. The primary end-point was objective response rate (ORR) evaluated by a blinded independent review committee (BIRC). ResultsA total of 30 and 34 patients were included in the 3 mg/kg (cohort A) and 5 mg/kg (cohort B) cohorts. On 31st August 2021, the median follow-up duration was 24.08 months (interquartile [IQR], 22.28, 24.84) and 19.35months (IQR, 17.25, 20.90) in the 3 mg/kg and 5 mg/kg cohorts, respectively. BIRC-assessed ORRs were 13.3% and 14.7% in the 3 mg/kg and 5 mg/kg cohorts, respectively. Median progression-free survival was 3.68 (95% confidence interval [CI] 3.22–7.29) and 3.68 (95%CI 1.81–7.39) months, while overall survival was 19.70 (95.5%CI 15.44-not estimated [NE]) and 13.04 (95.5%CI 9.86-NE) months, respectively. The most common treatment-related adverse events (TRAEs) were anaemia (28.1%), hyperglycaemia (26.7%), and infusion-related reactions (26.7%). The incidence rates of grade ≥ 3 TRAEs and TRAEs leading to treatment discontinuation were 42.2% and 14.1%, respectively. ConclusionsBoth 3 mg/kg and 5 mg/kg KN046 showed promising efficacy and favourable safety profile for advanced NSCLC after failure or intolerance to previous platinum-based chemotherapy. Trial registration numberNCT03838848

Tailored immunotherapy approach with nivolumab with or without ipilimumab in patients with advanced transitional cell carcinoma after platinum-based chemotherapy (TITAN-TCC): a multicentre, single-arm, phase 2 trial

Nivolumab is used after platinum-based chemotherapy in patients with metastatic urothelial carcinoma. Studies suggest improved outcomes for dual checkpoint inhibition with high ipilimumab doses. We aimed to examine the safety and activity of nivolumab induction and high-dose ipilimumab as an immunotherapeutic boost as a second-line treatment for patients with metastatic urothelial carcinoma. TITAN-TCC is a multicentre, single-arm, phase 2 trial done at 19 hospitals and cancer centres in Germany and Austria. Adults aged 18 years or older with histologically confirmed metastatic or surgically unresectable urothelial cancer of the bladder, urethra, ureter, or renal pelvis were eligible. Patients had to have progression during or after first-line platinum-based chemotherapy and up to one more second-line or third-line treatment, a Karnofsky Performance Score of 70 or higher, and measurable disease as per Response Evaluation Criteria in Solid Tumors version 1.1. After four doses of intravenous nivolumab 240 mg induction monotherapy every 2 weeks, patients with a partial or complete response at week 8 continued maintenance nivolumab, whereas those with stable or progressive disease (non-responders) at week 8 received a boost of two or four doses of intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks. Patients who subsequently had progressive disease during nivolumab maintenance also received a boost, using this schedule. The primary endpoint was the confirmed investigator-assessed objective response rate in the intention-to-treat population and had to exceed 20% for the null hypothesis to be rejected (based on the objective response rate with nivolumab monotherapy in the CheckMate-275 phase 2 trial). This study is registered with ClinicalTrials.gov, NCT03219775, and is ongoing. Between April 8, 2019, and Feb 15, 2021, 83 patients with metastatic urothelial carcinoma were enrolled and all received nivolumab induction treatment (intention-to-treat population). The median age of enrolled patients was 68 years (IQR 61-76), and 57 (69%) were male and 26 (31%) were female. 50 (60%) patients received at least one boost dose. A confirmed investigator-assessed objective response was recorded in 27 (33%) of 83 patients in the intention-to-treat population, including six (7%) patients who had a complete response. This objective response rate was significantly higher than the prespecified threshold of 20% or less (33% [90% CI 24-42]; p=0·0049). The most common grade 3-4 treatment-related adverse events were immune-mediated enterocolitis (nine [11%] patients) and diarrhoea (five [6%] patients). Two (2%) treatment-related deaths were reported, both due to immune-mediated enterocolitis. Treatment with nivolumab and nivolumab plus ipilimumab boosts in early non-responders and patients who progress late significantly improved objective response rate after previous platinum-based chemotherapy compared with the rate reported with nivolumab in the CheckMate-275 trial. Our study provides evidence for the added value of high-dose ipilimumab 3 mg/kg and suggests a potential role for the combination as a rescue strategy in platinum-pretreated patients with metastatic urothelial carcinoma. Bristol Myers Squibb.

Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRASG12C mutation: a randomised, open-label, phase 3 trial

Sotorasib is a specific, irreversible inhibitor of the GTPase protein, KRASG12C. We compared the efficacy and safety of sotorasib with a standard-of-care treatment in patients with non-small-cell lung cancer (NSCLC) with the KRASG12C mutation who had been previously treated with other anticancer drugs. We conducted a randomised, open-label phase 3 trial at 148 centres in 22 countries. We recruited patients aged at least 18 years with KRASG12C-mutated advanced NSCLC, who progressed after previous platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor. Key exclusion criteria included new or progressing untreated brain lesions or symptomatic brain lesions, previously identified oncogenic driver mutation other than KRASG12C for which an approved therapy is available (eg EGFR or ALK), previous treatment with docetaxel (neoadjuvant or adjuvant docetaxel was allowed if the tumour did not progress within 6 months after the therapy was terminated), previous treatment with a direct KRASG12C inhibitor, systemic anticancer therapy within 28 days of study day 1, and therapeutic or palliative radiation therapy within 2 weeks of treatment initiation. We randomly assigned (1:1) patients to oral sotorasib (960 mg once daily) or intravenous docetaxel (75 mg/m2 once every 3 weeks) in an open-label manner using interactive response technology. Randomisation was stratified by number of previous lines of therapy in advanced disease (1 vs 2 vs >2), ethnicity (Asian vs non-Asian), and history of CNS metastases (present or absent). Treatment continued until an independent central confirmation of disease progression, intolerance, initiation of another anticancer therapy, withdrawal of consent, or death, whichever occurred first. The primary endpoint was progression-free survival, which was assessed by a blinded, independent central review in the intention-to-treat population. Safety was assessed in all treated patients. This trial is registered at ClinicalTrials.gov, NCT04303780, and is active but no longer recruiting. Between June 4, 2020, and April 26, 2021, 345 patients were randomly assigned to receive sotorasib (n=171 [50%]) or docetaxel (n=174 [50%]). 169 (99%) patients in the sotorasib group and 151 (87%) in the docetaxel group received at least one dose. After a median follow-up of 17·7 months (IQR 16·4-20·1), the study met its primary endpoint of a statistically significant increase in the progression-free survival for sotorasib, compared with docetaxel (median progression-free survival 5·6 months [95% CI 4·3-7·8] vs 4·5 months [3·0-5·7]; hazard ratio 0·66 [0·51-0·86]; p=0·0017). Sotorasib was well tolerated, with fewer grade 3 or worse (n=56 [33%] vs n=61 [40%]) and serious treatment-related adverse events compared with docetaxel (n=18 [11%] vs n=34 [23%]). For sotorasib, the most common treatment-related adverse events of grade 3 or worse were diarrhoea (n= 20 [12%]), alanine aminotransferase increase (n=13 [8%]), and aspartate aminotransferase increase (n=9 [5%]). For docetaxel, the most common treatment-related adverse events of grade 3 or worse were neutropenia (n=13 [9%]), fatigue (n=9 [6%]), and febrile neutropenia (n=8 [5%]). Sotorasib significantly increased progression-free survival and had a more favourable safety profile, compared with docetaxel, in patients with advanced NSCLC with the KRASG12C mutation and who had been previously treated with other anticancer drugs. Amgen.

Endometrial cancer: news from ASCO

SummaryAt ASCO 2022 important abstracts were presented. The programmed death1 (PD1) inhibitor dostarlimab was investigated in the phase III GARNET study in advanced or metastatic endometrial cancer after failure of previous platinum-based combination chemotherapy. In the first group of patients with tumors with dMMR (mismatch repair-deficiency) or MSI‑H (microsatellite-high; group A), the median progression-free survival (PFS) was significantly higher than in the group with pMMR (mismatch repair-proficiency) or those with MSS (microsatellite-stable) tumors (group B), i.e., 6.0 months in group A and 2.7 months in group B. Overall survival was &gt; 50 months and 17 months, respectively. Immunotherapy-related adverse events were seen in 23% of patients, including grade 3 or 4 events in 8% of women. In all, 9% of patients discontinued treatment due to adverse events. Another important regimen is the combination of lenvatinib and pembrolizumab. In a randomized study of lenvatinib + pembrolizumab versus monotherapy with doxorubicin or paclitaxel in the second-line therapy of metastatic endometrial cancer, the chemotherapy-free regimen was superior. PFS2 was significantly higher in patients in the pMMR group and the all comer group if they received lenvatinib and pembrolizumab, compared to those receiving standard chemotherapy (p &lt; 0.0001). In conclusion, checkpoint inhibitors ± lenvatinib are now established in the second-line treatment of advanced endometrial cancer. Overall, the inclusion of PD1 or PDL1 inhibitors in systemic treatment regimens offers a significant opportunity for patients whose treatment options in the past only included conventional chemotherapy, radiotherapy or hormonal therapy.

A Prospective Observational Study of Proton Stereotactic Body Radiation Therapy and Immunotherapy for Recurrent Metastatic Head and Neck Cancer: Initial Report of MC ROR1771 Survival Analysis and Toxicity

<h3>Purpose/Objective(s)</h3> Patients with recurrent head and neck squamous cell carcinoma (HNSCC) after previous platinum-based chemotherapy have a median survival of 6 months or less. CheckMate 141 demonstrated that nivolumab administration to this patient population led to a median 7.5-month survival vs. 5.1-months with standard therapy, with 36% 1-year overall survival. The effect of radiotherapy on tumor immunogenicity when combined with immunotherapy has been an area of interest in immuno-oncology. However, proton therapy's role in this space is not well understood. MC ROR1771 was designed as a multisite prospective observational study to evaluate the addition of stereotactic body proton therapy (SBPT) to nivolumab in a platinum-refractory population. <h3>Materials/Methods</h3> Patients with metastatic histologically confirmed HNSCC from any primary site were eligible. Two cycles of nivolumab every other week were followed by SBPT to 1-2 target lesion(s). Maintenance nivolumab continued every other week with follow-up for progression and treatment toxicity. Subsequent oligoprogression was treated with stereotactic body radiotherapy or SBPT as indicated. Objective criteria included target lesion response rate, overall survival, progression-free survival, time to distant metastasis, toxicity, and evaluation of potential predictive biomarkers. Survival analysis was conducted using the Kaplan-Meier method in statistical software. The focus of this report was survival and toxicity analyses. <h3>Results</h3> 15 patients enrolled with 13 receiving SBPT, after which one treated patient withdrew. Of the remaining twelve, 3 had laryngeal primary, 1 nasopharyngeal, and 8 oropharyngeal. 4 patients underwent one round of prior chemotherapy before enrollment, 3 patients two rounds, and 5 patients three rounds: 10 received concurrent chemoradiation in first line (5 definitive, 5 adjuvant), with 1 receiving neoadjuvant chemotherapy prior to chemoradiation, and one presenting with metastatic disease. SBPT dosing ranged from 35-50 Gy. From initiation of nivolumab, median overall survival was 12.5 months (1-year overall survival 67%), with median progression free survival of 4.5 months. Two patients presented with baseline grade 3 cancer pain; no ≥grade 3 toxicity specific to nivolumab nor SBPT was reported. One patient is still alive at 40 months from initiation of nivolumab. <h3>Conclusion</h3> In this highly pretreated population, overall and progression-free survival compare favorably with CheckMate 141, suggesting that SBPT co-treatment may be beneficial in this population. No ≥grade 3 toxicity occurred with nivolumab nor SBPT. Biochemical analysis and correlation with delineated local, regional, and distant radiographic response are forthcoming. Further prospective evaluation of combination SBPT and immunotherapy is needed.

Associations with response to Poly(ADP-ribose) Polymerase (PARP) inhibitors in patients with metastatic breast cancer

PARP inhibitors (PARPi) have modest antitumor activity in patients with advanced breast cancer and mutation in BRCA. It is unclear whether some subgroups derive greater benefit from treatment. MEDLINE and EMBASE were searched from inception to March 2021 to identify trials of PARPi in patients with metastatic breast cancer. Objective response rate (ORR) and clinical benefit rate (CBR) to PARPi were extracted and pooled in a meta-analysis using the Mantel Haenszel random effects model. Meta-regression explored the influence of patient and tumor characteristics on ORR and CBR. For randomized trials, hazard ratio comparing PARPi to control therapy were pooled using inverse variance and random effects. Analysis included 43 studies comprising 2409 patients. Among these, 1798 (75%) patients had BRCA mutations and 1146 (48%) were triple negative. In 10 studies (28%; n = 680 patients), the PARPi was given in combination with platinum-based chemotherapy. Weighted mean ORR was 45%; 64% when combined with platinum vs 37% with PARPi monotherapy (p < 0.001). Previous platinum-based chemotherapy was associated with lower ORR (p = 0.02). Compared to standard chemotherapy, progression-free survival was improved (HR 0.64, p < 0.001), but there was no difference in overall survival (HR 0.87, p = 0.06). There were no differences in ORR or CBR between BRCA1 and BRCA2 mutations. PARPi are more active in combination with platinum than as monotherapy, with lower response if given as monotherapy after platinum exposure. Significant improvements in ORR translated to modest improvement in progression-free, but not overall survival. There was no association between ORR and BRCA mutations.

Efficacy of Platinum Rechallenge in Metastatic Urothelial Carcinoma After Previous Platinum-Based Chemotherapy for Metastatic Disease.

Fit patients with metastatic urothelial carcinoma (mUC) receive first-line platinum-based combination chemotherapy (fPBC) as standard of care and may receive additional later-line chemotherapy after progression. Our study compares outcomes with subsequent platinum-based chemotherapy (sPBC) versus subsequent non-platinum-based chemotherapy (sNPBC). Patients from 27 international centers in the Retrospective International Study of Cancers of the Urothelium (RISC) who received fPBC for mUC and at least two cycles of subsequent chemotherapy were included in this study. A multivariable Cox proportional hazards model compared overall survival (OS) and progression-free survival (PFS). One hundred thirty-five patients received sPBC and 161 received sNPBC. Baseline characteristics were similar between groups, except patients who received sPBC had higher baseline hemoglobin, higher disease control rate with fPBC, and longer time since fPBC. OS was superior in the sPBC group (median 7.9 vs 5.5 months) in a model adjusting for comorbidity burden, performance status, liver metastases, number of fPBC cycles received, best response to fPBC, and time since fPBC (hazard ratio, 0.72; 95% confidence interval, 0.53-0.98; p=.035). There was no difference in PFS. More patients in the sPBC group achieved disease control than in the sNPBC group (57.4% vs 44.8%; p=.041). Factors associated with achieving disease control in the sPBC group but not the sNPBC group included longer time since fPBC, achieving disease control with fPBC, and absence of liver metastases. After receiving fPBC for mUC, patients who received sPBC had better OS and disease control. This may help inform the choice of subsequent chemotherapy in patients with mUC. Patients with progressive metastatic urothelial carcinoma after first-line platinum-based combination chemotherapy may now receive immuno-oncology agents, erdafitinib, enfortumab vedotin, or sacituzumab govitecan-hziy; however, those ineligible for these later-line therapies or who progress after receiving them may be considered for subsequent chemotherapy. In this retrospective study of 296 patients, survival outcomes and disease control rates were better in those receiving subsequent platinum-based rechallenge compared with non-platinum-based chemotherapy, suggesting that patients should receive platinum rechallenge if clinically able. Disease control with platinum rechallenge was more likely with prior first-line platinum having achieved disease control, longer time since first-line platinum, and absence of liver metastases.

Evaluation of treatment response to niraparib in patients with platinum-sensitive recurrent ovarian cancer and measurable lesions at baseline: a sub-analysis of the phase III NORA trial

<h3>Objectives:</h3> This sub-analysis investigated treatment response to niraparib maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer (PSROC) included in the NORA trial who had measurable lesions after finishing chemotherapy and before initiating niraparib. <h3>Methods:</h3> In the double-blind, phase III NORA trial, 265 adult (≥18 years) Chinese women with PSROC were randomised 2:1 to receive oral niraparib (n=177; 300 mg/day, patients with bodyweight <77 kg or platelet count <150×10³/µL received 200 mg/day) or matched placebo (n=88)(NCT03705156). The primary endpoint was progression-free survival (PFS). This sub-analysis assessed treatment outcomes among patients with measurable lesions after finishing chemotherapy and before initiating niraparib maintenance therapy. Baseline disease assessment (before niraparib initiation) and subsequent tumour response was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by blinded independent central review (BICR). In patients with measurable lesions at baseline, the objective response rate (ORR) was evaluated. Odds ratios (OR) were adjusted for response to previous platinum-based chemotherapy and time to disease progression following the penultimate platinum-based chemotherapy, and were calculated using logistic regression. Adverse events (AEs) were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.03. <h3>Results:</h3> Of the 265 patients included in the NORA study, 64 (24.2%) had measurable lesions at baseline (niraparib, n=43; placebo, n=21), 21.9% (14/64) of whom had received secondary cytoreductive surgery before the last round of chemotherapy. Among patients with measurable lesions, those who received niraparib achieved a higher ORR compared with those receiving placebo (32.6 vs 14.3%; OR=2.7, 95% CI, 0.67-11.18), and niraparib also led to a higher ORR regardless of germline <i>BRCA</i> mutation status (g<i>BRCA</i> mutation: 50.0 vs 28.6%, non-g<i>BRCA</i> mutation: 25.8 vs 7.1%) (Table). Niraparib was well tolerated by patients in this sub-analysis, with a safety profile in-line with previous reports. <h3>Conclusions:</h3> Among patients included in the NORA study with measurable lesions at baseline, niraparib maintenance therapy induced additional antitumour activity versus placebo, with a higher ORR regardless of germline <i>BRCA</i> mutation status, and was well tolerated. The high rates of tumour response observed for niraparib-treated patients in the NORA study further support the role of niraparib as maintenance treatment for patients with PSROC and measurable lesions after chemotherapy.

Acute renal disease in patients with ovarian peritoneal carcinomatosis treated with cytoreduction and HIPEC: the influence of surgery and the cytostatic agent used

The main objective of this study was to evaluate the differences between cisplatin and paclitaxel in the development of postoperative renal toxicity, using as a reference the RIFLE (Risk, Injury, Insufficiency, Loss, and End-stage renal function) and AKIN (Acute Kidney Injury Network) criteria in patients with primary or recurrent ovarian cancer with peritoneal dissemination treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). One hundred fifty-two patients who were treated between December 2007 and June 2017 were analyzed. Patients who received previous platinum-based chemotherapy had higher baseline creatinine levels than those who had not (p = 0.05). A total of 11 (7.2%) and 4 (2.6%) patients developed an acute renal dysfunction (ARD) during the postoperative period of cytoreduction and HIPEC according to the RIFLE and AKI criteria respectively. RIFLE detects a higher rate of ARD due to different parameters such as GFR (7.2% versus 2.6%, p = 0.016). Performing ostomy (p = 0.007; OR: 39.320; 95% CI = 2.74-56.13) and using of cisplatin during HIPEC treatment (p = 0.017; OR = 13.619; 95% IC = 1.600-25.95) were factors independently related to a higher rate of ARD. ARD has a multifactorial origin. Cisplatin was associated with the development of a higher rate of ARD than paclitaxel. Diagnosis of ARD did not correlate with worse survival figures.

Testicular cancer in the cisplatin era: Causes of death and mortality rates in a population-based cohort.

5006 Background: Previous studies have reported an increased risk of premature mortality in testicular cancer (TC) survivors, probably associated with previous platinum-based chemotherapy (PBCT) or radiotherapy (RT). However, complete data regarding PBCT cycles are lacking in available literature. Using complete TC treatment data, this population-based cohort study aimed to investigate non-TC mortality in relation to TC treatment. Methods: Overall, 5,707 men diagnosed with TC 1980-2009 were included, identified from the Cancer Registry of Norway. Clinical parameters and treatment data were abstracted from medical records and linked with the Norwegian Cause of Death Registry. Causes of death were classified by the European Shortlist. Standardized mortality ratios (SMRs) were calculated to compare the cause-specific mortality in the cohort to an age-matched general population. Age-adjusted hazard ratios (HRs) were estimated to evaluate the impact of number of PBCT cycles on non-TC mortality. Results: During a median follow-up of 18.7 years, 665 (12%) men were registered with non-TC death. The overall excess non-TC mortality was 23% (SMR 1.23, 95% CI 1.14-1.33) compared with the general population, with increased risks after PBCT (SMR 1.23, 95% CI 1.06-1.42) and RT (SMR 1.28, 95% CI 1.15-1.43), but not after surgery (SMR 0.95, 95% CI 0.79-1.14). SMRs increased significantly with increasing follow-up time ≥10 years, and the overall risk of non-TC death reached a maximum after ≥30 years follow-up (SMR 1.64, 95% CI 1.31-2.06). The most important cause of death was non-TC second cancer with an overall SMR of 1.53 (95% CI 1.35-1.73). Increased risks appeared after PBCT (SMR 1.43, 95% CI 1.12-1.83) and RT (SMR 1.59, 95% CI 1.34-1.89). Treatment with PBCT was associated with significantly 1.69-6.78-fold increased SMRs for cancers of the oral cavity/pharynx, esophagus, lung, bladder, and leukemia. After RT, significantly 3.02- 4.91-fold increased SMRs emerged for cancers of the oral cavity/pharynx, stomach, liver, pancreas and bladder. Non-cancer mortality was also increased by 15% (SMR 1.15, 95% CI 1.04-1.27), and excesses appeared after PBCT (1.23, 95% CI 1.03-1.47) and RT (SMR 1.17, 95% CI 1.01-1.34). Importantly, we report excess suicides after PBCT (SMR 1.65, 95% CI 1.01-2.69). Long-term overall cardiovascular mortality was not increased in the study cohort nor according to treatment modality. Compared with surgery, the overall non-TC mortality was increased after 4 (HR 1.41, 95% CI 1.00-1.98) and &gt;4 (HR 2.03, 95% CI 1.24-3.33) PBCT cycles after &gt;10 years of follow-up. Conclusions: TC treatment with PBCT or RT is associated with significantly increased long-term non-TC mortality, with non-TC second cancer being the most important cause of death. Significantly elevated risks for non-TC mortality emerged after ≥4 PBCT cycles after &gt;10 years of follow-up.

Randomized phase II study comparing docetaxel versus paclitaxel in patients with esophageal squamous cell carcinoma who are refractory to fluoropyrimidine and platinum-based chemotherapy: OGSG1201.

4037 Background: Fluoropyrimidine and platinum-based chemotherapy are considered first-line therapy options for patients with unresectable advanced or recurrent metastatic esophageal squamous cell carcinoma(ESCC). After fluoropyrimidine and platinum-based chemotherapy is failed, taxanes (docetaxel(DTX) and paclitaxel(PTX)) was mainly used as a second-line treatment for ESCC. Therefore, we conducted a trial to compare DTX and PTX in patients with unresectable advanced or recurrent ESCC who were failed to previous fluoropyrimidine and platinum-based chemotherapy. Methods: We did a randomized, an open-labeled and multicentre phase 2 study. Inclusion criteria included age 20 to 80 years with unresectable advanced or recurrent ESCC, Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. Patients who were refractory to fluoropyrimidine and platinum-based chemotherapy. Treatment consisted of DTX 70 mg/m2 repeated every 21 days or PTX 100 mg/m2 once weekly on days 1, 8, 15, 22, 29, and 36 of a 49-day cycle. Results: 80 patients were enrolled between May 2012 and April 2019. 41 patients received DTX and 39 patients received PTX. After assessment of eligibility, two patients proved uneligible (one for double cancer, one for contraindication to DTX) and were excluded from the analysis. But, 80 patients were evaluable for the toxicity analyses. A median follow-up time was 32 months. Overall survival was significantly longer in the PTX group than in the DTX group (median, 8.8 months vs. 7.3 months; hazard ratio, 0.62; 95% CI, 0.38 to 0.9998; P = 0.047). The median progression-free survival was significantly longer in the PTX group than in the DTX group (median, 4.4 months vs. 2.1 months; hazard ratio, 0.49; 95% CI, 0.30 to 0.78; P = 0.002). The median time to treatment failure was significantly longer in the PTX group than in the DTX group (median, 3.8 months vs. 2.1 months; hazard ratio, 0.45; 95% CI, 0.28 to 0.73; P＜0.001). The most common adverse events of grade 3 or higher were a decreased neutrophil count (in 28% of the PTX group and in 80% of the DTX group). Febrile neutropenia was also more frequent in the DTX group than the PTX group (46％ vs. 0%). There was one death from sudden death in which treatment-related mortality could not be ruled out. Conclusions: Secound-line treatment with PTX, as compared with DTX, reduced the risk of ESCC. Clinical trial information: UMIN000007940.

Clinical Outcomes of Patients With Metastatic Urothelial Carcinoma After Progression to Immune Checkpoint Inhibitors: A Retrospective Analysis by the Meet-Uro Group (Meet-URO 1 Study).

Background:Immune checkpoint inhibitors (ICIs) are currently the standard of care for metastatic urothelial cancer (mUC) after the failure of previous platinum-based chemotherapy. The choice of further therapy after ICI progression is a new challenge, and scarce data support it. We aimed to examine the outcomes of mUC patients after progression to ICI, especially when receiving chemotherapy.Methods:Data were retrospectively collected from clinical records of mUC patients whose disease progressed to anti-programmed death 1 (PD-1)or programmed death ligand 1 (PD-L1) therapy at 14 Italian centers. Patients were grouped according to ICI therapy setting into SALVAGE (ie, ICI delivered ⩾ second-line therapy after platinum-based chemotherapy) and NAÏVE (ie, first-line therapy) groups. Progression-free survival (PFS) and overall survival (OS) rates were calculated using the Kaplan-Meier method and compared among subgroups. Cox regression assessed the effect of treatments after progression to ICI on OS. Objective response rate (ORR) was calculated as the sum of partial and complete radiologic responses.Results:The study population consisted of 201 mUC patients who progressed after ICI: 59 in the NAÏVE cohort and 142 in the SALVAGE cohort. Overall, 52 patients received chemotherapy after ICI progression (25.9%), 20 (9.9%) received ICI beyond progression, 115 (57.2%) received best supportive care only, and 14 (7.0%) received investigational drugs. Objective response rate to chemotherapy in the post-ICI setting was 23.1% (28.0% in the NAÏVE group and 18.5% in the SALVAGE group). Median PFS and OS to chemotherapy after ICI-PD was 5 months (95% confidence interval [CI]: 3-11) and 13 months (95% CI: 7-NA) for the NAÏVE group; 3 months (95% CI: 2-NA) and 9 months (95% CI: 6-NA) for the SALVAGE group, respectively. Overall survival from ICI initiation was 17 months for patients receiving chemotherapy (hazard ratio [HR] = 0.09, p < 0.001), versus 8 months for patients receiving ICI beyond progression (HR = 0.13, p < 0.001), and 2 months for patients who did not receive further active treatment (p < 0.001).Conclusions:Chemotherapy administered after ICI progression for mUC patients is advisable irrespective of the treatment line.

Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): post-progression outcomes and updated safety results from a randomised, placebo-controlled, phase 3 trial

In ARIEL3, rucaparib maintenance treatment significantly improved progression-free survival versus placebo. Here, we report prespecified, investigator-assessed, exploratory post-progression endpoints and updated safety data. In this ongoing (enrolment complete) randomised, placebo-controlled, phase 3 trial, patients aged 18 years or older who had platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 who had received at least two previous platinum-based chemotherapy regimens and responded to their last platinum-based regimen were randomly assigned (2:1) to oral rucaparib (600 mg twice daily) or placebo in 28-day cycles using a computer-generated sequence (block size of six with stratification based on homologous recombination repair gene mutation status, progression-free interval following penultimate platinum-based regimen, and best response to most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary endpoint of investigator-assessed progression-free survival has been previously reported. Prespecified, exploratory outcomes of chemotherapy-free interval (CFI), time to start of first subsequent therapy (TFST), time to disease progression on subsequent therapy or death (PFS2), and time to start of second subsequent therapy (TSST) and updated safety were analysed (visit cutoff Dec 31, 2017). Efficacy analyses were done in all patients randomised to three nested cohorts: patients with BRCA mutations, patients with homologous recombination deficiencies, and the intention-to-treat population. Safety analyses included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT01968213. Between April 7, 2014, and July 19, 2016, 564 patients were enrolled and randomly assigned to rucaparib (n=375) or placebo (n=189). Median follow-up was 28·1 months (IQR 22·0-33·6). In the intention-to-treat population, median CFI was 14·3 months (95% CI 13·0-17·4) in the rucaparib group versus 8·8 months (8·0-10·3) in the placebo group (hazard ratio [HR] 0·43 [95% CI 0·35-0·53]; p<0·0001), median TFST was 12·4 months (11·1-15·2) versus 7·2 months (6·4-8·6; HR 0·43 [0·35-0·52]; p<0·0001), median PFS2 was 21·0 months (18·9-23·6) versus 16·5 months (15·2-18·4; HR 0·66 [0·53-0·82]; p=0·0002), and median TSST was 22·4 months (19·1-24·5) versus 17·3 months (14·9-19·4; HR 0·68 [0·54-0·85]; p=0·0007). CFI, TFST, PFS2, and TSST were also significantly longer with rucaparib than placebo in the BRCA-mutant and homologous recombination-deficient cohorts. The most frequent treatment-emergent adverse event of grade 3 or higher was anaemia or decreased haemoglobin (80 [22%] patients in the rucaparib group vs one [1%] patient in the placebo group). Serious treatment-emergent adverse events were reported in 83 (22%) patients in the rucaparib group and 20 (11%) patients in the placebo group. Two treatment-related deaths have been previously reported in this trial; there were no new treatment-related deaths. In these exploratory analyses over a median follow-up of more than 2 years, rucaparib maintenance treatment led to a clinically meaningful delay in starting subsequent therapy and provided lasting clinical benefits versus placebo in all three analysis cohorts. Updated safety data were consistent with previous reports. Clovis Oncology.

LKB1 mutations are not associated with the efficacy of first-line and second-line chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC): a post hoc analysis of the TAILOR trial

PurposeIn patients with advanced lung adenocarcinoma, the impact of LKB1 mutations on cytotoxic chemotherapy efficacy remains poorly explored. Here, we aimed at investigating the potential impact of LKB1 mutational status on chemotherapy efficacy in advanced non-small-cell lung cancer (NSCLC) patients enrolled in the TArceva Italian Lung Optimisation tRial (TAILOR) trial.MethodsThe multicenter TAILOR trial randomised patients with EGFR-wild type (wt) advanced NSCLC progressing on/after previous platinum-based chemotherapy to receive docetaxel or erlotinib. Here, we evaluated the impact of LKB1 mutational status on progression-free survival (PFS) and overall survival (OS) in patients treated with second-line docetaxel/erlotinib or during prior platinum-based chemotherapy.ResultsOut of 222 patients randomised in the TAILOR trial, left-over tumour tissues were available for 188 patients, and 120 patients with evaluable LKB1 status were included. Of them, 17 (14.17%) patients had LKB1-mutated tumours, while 103 (85.83%) had LKB1-wt disease. During second-line treatment, PFS and OS were not statistically significantly different in patients with LKB1-mutated when compared with LKB1-wt NSCLC (adjusted HR (aHR)=1.29, 95% CI 0.75 to 2.21; p=0.364 and aHR=1.41, 95% CI 0.82 to 2.44; p=0.218, respectively). Similarly, we found no significant association between LKB1 mutations and patient PFS or OS during prior first-line platinum-based chemotherapy (aHR=1.04, 95% CI 0.55 to 1.97; p=0.910 and aHR=0.83, 95% CI 0.42 to 1.65; p=0.602, respectively).ConclusionAmong advanced NSCLC patients receiving two lines of systemic therapy, LKB1 mutations were not associated with PFS or OS during second-line docetaxel or prior first-line platinum-based chemotherapy. While larger prospective trials are needed to confirm our findings, cytotoxic chemotherapy remains the backbone of investigational combination strategies in this patient population.

Treatment of recurrent epithelial ovarian cancer.

The majority of patients with advanced ovarian cancer progress after first-line therapy and require further treatment. Tumor biology, prior chemotherapy, responses to previous therapy, performance status, and toxicity are the characteristics that influence treatment choice. These criteria have been linked to the time between relapse and last platinum therapy: the platinum-free interval. Today, patients are classified as either those who are eligible for a new platinum-based therapy or those for whom platinum is not an option. A nonplatinum regimen should be administered to patients who are not candidates for platinum re-treatment. This group includes patients with early relapse after, or progression during, previous platinum-based chemotherapy and patients with platinum intolerability. A single agent such as weekly paclitaxel, pegylated liposomal doxorubicin (PLD), gemcitabine, or topotecan represents the standard. For patients not treated with bevacizumab in the first line, this drug should be added to chemotherapy. For patients for whom platinum rechallenge is an option (because they are potentially platinum-responsive), different strategies are available with the incorporation of biological drugs targeting angiogenesis or the mechanisms of DNA repair. A BRCA mutation status predicts a better response to platinum and poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition. PARP inhibitors and antiangiogenic drugs have proven efficacy as maintenance therapy after chemotherapy and concurrently with chemotherapy, respectively. These agents have changed current practice, although few biomarkers are available to guide decisions. Patients potentially responsive to platinum who cannot receive the drug again can be treated with a combination of trabectedin and PLD, the most active nonplatinum therapy in this setting.