First-line Platinum Chemotherapy Research Articles

Consensus on drivers of maintenance treatment choice and patterns of care in advanced ovarian cancer

ObjectivesMaintenance therapies, including poly (ADP-ribose) polymerase (PARP) inhibitors and/or bevacizumab, have substantially improved the prognosis of patients with advanced ovarian cancer. Owing to the variability in treatment strategies across Europe,...

Prognostic value of baseline clinicopathological characteristics in first-line chemotherapy ± immunotherapy for extensive-stage small cell lung cancer: a retrospective cohort study.

The integration of chemotherapy and immunotherapy as a first-line treatment for extensive-stage small cell lung cancer (ES-SCLC) has been adopted in clinical practice, yet the response to immune checkpoint inhibitors (ICIs) is variable, benefiting only a fraction of patients. The current absence of reliable biomarkers for predicting treatment response and prognosis represents a significant gap in knowledge, hindering the optimization of patient stratification and treatment planning. This retrospective cohort study aims to assess the potential predictive and prognostic significance of clinicopathological baseline features in ES-SCLC patients. Our study retrospectively analyzed the data of consecutive patients with ES-SCLC treated with first-line etoposide plus platinum chemotherapy ± immunotherapy at The Affiliated Lihuili Hospital of Ningbo University from April 2017 to April 2023. Data on clinical information, serum laboratory indicators, pathological immunohistochemical markers, and progression-free survival (PFS) times were collected. Univariate and multivariate Cox regression analyses were employed to determine whether these indicators could serve as independent prognostic factors for PFS. Further, potential predictive markers for treatment efficacy were identified using a Cox regression model that incorporated an interaction term between treatment modality and the indicator. A total of 121 patients with ES-SCLC were enrolled in the study, of whom 62 received chemotherapy alone, and 59 received chemotherapy in combination with immunotherapy. Compared to chemotherapy alone, the addition of immunotherapy to first-line chemotherapy significantly extended the PFS time [P<0.001; hazard ratio (HR) =0.42; 95% confidence interval (CI): 0.28, 0.64] of the ES-SCLC patients. The multivariate analysis revealed that an immunochemotherapy regimen (P<0.001, HR =0.40; 95% CI: 0.24, 0.68), a low-density lipoprotein (LDL) level of >1.8 mmol/L (P=0.02; HR =0.41; 95% CI: 0.20, 0.85) were independent prognostic factors of favorable PFS in the first-line treatment of all ES-SCLC, while a lactate dehydrogenase (LDH) level of >273 U/L (P=0.04; HR =1.78; 95% CI: 1.03, 3.07), a neuron-specific enolase (NSE) concentration of >102.6 ng/mL (P=0.009; HR =6.49; 95% CI: 1.60, 26.32), an apolipoprotein A1 (ApoA1) concentration of >0.9 g/L (P<0.001; HR =4.15; 95% CI: 1.98, 8.71), and an apolipoprotein B (ApoB) concentration of >0.8 g/L (P=0.002; HR =2.24; 95% CI: 1.34, 3.75) were independent prognostic factors of poorer PFS. Further, the interaction effect analysis demonstrated that an LDL level of >1.8 mmol/L and the absence of bone metastasis were potential predictors of an improved response to ICI therapy compared to chemotherapy alone. This study showed the survival benefit of receiving a chemoimmunotherapy regimen as the first-line treatment in a real-world scenario. It also suggests the prognostic significance of pre-treatment LDL, LDH, NSE, ApoA1, and ApoB with optimal cut-off values in the first-line treatment of all ES-SCLC, and the potential utility of baseline LDL level or the presence of bone metastasis in guiding first-line treatment strategies.

421P Maintenance therapy with regorafenib (REGO) versus placebo after first-line (1L) platinum and fluoropyrimidines-based chemotherapy in HER2-negative advanced gastric (GC)/gastroesophageal junction (GEJ) cancer: Results of phase II randomized a-MANTRA study (GOIRC-05-2016)

421P Maintenance therapy with regorafenib (REGO) versus placebo after first-line (1L) platinum and fluoropyrimidines-based chemotherapy in HER2-negative advanced gastric (GC)/gastroesophageal junction (GEJ) cancer: Results of phase II randomized a-MANTRA study (GOIRC-05-2016)

Phase II randomized study of maintenance therapy with regorafenib (REGO) versus placebo after first-line platinum and fluoropyrimidines-based chemotherapy in HER2 negative locally advanced/metastatic gastric (GC) or gastroesophageal junction (GEJ) cancer: Results of a-MANTRA study (GOIRC-05-2016).

4056 Background: REGO is an oral multi-targeted TKI that showed promising activity in advanced HER2-neg gastric cancer pts. The a-MANTRA study aimed to evaluate the efficacy and safety of REGO as maintenance after first-line (1L) therapy in advanced GC/GEJ tumors. Methods: This is a randomized, double-blind, placebo-controlled, multicenter Phase-II study in which HER2 neg advanced GC/GEJ pts with disease control after 1L platinum and fluoropyrimidines-based therapy, were randomized (1:1 ratio) to receive maintenance placebo (ARM A) or REGO (ARM B) starting at 80 mg with an escalation up to 160 mg (once daily on d1-21 q28 days), until intolerance or PD. The primary endpoint was Progression Free Survival 1 (PFS1). Two-sided 80% CIs were calculated to detect HR of 0.57, using a one-sided α=0.10 to have 90% power, translating to 3 months of improvement in mPFS. 118 subjects were required to observe 88 events. The interim analysis (IA) was planned after 44 events. Results: 67 pts were randomized in 18 Italian Cancer Centers; 64 pts (33 in ARM A and 31 in ARM B) received treatment. Most of the pts were male (64.1%), Caucasian (96.8%), ECOG PS 0 (81.2%), and median age 66 (40-80) yrs; the main primary tumor side was proximal (64.1%) with intestinal subtype (54.7%). Peritoneum metastases were present in 42.2%. IA showed a 98% probability of achieving a positive and statistically significant result for mPFS1. The study was stopped early due to the introduction of ICIs as 1L in PD-L1-positive pts. The objective responses to 1L chemotherapy were RP (50.0%), SD (42.2%), and CR (7.8%). At a median follow-up of 31 months (IQR 19.1-33-8), 28 (84.8%) and 26 (83.8%) events for each arm were reported. The main reason for discontinuation was PD (66.7% and 35.5%). The mPFS was 3.91 (80% CI, 2.27-5.98) and 5.19 months (80% CI, 4.0-7.26) with HR= 0.736 (80%CI, 0.51-1.04; p=0.1318). The mOS was 11.25 and 16.97 months (80%CI, HR=0.596 [0.318-1.103], p=0.1003). The most common G3-4 toxicities in ARM A and B were fatigue (3.0 vs 6.4%), thrombocytopenia (3.0 vs 3.2%), hand-foot syndrome (0 vs 12.9%), diarrhea and skin rash (0 vs 3,2%, respectively). Conclusions: Despite the promising trend, considering the sample was not sized for the statistical study hypothesis, REGO maintenance therapy after 1L chemotherapy did not reach statistically significant results in mPFS1. No significant safety concerns were raised. New study designs following the REGO with ICIs are currently underway. Clinical trial information: NCT03627728 .

Targeting replication stress in pancreatic cancer: A phase II trial investigating azenosertib in combination with gemcitabine in second-line advanced pancreatic cancer.

TPS4211 Background: A major unmet need in pancreatic cancer (PDAC) is molecularly targeted treatment options for patients who develop resistance to first-line platinum chemotherapy. While combined gemcitabine and nab-paclitaxel is commonly used after progression with first-line therapy, the efficacy in the second-line setting is fair, with recent phase clinical trial data demonstrating a median progression-free survival (PFS) of 2.7 months and a median overall survival of 6.6 months (1). In recent years, preclinical work has identified that replication stress is a potential PDAC vulnerability. The WEE1 kinase regulates the checkpoint governing the G2/M transition of the cell cycle to compensate for replication stress. The G2/M checkpoint is critically important in malignancies like PDAC where over 75% of tumors have p53 pathway deficits. Therapies that inhibit cancer cells’ ability to compensate for replication stress are particularly attractive in cancers that have genomic alterations that generate replication stress. It has been demonstrated that in vitro and in vivo PDAC models were exquisitely sensitive to WEE1 inhibition in combination with gemcitabine. Azenosertib (Zn-c3) is an orally available, highly selective, nanomolar inhibitor of the WEE1 kinase and when combined with gemcitabine in PDAC cell lines, synergistic cytotoxicity is observed. Methods: NCT06015659 is an ongoing phase II clinical trial with safety lead-in that is testing the azenosertib WEE1 inhibitor combined with gemcitabine in patients with advanced pancreatic cancer after progression or intolerance with FOLFIRINOX. Subjects are dosed once daily, days 1-5, 8-12, and 15-19 with azenosertib and receive gemcitabine 800 mg/m2 on days 1 and 8 of 21-day cycles. Up to 12 subjects are expected to enroll in the safety lead-in portion based on a typical 3 + 3 design. Once the recommended phase 2 dose is confirmed, we will use a Simon two-stage minimax design to evaluate efficacy where the null hypothesis is that the true 6-month PFS rate is ≤ 24% (unacceptable historical control data) and the alternative hypothesis is that the true 6-month PFS is ≥ 44%. Pretreatment and on-treatment tumor biopsies are incorporated into the trial to identify potential biomarkers of treatment response. Subjects must be able to swallow oral tablets and have measurable disease by RECIST v1.1; prior exposure to gemcitabine is not allowed. Enrollment began November 21, 2023, and is ongoing. 1. Huffman BM, Basu Mallick A, Horick NK, et al. JAMA Netw Open. 2023;6(1):e2249720. Clinical trial information: NCT06015659 .

Abstract B045: Deep genomic and single cell molecular profiles define immunogenic pancreatic cancer

Abstract Background: Most pancreatic cancers (PC) are resistant to immunotherapy and have a poor prognosis with advanced stage (III/IV, 80%). However, recent cancer vaccine trials have demonstrated that long-term host anti-cancer immunity can improve outcomes of patients (pts) with resectable PC (stage I/II, 20%), harboring high-quality neoantigens or select KRAS alterations. It has been proposed that immunogenic PC is a genetically defined subgroup (5-10%), enriched by hypermutated PC with DNA-damage repair deficiencies including homologous repair (HRD) and mismatch repair (dMMR). Until now, comprehensive molecular studies have been mostly conducted in resected PC. Methods: All tissues were collected following an Institutional Review Board (IRB 21-275) protocol at the Memorial Sloan Kettering. Whole-exome from N=78, exome-captured bulk RNA from N=61, and single-nucleus RNA from N=23 biopsy samples of advanced PC were analyzed. Gene set enrichment and digital cytometry, singe base substitution (SBS) mutational signature, neoantigen, and genomic instability score (GIS) for HRD and immunogenicity were evaluated. Demographics, treatment history, and overall survival (OS) for pts with PC with or without HRD and dMMR were abstracted from the medical record. Results: A total of N=77 WES samples included N=21 core HRD (cHRm: 3 BRCA1, 17 BRCA2, 1 both), N=7 non-core HRD (ncHRm: 3 ATM, 2 CHEK2, 1 RAD50, 1 BARD1), and N=7 dMMR, and N=42 No DDR. N=46 males. Median age 65 years. Median OS (95% confidence interval): 26 months (m) (17-NR) for cHRm, 90m (14-NR) for dMMR, 7.4m (6.8-NR) for ncHRm, and 19m (15-27) for No DDR group. N=49 (63%) pts received first-line platinum chemotherapy. Median tumor mutation burden (TMB-WES): 2 (IQR: 2-3), 35 (30-47), 1 (1-2), and 1, respectively for cHRm, dMMR, ncHRm, and No DDR. TMB-WES significantly higher for dMMR vs. No DDR (95%CI: 35 [30-47] vs 1 [1-2], p=0.001). GIS higher for cHRm vs. No DDR (95%CI: 31 [18-38) vs 14 [9-18], p=0.008). Only two BRCA1m tumors had significant SBS3. N=61 exome captured RNAseq analysis showed cHRm (N=17) vs. No DDR (N=39) had highly enriched gene programs for upregulated immune activity in adaptive immune response (odds ratio [OR]: 0.49, p=1.7e-10), humoral immune response, and T cell activation (OR: 0.44, p=2.7e-8). Digital cytometry showed higher infiltration of gamma delta T cells (p=0.039) and lower regulatory T cells (p=0.001) in cHRm vs. No DDR. 59,771 nuclei were profiled from 23 (16 baseline and 7 follow-ups [5 matched]) biopsy samples from pts with HRD [gBRCA1 (N=3), gBRCA2 (N=14)] and No DDR (N=6). HRD tumors vs. No DDR had higher level of infiltrating CD8+ cytotoxic T cells (p&amp;lt;0.01). Tumors of long-term survivors (&amp;gt; 18m) vs. short-term survivors had significantly lower-level infiltration of macrophages (p&amp;lt;0.01) and Tregs (p=0.05). Conclusions: Our deep genomic and single-cell resolution transcriptomic analyses successfully profiled advanced PC enriched with DDR. HRD and dMMR render PC immunogenic. Further investigations for targeted immunotherapy is warranted. Citation Format: Wungki Park, Shigeaki Umeda, Catherine O'Connor, Haochen Zhang, Roshan Sharma, Allison Richards, Yingjie Zhu, Elias-Ramzey Karnoub, Xin Pei, Anna M. Varghese, Kevin Soares, Alejandro Jimenez Sanchez, Hulya Ozkan Sahin, Kenneth Yu, Vinod P. Balachandran, Joanne Chou, Fergus Keane, David Kelsen, Olca Basturk, Chaitanya Bandlamudi, Marinela Capanu, Tal Nawy, Michael Berger, Ronan Chaligne, Ghassan Abou-Alfa, Jorge S. Reis-Filho, Nadeem Riaz, Dana Pe'er, Christine A. Iacobuzio-Donahue, Eileen M. O'Reilly. Deep genomic and single cell molecular profiles define immunogenic pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B045.

Selection of Chemotherapy in Advanced Poorly Differentiated Extra-Pulmonary Neuroendocrine Carcinoma.

Extra-pulmonary poorly differentiated neuroendocrine carcinoma is rare, and evidence for treatment has been limited. In this article, the evidence behind the cytotoxic chemotherapy choices used for metastatic or unresectable EP-PD-NEC is reviewed. In the first-line setting, etoposide and platinum chemotherapy or irinotecan and platinum have been demonstrated to be equivalent in a large phase III trial. Questions remain regarding the optimal number of cycles, mode of delivery, and the precise definition of platinum resistance in this setting. In the second-line setting, FOLFIRI has emerged as an option, with randomized phase 2 trials demonstrating modest, but significant, response rates. Beyond this, data are extremely limited, and several regimens have been used. Heterogeneity in biological behaviour is a major barrier to optimal EP-PD-NEC management. Available data support the potential role of the Ki-67 index as a predictive biomarker for chemotherapy response. A more personalised approach to management in future studies will be essential, and comprehensive multi-omic approaches are required to understand tumour somatic genetic changes in relation to their effects on the surrounding microenvironment.

Cost-Effectiveness Analysis of Biomarker Testing to Guide First-Line PARP Inhibitor Maintenance for Patients with Advanced Ovarian Cancer After Response to First-Line Platinum Chemotherapy in the USA.

Poly(ADP-ribose) polymerase inhibitor maintenance treatments are available for platinum-sensitive advanced ovarian cancer. Olaparib (O) is available for BRCA mutation patients or in combination with bevacizumab (O+B) for patients with homologous recombination deficiency (HRD+); niraparib (N) is available for all patients. This study aimed to evaluate the cost effectiveness of biomarker testing and maintenance treatments(mTx) with poly(ADP-ribose) polymerase inhibitor in platinum-sensitive advanced ovarian cancer in the USA. Ten strategies were evaluated (S1-S10), representing biomarker testing (none, BRCA or HRD), and mTx (O, O+B, Nor B). PAOLA-1 data were used to build a model estimating progression-free survival (PFS), second PFS (PFS2) and overall survival for O+B. PFS was modelled through mixture cure models; PFS2 and overall survival were modelled by standard parametric models. Hazard ratios of PFS for O+B versus B, N and O were obtained from the literature to estimate PFS for B, N and O. PFS2 and OS for B, N and O were informed by PFS benefits. S2 (no testing, B) had the lowest cost while S10 (HRD testing, O+B for HRD+ and B for HRD-) had the highest quality-adjusted life-years (QALYs). All niraparib strategies were dominated. S2, S4 (BRCA testing, O for BRCA+ and B for BRCA-), S6 (BRCA testing, olaparib plus bevacizumab for BRCA+ and bevacizumab for BRCA-) and S10 were the non-dominated strategies with an incremental cost-effectiveness ratio of $29,095/QALY, $33,786/QALY and $52,948/QALY for S4 versus S2, S6 versus S4 and S10 versus S6, respectively. Homologous recombination deficiency testing followed by O+B for HRD+ and B for HRD- is a highly cost-effective strategy for patients with platinum-sensitive advanced ovarian cancer. A HRD biomarker-guided approach provides most QALYs with good economic value.

Chemotherapy response in low-grade serous ovarian carcinoma at a comprehensive cancer center: Readdressing the roles of platinum and cytotoxic therapies.

Data on platinum sensitivity of low-grade serous ovarian carcinoma (LGSOC) in the upfront setting is lacking, and there is limited and contradictory information on chemotherapy responses in recurrent disease. Patients with LGSOC seen at a comprehensive cancer center from January 1, 1998 to September 30, 2021 were identified from institutional databases. Response to neoadjuvant chemotherapy (NACT) or adjuvant platinum-based chemotherapy and to second- to fifth-line regimens was retrospectively characterized by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Wilcoxon rank-sum and two-tailed Fisher exact tests were employed. Of 50 patients, 12 received platinum doublets for suboptimal residual disease and 11 as NACT. Of 12 patients with suboptimal residual disease, seven (58%) achieved objective responses (five partial responses [PRs] and two complete responses); of the 11 patients who underwent NACT, one (9%) achieved a PR (p=.027). The 15 remaining patients had stable disease on first-line platinum chemotherapy. Of 44 patients who recurred, 20 had RECIST-evaluable responses to second-line and 27 to third-line chemotherapy. Objective response rates to platinum-based chemotherapy were 22% (two of nine) in the second line and 10% (one of 10) in the third. In second and third lines, highest response rates were observed with nonplatinum chemotherapy with bevacizumab, at 100% (two of two) and 30% (three of 10), respectively. Primary platinum-based chemotherapy has moderate activity in LGSOC and minimal activity in the recurrent setting, suggesting standard definitions of platinum sensitivity may not apply in LGSOC. In the second and third lines, nonplatinum chemotherapy/bevacizumab elicited the highest response rates.

Prognostic value of mismatch repair deficiency in patients receiving first-line fluoropyrimidine plus platinum chemotherapy for metastatic, recurrent, or locally advanced unresectable gastric cancer.

461 Background: In localized gastric cancer (GC), deficient mismatch repair (dMMR) tumors reportedly have a favorable prognosis. However, a potentially detrimental effect of the dMMR status was suggested in patients treated with adjuvant chemotherapy. It remains unclear whether the mismatch repair (MMR) status can impact clinical outcomes in patients with metastatic GC (mGC) receiving palliative chemotherapy. We examined the impact of the MMR status on survival outcomes of patients with HER2-negative mGC receiving first-line fluoropyrimidine plus platinum (FP) chemotherapy. Methods: We reviewed patients with histologically confirmed metastatic, recurrent, or locally advanced unresectable adenocarcinoma of the stomach or gastroesophageal junction receiving first-line FP chemotherapy between January 2015 and August 2018 at Asan Medical Center, Korea. MMR status was correlated with clinical characteristics and survival outcomes for patients with available MMR immunohistochemistry results. Results: Of 895 patients, we analyzed 543 with available MMR protein expression results, and dMMR was detected in 4.4% (n=24). Patients with dMMR exhibited a significantly higher median age than those with proficient MMR (pMMR) (64 vs. 58 years, p=0.044). No signet ring cell carcinoma (SRCC) was detected among dMMR tumors, whereas SRCC was found in 17.5% of pMMR tumors. Based on our prognostic model (Koo DH et al, 2011), only 4.2% of patients with dMMR were classified as the poor-risk group (vs. 16.8% of patients with pMMR, p=0.097). No significant difference in progression-free survival (PFS) was noted between patients with dMMR and pMMR tumors (median, 5.6 vs. 5.8 months, p=0.266). Patients with dMMR tumors tended to have better overall survival than those with pMMR tumors; this difference was not statistically significant (median, 17.9 vs. 12.2 months, p=0.183). In the good-risk subgroup, patients with dMMR tumors had a significantly worse PFS than those with pMMR tumors (median, 5.6 vs. 9.2 months, p=0.009); multivariate analysis revealed that MMR status was an independent factor for poor PFS in this subgroup. Conclusions: Survival outcomes of dMMR mGC did not differ from pMMR in patients who received first-line FP chemotherapy. However, in the good-risk subgroup, patients with dMMR tumors had a significantly shorter PFS than those with pMMR, suggesting a potentially reduced efficacy of cytotoxic chemotherapy in these patients.

Influence of first-line chemotherapy regimen on survival outcomes of patients with advanced urothelial carcinoma who received second-line immune checkpoint inhibitors.

The therapeutic landscape for advanced urothelial carcinoma (mUC) has changed significantly since studies establishing superiority of cisplatin as first-line therapy were conducted. Most patients who are eligible now receive either maintenance or second-line immune checkpoint inhibitors (ICI) and data comparing first-line platinum chemotherapy agents in this setting is limited. The objective of this study was to determine the impact of first-line platinum chemotherapy agent on survival for patients who receive second-line ICI. This is a retrospective cohort study of real-world data, performed from January 1, 2015, to March 21, 2021, included patients with a diagnosis of metastatic or locally advanced urothelial carcinoma. Exposure of interest was first-line platinum-doublet chemotherapy (gemcitabine and/or cisplatin or gemcitabine and/or carboplatin) followed by single-agent second-line ICI. The primary endpoint was overall survival from start of second-line therapy. 2,042 patients received either gemcitabine and cisplatin (gem/cis) or gemcitabine and carboplatin (gem/carbo) as first-line therapy. The primary analysis of 890 patients who received second-line single-agent ICI had a median follow-up was 24.2 months from initiation of second-line therapy. Important differences in baseline demographics and/or clinical factors between groups were age, performance status, incidence of upper tract disease, and cisplatin eligibility. Unadjusted overall survival (OS) calculated from start of second-line therapy was longer in patients who received gem/cis compared to gem/carbo followed by ICI (median 9.3 vs. 8.8 months, P = 0.0009). However, OS adjusted for covariates was not significantly different with a hazard ratio (HR) of 0.94 (95% CI, 0.79-1.13; P = 0.50). A separate time-varying covariate model also showed no association between OS and first-line gem/cis (HR 1.00 [95% CI, 0.84-1.19]) while receiving second-line ICI. Survival time on ICI in the second-line setting is the same regardless of choice of prior platinum agent (cisplatin vs. carboplatin) suggesting against specific synergy for one of these agents with ICI. However, a significantly greater proportion of patients in a landmark analysis had long-term benefit with cisplatin strongly supporting it is as the preferred first-line platinum agent.

Biomarker testing to guide first-line PARP inhibitor maintenance for patients with advanced ovarian cancer after response to first- line platinum chemotherapy: A cost-effectiveness study (382)

Biomarker testing to guide first-line PARP inhibitor maintenance for patients with advanced ovarian cancer after response to first- line platinum chemotherapy: A cost-effectiveness study (382)

CO77 Efficacy of PD1/PD-L1 Inhibitors VS Chemotherapy As First-Line Treatment of Non-Small Cell Lung Cancer Among Patients with Different PD-L1 Expression Levels

Since the efficacy of programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) immune checkpoint inhibitor monotherapy (PD1-mono) correlates with PD-L1 expression levels, a meta-analysis was conducted to assess the efficacy of first-line PD1-mono vs platinum chemotherapy in patients with different PD-L1 expression levels.

A Pan-Canadian Consensus Statement on First-Line PARP Inhibitor Maintenance for Advanced, High-Grade Serous and Endometrioid Tubal, Ovarian, and Primary Peritoneal Cancers.

The majority of patients with advanced, high-grade epithelial-tubo ovarian cancer (EOC) respond well to initial treatment with platinum-based chemotherapy; however, up to 80% of patients will experience a recurrence. Poly(ADP-ribose) Polymerase (PARP) inhibitors have been established as a standard of care maintenance therapy to prolong remission and prevent relapse following a response to first-line platinum-chemotherapy. Olaparib and niraparib are the PARP inhibitors currently approved for use in the first-line maintenance setting in Canada. Selection of maintenance therapy requires consideration of patient and tumour factors, presence of germline and somatic mutations, expected drug toxicity profile, and treatment access. This paper discusses the current clinical evidence for first-line PARP inhibitor maintenance therapy in patients with advanced, high-grade EOC and presents consensus statements and a treatment algorithm to aid Canadian oncologists on the selection and use of PARP inhibitors within the Canadian EOC treatment landscape.

Outcomes of second-line therapies in patients with metastatic de novo small cell prostate cancer (SCPC) and treatment-emergent neuroendocrine prostate cancer (tNEPC).

e17022 Background: De novo SCPC and tNEPC in metastatic castrate resistant prostate cancer (mCRPC) are rare, aggressive cancers with a poor prognosis. After first-line (1L) platinum chemotherapy (PLT), there is no consensus on 2L treatments. This multi-institutional, retrospective study examines practice patterns among clinicians and evaluates the outcomes of patients (pts) with SCPC or tNEPC in the 2L setting. Methods: After IRB approval, pts with a pathologic diagnosis of SCPC or tNEPC (any % of SC or NE histology defined by institutional review) were identified. Pts diagnosed between 2000-2020 who received 1L PLT and any 2L systemic therapy (tx) for SCPC or tNEPC were included. Standardized data collection templates containing demographic, clinical, and pathologic variables were collected. The primary endpoint was objective response rate (ORR) to 2L tx. Secondary endpoints included PSA response, time on 2L treatment, and overall survival (OS) from time of 2L tx. Data was analyzed using descriptive statistics. Results: Forty-two pts (21 SCPC, 21 tNEPC) from 6 institutions were included. At SCPC/tNEPC diagnosis, the overall cohort had a median age of 65.0 years (IQR 60.5, 68.0) and median PSA of 3.0 ng/dL (IQR 0.5, 21.8). The most common sites of metastasis included lymph node (78.6%), bone (54.8%), and liver (52.4%). For 1L tx, 37 pts (88.1%) received PLT and 5 (11.9%) had PLT + immunotherapy (IMM). For treatment to the prostate, 21 (51.2%) had none, 7 (17.1%) radiation (RT), 9 (22.0%) surgery, 3 (7.3%) RT + surgery, and 1 (2.4%) brachytherapy alone. Concurrent ADT was given to 32 pts (76.2%) in the 1L and 2L. At last follow-up, 34 pts (81.0%) were dead, 4 (9.5%) were alive, and 4 (9.5%) were lost to follow-up/censored. For 2L tx, 10 pts (23.8%) received PLT, 8 (19.0%) taxane monotherapy (TAX), 10 (23.8%) IMM, 8 (19.0%) other chemotherapy (CHX), and 6 (14.3%) other tx. Among 38 pts evaluable for response, the ORR was 15.8% (6 pts with PR: 4 PLT, 1 IMM, 1 CHX). PSA response ≥ 50% to 2L tx was seen in 5 of 29 pts with PSA data (17.2%). Other outcomes data are reported in Table. Conclusions: In this retrospective study, pts with SCPC or tNEPC who reached 2L tx received a wide variety of treatment regimens, reflecting the lack of consensus in this tx setting. ORR was low and overall prognosis was poor in the 2L regardless of tx choice. Pts on 2L immunotherapy seemed to have the shortest mOS. [Table: see text]

Dose Modification of Etoposide plus Platinum in Elderly Patients with Extensive-Disease Small-Cell Lung Cancer

Background: Elderly patients with extensive-disease small-cell lung cancer (ED-SCLC) have a high risk of chemotherapy toxicity due to multiple comorbidities and poor performance status. Although dose modification is often used to avoid toxicity in elderly patients with ED-SCLC, there is little data on the effect of initial dose-reduced chemotherapy on survival outcomes. Methods and Patients: We retrospectively reviewed 100 elderly patients (≥70 years) with ED-SCLC who received first-line etoposide plus platinum chemotherapy between January 2006 and December 2020. Results: The median age was 74 years. Eighty-nine patients (89%) had a history of smoking, and 38 (38%) had chronic lung disease. Thirty-four patients (34%) received dose-reduced etoposide plus platinum in the first cycle. The dose-reduced group had significantly higher age, lower body mass index, and poor Eastern Cooperative Oncology Group Performance Score. There were no significant differences in survival outcomes between the dose-reduced and full-dose chemotherapy (median overall survival [OS], 4.9 vs. 6.5 months, p = 0.440; median progression-free survival [PFS], 3.7 vs. 4.6 months, p = 0.272). In multivariate analyses, DR in the first cycle (hazard ratio 0.519, 95% CI: 0.269–1.000, p = 0.050) was significantly associated with OS. Following a subgroup analysis of 59 patients who received minimum four cycles, no significant differences in survival outcomes between the two groups (median OS, 10.9 vs. 9.4 months, p = 0.817; median PFS, 6.3 vs. 6.5 months, p = 0.902) were noted. Conclusions: The dose-reduced chemotherapy with first-line etoposide plus platinum had non-inferior survival outcomes compared to the full-dose chemotherapy in elderly patients with ED-SCLC.

SEOM-SOGUG clinical guideline for localized muscle invasive and advanced bladder cancer (2021)

Most muscle-invasive bladder cancer (BC) are urothelial carcinomas (UC) of transitional origin, although histological variants of UC have been recognized. Smoking is the most important risk factor in developed countries, and the basis for prevention. UC harbors high number of genomic aberrations that make possible targeted therapies. Based on molecular features, a consensus classification identified six different MIBC subtypes. Hematuria and irritative bladder symptoms, CT scan, cystoscopy and transurethral resection are the basis for diagnosis. Radical cystectomy with pelvic lymphadenectomy is the standard approach for muscle-invasive BC, although bladder preservation is an option for selected patients who wish to avoid or cannot tolerate surgery. Perioperative cisplatin-based neoadjuvant chemotherapy is recommended for cT2-4aN0M0 tumors, or as adjuvant in patients with pT3/4 and or pN + after radical cystectomy. Follow-up is particularly important after the availability of new salvage therapies. It should be individualized and adapted to the risk of recurrence. Cisplatin–gemcitabine is considered the standard first line for metastatic tumors. Carboplatin should replace cisplatin in cisplatin-ineligible patients. According to the EMA label, pembrolizumab or atezolizumab could be an option in cisplatin-ineligible patients with high PD-L1 expression. For patients whose disease respond or did not progress after first-line platinum chemotherapy, maintenance with avelumab prolongs survival with respect to the best supportive care. Pembrolizumab also increases survival versus vinflunine or taxanes in patients with progression after chemotherapy who have not received avelumab, as well as enfortumab vedotin in those progressing to first-line chemotherapy followed by an antiPDL1/PD1. Erdafitinib may be considered in this setting in patients with FGFR alterations. An early onset of supportive and palliative care is always strongly recommended.

Metastatic Renal Medullary and Collecting Duct Carcinoma in the Era of Antiangiogenic and Immune Checkpoint Inhibitors: A Multicentric Retrospective Study.

Simple SummaryCollecting duct carcinoma (CDC) and renal medullary carcinoma (RMC) are two rare cancers with a very poor prognosis. Currently, first-line treatment is a platinum-based doublet, but very few studies have evaluated the effectiveness of treatments for subsequent lines. Additionally, despite the advent of new therapies in renal clear cell carcinoma, data are lacking on these types of cancers. Thus, we conducted a retrospective study in 11 centers in France to evaluate the different types and effectiveness of treatments received beyond first-line treatment in patients with metastatic CDC or RMC. Subsequent treatments showed limited efficacy regardless of the type of therapy received. This study supports the importance of finding therapeutic targets and/or biomarkers to improve patient outcomes.Collecting duct carcinoma (CDC) and renal medullary carcinoma (RMC) are two rare subtypes of kidney cancer with a poor prognosis in the metastatic setting. Beyond first-line treatment, there are no standard-of-care therapies. This retrospective study assessed the efficacy of treatments after first-line chemotherapy in 57 patients with metastatic (m) CDC (n = 35) or RMC (n = 22) treated between 2010 and 2019 at 11 French centers. The median age was 53 years; overall, 60% (n = 34) of patients were metastatic at diagnosis. After a median follow-up of 13 months, the median overall survival was 12 (95% CI, 11–16) months. All patients received first-line platinum chemotherapy ± bevacizumab, with a median time to progression of 7.27 (95% CI, 7–100 months and an objective response rate (ORR) of 39% (95% CI, 26–52%). Patients received a median of two (1–5) treatment lines. Subsequent treatments included tyrosine kinase inhibitors (n = 12), chemotherapy (n = 34), and checkpoint inhibitors (n = 20), with ORR ranging 10–15% and disease control rates ranging 24–50%. The duration of response for all treatments was ~2 months. Notably, nine patients with CDC were still alive > two years after metastatic diagnosis. Beyond first-line therapy, treatments showed very low antitumor activity in mCDC/RMC. A better understanding of the biology of those rare tumors is urgently needed in order to identify potential targets.

A Real-World Analysis of the Use of Systemic Therapy in Malignant Pleural Mesothelioma and the Differential Impacts on Overall Survival by Practice Pattern

IntroductionMalignant pleural mesothelioma (MPM) is an aggressive malignancy that affects older adults with frequent comorbidities, making real-world treatment decisions challenging. This study compares the overall survival (OS) of patients with MPM by physician’s choice of first-line (1L) platinum chemotherapy (PC), second-line (2L) immunotherapy versus chemotherapy, and by receipt of maintenance therapy (MT). MethodsThe study included patients diagnosed with advanced MPM in the Flatiron Health electronic health record–derived database who initiated PC with pemetrexed in the 1L setting between 2011 and 2019. Patients in the 2L therapy analysis received single-agent chemotherapy versus immunotherapy after the progression of disease from our 1L cohort. Patients in the MT cohort were identified on the basis of continued receipt of pemetrexed with or without bevacizumab after dropping PC at prespecified intervals. The OS of patients by choice of 1L PC, 2L immunotherapy versus chemotherapy, and receipt of MT was summarized by means of Kaplan-Meier survival estimates and compared in the context of propensity score matching weighted analyses. ResultsIn propensity score matching weighting analysis from 2065 patients with MPM, there was no evidence of an OS difference by choice of 1L PC (hazard ratio [HR] = 1.08, 95% confidence interval [CI]: 0.89–1.31, p = 0.43), suggestive evidence of an OS difference by choice of 2L immunotherapy versus chemotherapy (HR = 0.68, 95% CI: 0.42–1.08; p = 0.10), and no evidence of an OS difference by receipt of MT (HR = 0.92, 95% CI: 0.72–1.16, p = 0.46). ConclusionsUsing real-world, propensity score–matched weighted analysis of MPM, we found there was no difference in OS by choice of 1L PC, 2L immunotherapy or chemotherapy, or by receipt of MT.

Comparative Outcomes of Second-line Topoisomerase-I Inhibitor Therapies on Neuroendocrine Carcinoma.

This investigation aims to assess the outcomes for second-line therapies to treat extrapulmonary neuroendocrine carcinoma (EP-NEC) after first-line platinum-based chemotherapy. With IRB approval, we conducted a retrospective study of EP-NEC patients that progressed on first-line platinum chemotherapy from 2008 to 2018. Demographic data and treatment-related characteristics were collected and represented as descriptive statistics. The primary endpoints include overall survival (OS) and progression-free survival (PFS). OS and PFS were estimated and stratified by site of primary (gastroenteropancreatic [GEP] versus non-GEP) and type of second-line therapy (irino/topotecan versus others). Log-rank test and Kaplan-Meier curves were used to compare survival distributions between groups. Forty-seven patients met eligibility, with median age 65 (range 31-82), 62% male, and 83% White; 22 were GEP and 25 were non-GEP primary. Thirty patients (63.8%) received second-line therapy where 11 received irinotecan/topotecan (ir/to), while 19 received other agents (temozolomide, other platinum agents, gemcitabine, paclitaxel, pembrolizumab, and sunitinib). The median OS was 10.3months in the ir/to group versus 13.4months for other therapies, p = 0.10. The median PFS for ir/to therapy compared to other therapies was 2.0months versus 1.8months, respectively, p = 0.72. The OS and PFS with and without ir/to were not significantly different by the primary site (p = 0.61 and p = 0.21). Many EP-NEC patients undergo second-line therapies. Interestingly, outcomes for ir/to-containing second-line therapies were not statistically different from other agents, regardless of the site of primary. With approval of new second-line therapies for small cell lung cancer, further research in therapeutic options is needed for this aggressive disease.