• Irinotecan with or without capecitabine as a beyond 2nd line regime for esophago-gastric adenocarcinomas

      Hapuarachi, Sonal B; Dawod, Mohammed; Weaver, Jamie M; Shaheen, Fadhel; Khan, Adeel; Hubner, Richard A; Waddell, Tom; Mansoor, Was; Christie NHS Foundation Trust, Manchester (2020)
      Background: Purpose: The aim of this retrospective study was to assess the efficacy and toxicity of irinotecan +/- capecitabine for patients with metastatic esophago-gastric (EG) adenocarcinomas previously treated with at least two chemotherapy regimens including platinum-based, fluoropyramidines and taxanes. Introduction: Treatment for metastatic EG cancer beyond 2nd line remains controversial. Recently, the TAGS phase III trial (Shitara et al., 2018) showed overall survival benefit with Trifluridine/tipiracil of 2.1 months compared to placebo as a third line. Apatinib is also approved for use as third line in China (Li et al., 2013). Based on minimal evidence (Kang et al., 2013), irinotecan in combination with capecitabine is used in the UK. We performed a retrospective study to assess the efficacy and toxicity of irinotecan as a beyond 2nd line regime in metastatic EG adenocarcinomas in one of Europe’s largest cancer centres, The Christie. Methods: Data was collected retrospectively from all metastatic EG adenocarcinoma patients who were treated with irinotecan +/- capecitabine as a beyond 2nd line palliative treatment at the Christie Hospital from January 2014 to December 2019. Irinotecan was either given 2 or 3 weekly at dose of 180 mg/m² with or without capecitabine 800 mg/m². Response rate (RR) was calculated according to RECIST version 1.1, overall survival measured and toxicity data collected. Results: Fifty-six patients received irinotecan as beyond 2nd line palliative chemotherapy. Out of the thirty-seven patients with measurable disease on their scans, the overall response rate was 8.1% and the disease control rate was 51.4% as per RECIST 1.1. Median overall survival was 5 months (95% CI 4.2-5.8). The presence of grade 3-4 toxicities was 16% (9 patients) and included neutropenia, fatigue, nausea and diarrhea. On average, 3.7 cycles were administered, 32% (18 patients) required dose reductions, mainly secondary to grade 2 diarrhea and fatigue. Conclusions: Irinotecan in combination with capecitabine is efficacious as a beyond 2nd line regime in metastatic EG with an acceptable toxicity profile with a limited role in patients with resistant disease to first line platinum-based chemotherapies with fluoropyramidines.
    • Nivolumab in combination with alternatively scheduled ipilimumab in first-line treatment of patients with advanced renal cell carcinoma: A randomized phase II trial (PRISM)

      Vasudev, N. S.; Ainsworth, G.; Brown, S.; Pickering, L.; Waddell, Tom; Fife, K.; Griffiths, R.; Sharma, A.; Katona, E.; Howard, H.; et al. (2021)
      Background Ipilimumab (IPI) plus nivolumab (N) is a standard first-line treatment for patients (pts) with intermediate and poor-risk advanced renal cell carcinoma (aRCC). Grade 3/4 (G3/4) treatment-related adverse events (trAE) are relatively common during the initial combination period. The aim of this randomized phase II trial was to determine whether modified scheduling of IPI, in combination with N, is associated with improved tolerability, whilst maintaining treatment efficacy in line with previous comparative studies with sunitinib. Methods Pts with untreated clear cell aRCC were randomized 1:2 to receive 4 doses of IPI 1mg/kg Q3W (conventional IPI) or Q12W (modified IPI), in combination with N (3mg/kg), until disease progression or unacceptable toxicity. The primary endpoint was the proportion of pts with a G3/4 trAE within 12 months of initiating treatment (from those who received at least one dose of therapy (modified intention-to-treat)). Secondary endpoints included progression-free survival (PFS) at 12 months and objective response rate (ORR). Results 192 pts (69.8% intermediate/poor-risk) received at least one dose of study drug. G3/4 trAE were significantly lower amongst pts receiving modified IPI compared to conventional IPI (32.8% v 53.1%; OR 0.43 [90% CI: 0.25, 0.72]; p=0.0075). Efficacy endpoints are given in the table and were similar between treatment arms and pre-specified IMDC risk subgroups. Conclusions Giving IPI 12-weekly, instead of 3-weekly, in combination with N, was associated with a clinically significant reduction in rates of G3/4 trAE. Outcome data suggested there was no clear reduction in ORR or PFS with the modified schedule and is in line with previous comparative studies with sunitinib (Table).
    • Subsequent therapy following pembrolizumab plus axitinib or sunitinib treatment for advanced renal cell carcinoma (RCC) in the phase III KEYNOTE-426 study

      Gafanov, R.; Powles, T. B.; Bedke, J.; Stus, V.; Waddell, Tom; Nosov, D.; Pouliot, F.; Soulieres, D.; Melichar, B.; Azevedo, S.; et al. (2021)
      Background:In the phase III KEYNOTE-426 study, pembrolizumab + axitinib showedsignificant improvement in OS, PFS, and ORR vs sunitinib in patients with RCC. Thisanalysis assessed subsequent treatment in patients enrolled in KEYNOTE-426.Methods:Treatment-naive patients with clear cell RCC, KPS score =70%, andmeasurable disease (RECIST v1.1) were randomly assigned 1:1 to receive pem-brolizumab 200 mg IV every 3 weeks for up to 35 doses + axitinib 5 mg orally twicedaily or sunitinib 50 mg once daily (4 weeks on/2 weeks off) until progression, toxicity,or withdrawal. Type of and time to subsequent therapy were assessed.Results:Of patients in the pembrolizumab + axitinib arm and in the sunitinib arm,81.4% (349/432) and 90.6% of patients (385/429), respectively, discontinued treat-ment; radiologic or clinical PD was the most common reason for discontinuation inboth (pembrolizumab + axitinib: 65.0% [227/349]; sunitinib: 68.1% [262/385]). Ofpatients who discontinued, 58.5% of patients (204/349) in the pembrolizumab +axitinib arm and 73.0% (281/385) in the sunitinib arm received subsequent therapy(Table). Although a similar proportion of patients in both arms received subsequenttherapy with a VEGF/VEGFR inhibitor (pembrolizumab + axitinib: 88.2% [180/204];sunitinib: 68.7% [193/281]), a greater proportion of patients in the sunitinib arm(74.4% [209/281]) received subsequent PD-1/PD-L1 inhibitor therapy than in thepembrolizumab + axitinib arm (21.6% [44/204]). Of patients in the pembrolizumab +axitinib arm and the sunitinib arm, 32.4% (66/204) and 22.8% (64/281), respectively,received other therapies.Conclusions:The superior efficacy of pembrolizumab + axitinib compared withsunitinib is observed despite the increased use of subsequent therapy in the sunitinibarm. These data continue to support the use offirst-line pembrolizumab + axitinib in patients with RCC