• Alternating irinotecan with oxaliplatin combined with UFT plus leucovorin (SCOUT) in metastatic colorectal cancer.

      Sheikh, Hamid Y; Valle, Juan W; Waddell, Thomas K; Palmer, Karen; Wilson, Gregory; Sjursen, Ann-Marie; Craven, Olive; Swindell, Ric; Saunders, Mark P; Department of Clinical Oncology, Christie Hospital, Manchester, UK. (2008-08-19)
      Tegafur-uracil (UFT) plus leucovorin (LV, folinic acid) with alternating irinotecan and oxaliplatin were effective and well tolerated in patients with metastatic colorectal cancer (mCRC) in a phase I study. This study expanded the maximum tolerated dose group. Patients aged >or=18 years had histologically confirmed, inoperable, previously untreated, measurable mCRC. Patients received irinotecan 180 mg m(-2) on day 1, oxaliplatin 100 mg m(-2) on day 15 and UFT 250 mg m(-2) plus LV 90 mg on days 1-21 every 28 days. The phase I/II study comprised 45 patients, 29 at the maximum tolerated dose (MTD). The response rate in 38 evaluable patients was 63% (95% confidence interval (CI): 49-80). Median time to progression and overall survival were 8.7 months (95% CI: 7.9-10.4) and 16.8 months (95% CI: 9.6-25.3), respectively. In the MTD group, one patient had grade 3 leucopenia; one had grade 3 neutropaenia; three had grade 3 diarrhoea; and one had grade 3 neurotoxicity. No hand-foot syndrome grade >1 was seen. In total, 67% of eligible patients received second-line therapy. UFT plus LV with alternating irinotecan and oxaliplatin is an efficacious first-line treatment for mCRC, with minimal neurotoxicity and hand-foot syndrome.
    • Axitinib and avelumab (AA) as first-line treatment of metastatic renal cell carcinoma (mRCC): A real-world outcome review in the Northwest of England, United Kingdom

      Allison, Jennifer; Charnley, Natalie; Stevenson, R.; Waddell, Thomas K; Pillai, Manon; Christie NHS Foundation Trust, Manchester, (2021)
      Background: The combination of the immune checkpoint inhibitor avelumab and VEGF-targeted, antiangiogenic tyrosine kinase inhibitor axitinib (AA) has demonstrated superior PFS and ORR compared to sunitinib in patients with mRCC and is an option for first line treatment across all IMDC risk scores. In this retrospective review we report our real world experience of this combination in three cancer centres in the Northwest of England. Methods: Treatment naïve mRCC patients receiving AA through the Early Access to Medicine Scheme at 3 cancer sites in the UK between May 2019 and July 2020 were identified. Primary outcomes of interest include overall response rate (ORR), adverse events (AEs) and preliminary survival observations. Results: A total of 44 patients were identified with a median follow up of 6.9 months (0.8-13.5 mo). Median age was 68 (48-81); 68% were male. The patients’ adult comorbidity evaluation score (ACE-27) was calculated: 0 = 43%, 1 = 30%, 2 = 7% and 3 = 20% . 45%, 48% and 7% of patients had favourable (F), intermediate (I) and poor (P) IMDC risk scores respectively. All had clear cell histology with 16% demonstrating sarcomatoid change. Most patients had undergone a nephrectomy (70%) and 36% had a single organ site of metastatic disease. ORR in the whole cohort was 60% (CR 5%, PR 55%, SD 25%, PD 2%, NE 13 %). Median time to first response was 2.6 months (0.6- 8.2mo). At time of data cut-off, 64% of patients remain on treatment (80% F, 48% I and 67% P). 14% of patients discontinued treatment due to disease progression while 22% stopped due to toxicity. The majority of patients (68%) continued axitinib at the starting dose of 5mg BD. Dose escalation of axitinib was possible in 9% patients while 23% needed a dose reduction due to toxicities. AEs were observed in 36 (82%) patients (G3 36%); the commonest being mucositis 30%; hypertension 23% (G3 11%); fatigue 25%; thyroid dysfunction 18%; diarrhoea 20% (G3 5%); hepatitis 20% (G3 11%). 9% of patients experienced an infusion reaction to avelumab. Overall, 9 (20%) patients received steroids for suspected immune related adverse events (irAEs); 6 (14%) were managed as G3≤ irAEs. 9 (20%) patients required inpatient admission due to AEs; 5 (11%) were associated with irAEs. Of the patients who discontinued AA treatment, 50% received subsequent therapy (12.5%, 75% and 12.5% receiving combination checkpoint inhibitor therapy, other VEFG TKi and TKi/MTOR combination respectively). 4 patients remain on active surveillance with no evidence of progression. Conclusions: Our early experience of AA in this real world setting reports comparable clinical responses to the published data. Treatment is well tolerated, with lower than expected levels of G3 or above AEs which is reassuring in a non-trial selected population. Follow-up is ongoing and updated efficacy and safety outcomes will be presented.
    • Digital histological markers based on routine H&E slides to predict benefit from maintenance immunotherapy in esophagogastric adenocarcinoma

      Vu, Q. D.; Fong, C.; von Loga, K.; Raza, S. E. A.; Rodrigues, D. N.; Patel, B.; Peckitt, C.; Begum, R.; Athauda, A.; Starling, N.; et al. (2021)
      Background: Immune checkpoint inhibition (ICI) is an effective treatment for a subset of patients with inoperable esophagogastric (EG) adenocarcinoma. Robust predictive biomarkers are required to identify these patients and a variety of strategies including immunohistochemical staining of PD-L1 and tumor mutational burden (TMB) assessment have been employed. Here, we explore digital histological (dHis) markers based on routine hematoxylin and eosin (H&E) slides alone or in combination with molecular markers (PD-L1 and TMB) as predictive biomarkers of benefit from maintenance immunotherapy in patients with inoperable EG adenocarcinoma. Methods: We developed a deep learning based algorithm to construct novel digital histological (dHis) markers by summarizing the statistics of all different types of nuclei present in the tumor tissue sections, their morphological features and their colocalization across each of the whole slide image. The dHis markers were then input into a decision-tree based approach to test for prognostic and predictive power alone or in combination with molecular markers. We assessed two cohorts of patients randomized to surveillance (n=38) or maintenance durvalumab (n=35) after 18 weeks of first-line platinum-based chemotherapy in the PLATFORM trial (NCT02678182) according to the 12-week progression-free rate. We measured the accuracy as the area under the receiver operating characteristics curve (AUROC) to determine the prognostic and predictive power of each marker set. We conducted a stratified 3-fold cross-validation, repeated 5 times and report the overall AUROC results. Results: Molecular markers alone yielded an AUROC of 0.5581±0.0939 on the surveillance arm, 0.6671±0.1479 on the treatment arm, and 0.6376±0.0958 for both the arms. Digital histological markers alone yielded an AUROC of 0.8952±0.0638, 0.8995±0.0719 and 0.8488±0.0700 on surveillance, immunotherapy and both arms, respectively. When using these two sets of markers together for both arms, molecular markers offered a limited improvement (around 0.02). Patients with TMB in the highest tertile were associated with lower likelihood of having progressive disease 12 weeks after randomization. Interestingly, dHis markers from morphology of connective and inflammatory nuclei were highly predictive for treatment benefit. Conclusions: Preliminary results suggest digital histological markers offer significant improvement over PD-L1 and TMB markers alone for predicting benefit from immunotherapy in EG adenocarcinoma with the added advantages of scalable, rapid, low-cost and objective quantification on routine histology sections. We are further validating their effectiveness on a larger cohort.
    • Efficacy of reduced-intensity chemotherapy with oxaliplatin and capecitabine on quality of life and cancer control among older and frail patients with advanced gastroesophageal cancer: The GO2 phase 3 randomized clinical trial

      Hall, P. S.; Swinson, D.; Cairns, D. A.; Waters, J. S.; Petty, R.; Allmark, C.; Ruddock, S.; Falk, S.; Wadsley, J.; Roy, R.; et al. (2021)
      Importance: Older and/or frail patients are underrepresented in landmark cancer trials. Tailored research is needed to address this evidence gap. Objective: The GO2 randomized clinical trial sought to optimize chemotherapy dosing in older and/or frail patients with advanced gastroesophageal cancer, and explored baseline geriatric assessment (GA) as a tool for treatment decision-making. Design, setting, and participants: This multicenter, noninferiority, open-label randomized trial took place at oncology clinics in the United Kingdom with nurse-led geriatric health assessment. Patients were recruited for whom full-dose combination chemotherapy was considered unsuitable because of advanced age and/or frailty. Interventions: There were 2 randomizations that were performed: CHEMO-INTENSITY compared oxaliplatin/capecitabine at Level A (oxaliplatin 130 mg/m2 on day 1, capecitabine 625 mg/m2 twice daily on days 1-21, on a 21-day cycle), Level B (doses 0.8 times A), or Level C (doses 0.6 times A). Alternatively, if the patient and clinician agreed the indication for chemotherapy was uncertain, the patient could instead enter CHEMO-BSC, comparing Level C vs best supportive care. Main outcomes and measures: First, broad noninferiority of the lower doses vs reference (Level A) was assessed using a permissive boundary of 34 days reduction in progression-free survival (PFS) (hazard ratio, HR = 1.34), selected as acceptable by a forum of patients and clinicians. Then, the patient experience was compared using Overall Treatment Utility (OTU), which combines efficacy, toxic effects, quality of life, and patient value/acceptability. For CHEMO-BSC, the main outcome measure was overall survival. Results: A total of 514 patients entered CHEMO-INTENSITY, of whom 385 (75%) were men and 299 (58%) were severely frail, with median age 76 years. Noninferior PFS was confirmed for Levels B vs A (HR = 1.09 [95% CI, 0.89-1.32]) and C vs A (HR = 1.10 [95% CI, 0.90-1.33]). Level C produced less toxic effects and better OTU than A or B. No subgroup benefited from higher doses: Level C produced better OTU even in younger or less frail patients. A total of 45 patients entered the CHEMO-BSC randomization: overall survival was nonsignificantly longer with chemotherapy: median 6.1 vs 3.0 months (HR = 0.69 [95% CI, 0.32-1.48], P = .34). In multivariate analysis in 522 patients with all variables available, baseline frailty, quality of life, and neutrophil to lymphocyte ratio were independently associated with OTU, and can be combined in a model to estimate the probability of different outcomes. Conclusions and relevance: This phase 3 randomized clinical trial found that reduced-intensity chemotherapy provided a better patient experience without significantly compromising cancer control and should be considered for older and/or frail patients. Baseline geriatric assessment can help predict the utility of chemotherapy but did not identify a group benefiting from higher-dose treatment.
    • EGFR amplification (amp) and survival in the REAL-3 trial

      Smyth, E; Kouvelakis, K; Cunningham, D; Hahne, JC; Peckitt, C; Vlachogiannis, G; Watkins, D; Rao, S; Starling, N; Wilson, SH; et al. (2018)
    • Examining core needle biopsy vs fine needle aspiration in a tertiary cancer centre

      Adderley, Helen; Chan, Clara; Rack, Samuel; Lunt, Christopher; Taylor, B; Waddell, Thomas K; Blackhall, Fiona H; Lindsay, Colin R; The Christie NHS Foundation Trust, Manchester (2020)
      Introduction: Minimally invasive biopsies such as core needle biopsy (CNB) and fine needle aspiration (FNA) play a fundamental role in cancer diagnosis and molecular profiling. With the advent of novel therapeutic agents and an increasing number of biomarkers, the demand for tissue acquisition and further ancillary testing is growing. Here we compare CNB and FNA in lung cancer and pantumour at a UK tertiary cancer centre. Methods: A retrospective review was conducted for standard of care and research patients who had undergone a minimally invasive biopsy at The Christie NHS Foundation Trust between January 2017 and April 2019. Data collected included: adequacy for diagnosis, adequacy for ancillary testing, scheduling and complication rates. Fisher’s exact test was used to compare categorical variables. Results: 445 biopsies were performed including 61.1% (272/445) CNB vs. 38.9% (173/445) FNA. In the lung cohort (n=49), there was no statistical difference between adequacy yield for CNB vs FNA (94.6% vs. 85.7%, respectively; p=0.41), nor for ancillary testing (100% CNB vs 75% FNA; p 0.15). In pan tumour analysis, CNB was adequate for diagnosis in 85% vs. 79.2% FNA (p=0.16), and was associated with a significant increased adequacy for ancillary testing (98.7% CNB vs 76.9% FNA; p<0.0001). There was no significant difference in complication rates between CNB and FNA, 1.1% vs. 0.6%. Conclusion: CNB is associated with an increased likelihood that a sample provides sufficient material for ancillary testing. Whilst lung cancer-specific analysis yielded no statistically significant outcomes, incongruency to the pan-disease results may be attributed to smaller sample size. Our results demonstrate that CNB is safe and should be considered as the preferred technique where possible for minimally invasive biopsies.
    • Genomic loss of heterozygosity and survival in the REAL3 trial

      Smyth, E; Cafferkey, C; Loehr, A; Waddell, Thomas K; Begum, R; Peckitt, C; Harding, T; Nguyen, M; Okines, A; Raponi, M; et al. (2018)
      Homologous recombination deficiency (HRD) measured using a genomic signature for loss of heterozygosity (LOH) predicts benefit from rucaparib in ovarian cancer. We hypothesized that some oesophagogastric cancers will have high-LOH which would be prognostic in patients treated with platinum chemotherapy. Methods: Diagnostic biopsy DNA from patients treated in the REAL3 trial was sequenced using the Foundation Medicine T5 next-generation sequencing (NGS) assay. An algorithm quantified the percentage of interrogable genome with LOH. Multidimensional optimization was performed to identify a cut-off dichotomizing the population into LOH-high and low groups associated with differential survival outcomes. Results: Of 158 available samples, 117 were successfully sequenced; LOH was derived for 74 of these. A cut-off of 21% genomic LOH defined an LOH-high subgroup (n=10, 14% of population) who had median overall survival (OS) of 18.3 months (m) versus 11m for the LOH-low group (HR 0.55 95% CI 0.19-0.97, p= 0.10). Progression free survival (PFS) for LOH-high and LOH-low groups was 10.7m and 7.3m (HR 0.61 (95% CI 0.21 - 1.09, p=0.09). Sensitivity analysis censoring operated patients (n=4), demonstrated OS of 18.3m vs. 10.2m (HR 0.43, 95% CI (0.20-0.92), p=0.02; PFS was 10.5m vs. 7.2m (HR 0.55, (95% CI 0.26-1.17), p=0.09 for LOH-high and LOH-low. Conclusion: HRD assessment using an algorithmically derived LOH signature on a standard NGS panel identifies oesophagogastric cancer patients with high LOH who have prolonged survival when treated with platinum chemotherapy. Validation work will determine the signature's predictive value in patients treated with a PARP inhibitor and with platinum chemotherapy.
    • The impact of the UK Government ‘two week rule’ (TWR) on lung cancer stage and 5-year survival – a decade of experience from the Royal Marsden Hospital (RMH).

      Dolly, S; Brandão, M; Taylor, C; Gunapala, R; Myerson, J; Waddell, Thomas K; Popat, S; Bhosle, J; O’Brien, M; Lung Unit, Royal Marsden Hospital, Sutton, Surrey (2018-01)
    • Ipilimumab and nivolumab (I plus N) as first-line treatment of metastatic renal cell carcinoma (mRCC): A real-world review in North West of England, United Kingdom

      Allison, Jennifer; Griffiths, R.; Waddell, Thomas K; Pillai, Manon; Christie NHS Foundation Trust, Manchester, United Kingdom (2021)
      Background: Ipilimumab and Nivolumab (I+N) is now an established first line option for patients with advanced RCC of intermediate (I) or poor (P) IMDC risk score. In this retrospective review, we review our experience of this combination in two cancer centres in North West England with a focus on immune related adverse events (irAEs) and their impact on the patient pathway. Methods: Treatment naïve mRCC patients starting I+N between May 2019 and July 2020 were identified. Primary outcomes of interest include overall response rate (ORR), the management of irAEs and early survival observations. Results: A total of 69 patients were identified. Median age was 60yr (19-82yr), 77% had clear cell histology. The IMDC risk was 72% I and 28% P. Median follow-up was 11.0 mo (1-22mo). ORR was 45% (CR 9%, PR 36%, SD 28%, PD 23%, NE 4%) Median time to first response was 2.9mo. (1.8- 15.5mo). 10% of patients experienced pseudoprogression. Median PFS and OS are not yet reached with 86% of patients still alive at the time of data cut-off. The majority (75%) of patients completed all 4 doses of I+N. Of the 10% receiving less than 4 doses due to toxicity, 14% continued on single agent N. Overall, 15% discontinued therapy due to toxicity and 28% experienced at least one treatment delay. Any grade irAEs were seen in 74% of patients (G3 35%) with no treatment related deaths. The commonest irAEs were: rash/pruritis 39%; endocrinopathies 30%(G3 7%); diarrhoea 29% (G3 14%); hepatitis 22% (G3 6%); and nephritis 3% (G3 3%). Of the patients developing irAEs, 71% received steroids with 16% requiring additional immunosuppression including infliximab (6%) and mycophenolate mofetil (8%). A third of all patients required admission for irAE management with a total of 37 inpatient episodes across the cohort with a median length of 7 days (1-24). 7% of patients proceeded to surgery for either primary or metastatic disease, which contributed to ongoing disease response in these patients. At the time of data cut-off, 45% of patients were no longer on treatment due to PD (29%), toxicity (15%) or unrelated death (1%). Of those who stopped due to toxicity, 50% subsequently progressed with a median time to progression of 4mo (3-6 mo) and 50% remain on active surveillance with a median follow-up of 7.5mo (1-10). 62% of patients with PD received second line treatment; most frequently, cabozantinib (83%). Conclusions: Our experience of I+N shows comparable efficacy and toxicity profiles to available reports. irAEs requiring intervention are frequent and may be associated with prolonged hospital admission, and patients should be counselled appropriately. Data within mirrors published reports of ongoing responses in a subset of patients who stop treatment due to toxicity and also suggests a possible role for resection of residual or metastatic disease in disease control. Updated survival data will be presented
    • Maintenance durvalumab after first-line platinum-based chemotherapy in advanced oesophago-gastric (OG) adenocarcinoma: Results from the PLATFORM trial

      Fong, C.; Patel, B.; Peckitt, C.; Bourmpaki, E.; von Loga, K.; Begum, R.; Davidson, M.; Anandappa, G.; Cafferkey, C.; Watkins, D. J.; et al. (2021)
      Background: PLATFORM is a prospective, open-label, multicentre, adaptive phase II trial assessing maintenance therapy in patients (pts) with OG adenocarcinoma after platinum-based first-line induction chemotherapy. HER2 negative pts were initially randomised 1:1:1:1:1 to surveillance (A1), capecitabine (A2), durvalumab (A3), with rucaparib (A4) and capecitabine + ramucirumab (A5) added later as per adaptive design. Here we report the primary analysis of durvalumab maintenance vs. surveillance. Methods: Pts were randomised upon achieving response or stable disease following 18 weeks of platinum-based chemotherapy and were stratified by region, disease extent and performance status. A1 pts had 4 weekly surveillance visits and A3 pts received 10mg/kg durvalumab iv Q2W. Target accrual was 154 pts/arm; however, A3 was closed prematurely after cessation of industry support. The primary endpoint was progression-free survival (PFS) from randomisation post induction chemotherapy to disease progression according to RECIST 1.1 criteria, or death. Secondary endpoints were time to treatment failure (TTF), objective response rate (ORR), overall survival (OS) and toxicity. Survival analyses according to PD-L1 using the combined positive score (CPS, Ventana SP263 assay) was conducted. Results: A total of 205 pts were concurrently randomised into A1 (n = 100) and A3 (n = 105). At data cut-off (02 Feb 2021), median follow up was 24.2 months [95% confidence interval (CI) 21.6-36.8]. There was no significant difference in PFS between A1 and A3 [median PFS: 3.2 vs. 4.7 months (hazard ratio (HR) 0.79 (95% CI 0.59-1.06, p = 0.122) respectively]. Median OS was 11.4 vs. 11.3 months (HR 0.92, 95% CI 0.66-1.27, p = 0.60) in A1 and A3 respectively and no significant difference in TTF was detected between both arms (median TTF: 3.2 vs. 3.5 months (HR 0.92, 95% CI 0.69-1.23, p = 0.558)]. ORR was 6% in A3 (n = 2 complete and n = 4 partial responses) whereas no radiological responses were seen in A1. PD-L1 results were available for 76 pts in A1 and 77 pts in A3. PFS was comparable between subgroups using the PD-L1 CPS thresholds of ≥1, ≥5 and ≥10. The safety population consisted of 199 pts (A1: 98 pts and A3: 101 pts). Grade ≥3 treatment-related adverse events were reported in 18% of A3 pts and no new safety signals were identified. Conclusions: Although a survival advantage was not seen with maintenance durvalumab compared to surveillance, a subset of patients who received durvalumab demonstrated incremental radiological responses. Exploratory analysis of PD-L1 expression was not associated with improved survival outcomes.
    • Neoadjuvant FLOT: teal world toxicity from a specialist UK centre.

      Kordatou, Zoe; Papaxoinis, Georgios; Waddell, Thomas K; Owen-Holt, Vikki; Weaver, Jamie M; Hubner, Richard A; Mansoor, Was; The Christie NHS Foundation Trust, Manchester, UK; The Christie NHS Foundation Trust, Manchester, UK; Laiko General Hospital, Athina, Greece; et al. (2018-06)
    • Optimizing chemotherapy for frail and elderly patients with advanced gastroesophageal cancer (aGOAC): the GO2 phase III trial

      Hall, P; Swinson, D; Lord, S; Marshall, H; Cairns, D; Ruddock, S; Batman, E; Velikova, G; Petty, R; Waters, J; et al. (2019)
    • Outcomes for patients in the pembrolizumab plus axitinib arm with advanced renal cell carcinoma (RCC) who completed two years of treatment in the phase III KEYNOTE-426 study

      Plimack, E. R.; Powles, T.; Bedke, J.; Pouliot, F.; Stus, V.; Waddell, Thomas K; Gafanov, R.; Nosov, D.; Alekseev, B.; McDermott, R. S.; et al. (2021)
      Background: In the randomized, open-label, phase III KEYNOTE-426 study (NCT02853331), pembrolizumab + axitinib significantly improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) versus sunitinib as first-line therapy for advanced RCC. Per protocol, patients could discontinue pembrolizumab or axitinib and continue the other agent. Pembrolizumab was stopped for all patients at 2 years. Axitinib could be continued until progression or toxicity. This exploratory subgroup analysis of KEYNOTE-426 describes outcomes of patients who completed 2 years of pembrolizumab. Methods: Patients included in KEYNOTE-426 were treatment naive, with clear cell RCC, KPS ≥70%, and measurable disease (RECIST v1.1). Patients were randomly assigned 1:1 to receive pembrolizumab 200 mg intravenously every 3 weeks for up to 35 doses + axitinib 5 mg orally twice daily or sunitinib 50 mg once daily (4 weeks on/2 weeks off) until progression, toxicity, or withdrawal. Primary end points of the original analysis were OS and PFS. Key secondary end points were ORR and safety. Results: Of 432 patients treated with pembrolizumab + axitinib, 129 (29.9%) completed 2 years of study therapy. Median (range) age of these patients was 61 (36-82) years, and 72.1% were male; 42 (32.6%) and 87 (67.4%) patients had International mRCC Database Consortium favorable and intermediate/poor risk, respectively, consistent with the intention-to-treat population (31.9% vs 68.1%). Median (range) follow-up (time from randomization to data cutoff) was 31.1 (24.0-37.7) months. For patients who completed 2 years of study therapy, the OS rates at 36 months was 93.8% (95% CI, 85.5%-97.4%). The PFS rates at 24 and 36 months were 72.7% (95% CI, 64.0%-79.7%) and 57.7% (95% CI, 46.3%-67.5%), respectively. The ORR was 85.3%, and the CR rate was 14.0%. 59.7% of patients experienced grade 3-5 treatment-related adverse events and 8.5% experienced grade 3-5 immune-mediated adverse events. Conclusions: In this exploratory analysis, a significant proportion of patients in the pembrolizumab + axitinib arm completed 2 years of pembrolizumab with ongoing clinical benefit
    • Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): Results from 42-month follow-up of KEYNOTE-426

      Rini, B. I.; Plimack, E. R.; Stus, V.; Waddell, Thomas K; Gafanov, R.; Pouliot, F.; Nosov, D.; Melichar, B.; Soulieres, D.; Borchiellini, D.; et al. (2021)
      Background: In the first interim analysis of the randomized, multicenter, open-label, phase 3 KEYNOTE-426 study (NCT02853331), treatment with pembro + axi significantly improved OS, PFS, and ORR vs sunitinib monotherapy in treatment-naive advanced ccRCC. Extended follow-up (median, 30.6 mo) continued to demonstrate the superior efficacy of pembro + axi vs sunitinib monotherapy in this patient population. Here, we present the results of the prespecified final analysis with 42.8-mo median follow-up. Methods: Treatment-naive patients (pts) with advanced ccRCC, KPS ≥70%, and measurable disease (RECIST v1.1) were randomly assigned 1:1 to receive pembro 200 mg IV Q3W for up to 35 doses + axi 5 mg orally BID or sunitinib 50 mg orally QD on a 4-wk on/2-wk off schedule until progression, intolerable toxicity, or withdrawal. Randomization was stratified by IMDC risk (favorable vs intermediate vs poor) and geographic region (North America vs Western Europe vs Rest of World). Dual primary endpoints were OS and PFS. Secondary endpoints were ORR, DOR, and safety. The protocol-specified final analysis was based on a target of 404 OS events. No formal hypothesis testing was performed because all efficacy endpoints were met previously at the first interim analysis; nominal P values are reported. Results: Overall, 861 pts were randomly assigned to receive pembro + axi (n=432) or sunitinib (n=429). Median duration of follow-up, defined as time from randomization to the database cutoff date, was 42.8 mo (range, 35.6-50.6). At data cutoff, 418 pts had died: 193 (44.7%) of 432 pts in the pembro + axi arm vs 225 (52.4%) of 429 pts in the sunitinib arm. Compared with sunitinib, pembro + axi improved OS (median: 45.7 vs 40.1 mo; HR, 0.73 [95% CI, 0.60-0.88]; P<0.001) and PFS (median: 15.7 vs 11.1 mo; HR, 0.68 [95% CI, 0.58-0.80]; P<0.0001). The 42-mo OS rate was 57.5% with pembro + axi vs 48.5% with sunitinib; the 42-mo PFS rate was 25.1% with pembro + axi vs 10.6% with sunitinib. For pembro + axi vs sunitinib, ORR was 60.4% vs 39.6% (P<0.0001); CR rate was 10.0% vs 3.5%; median DOR was 23.6 mo (range 1.4+ to 43.4+) vs 15.3 mo (range, 2.3-42.8+). Subsequent anticancer therapy was administered to 47.2% of pts in pembro + axi arm vs 65.5% of pts in sunitinib arm. Although a similar proportion of pts in each arm received VEGF/VEGFR inhibitors, only 10.2% of pts in the pembro + axi arm received subsequent treatment with a PD-1/L1 inhibitor compared to 48.7% of pts in the sunitinib arm. No new safety signals were observed. Conclusions: With a median follow-up of 42.8 mo, this is the longest follow-up of an anti-PD–1/L1 immunotherapy combined with a VEGF/VEGFR inhibitor for first-line RCC. These results show that pembro + axi continues to demonstrate superior efficacy over sunitinib with respect to OS, PFS, and ORR, with no new safety signals.
    • Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced renal cell carcinoma (RCC): Updated analysis of KEYNOTE-426

      Plimack, E. R.; Rini, B. I.; Stus, V.; Gafanov, R.; Waddell, Thomas K; Nosov, D.; Pouliot, F.; Soulieres, D.; Melichar, B.; Vynnychenko, I.; et al. (2020)
      Background: The randomized, open-label, phase 3 KEYNOTE-426 study (NCT02853331) demonstrated that pembrolizumab (pembro) + axitinib (axi) significantly improved OS, PFS, and ORR vs sunitinib as first-line therapy for advanced RCC (aRCC) at the first pre-planned interim analysis (minimum study follow-up of 7 mo). Updated analyses are presented here. Methods: Treatment-naive patients (pts) with clear cell aRCC, KPS ?70%, and measurable disease (RECIST v1.1) were randomly assigned 1:1 to receive pembro 200 mg IV Q3W for up to 35 doses + axi 5 mg orally BID or sunitinib 50 mg orally QD on a 4-wk on/2-wk off schedule until progression, toxicity, or withdrawal. Randomization was stratified by IMDC risk (favorable vs intermediate vs poor) and geographic region (North America vs Western Europe vs rest of world). Primary end points were OS and PFS. Secondary end points were ORR, DOR, and safety. All P values are nominal. A post-hoc exploratory analysis was done to evaluate association of depth of response (maximum reduction from baseline in sum of diameters of target lesions) and OS using landmark analysis up to 6 mo after randomization. Results: 861 pts were randomly assigned (pembro + axi, n = 432; sunitinib, n = 429). Median (range) duration of follow-up for all pts was 27.0 mo (0.1-38.4). Pembro + axi improved OS (HR, 0.68 [95% CI, 0.55-0.85]; P < 0.001; 24-mo OS rate, 74% vs 66%) vs sunitinib. Median (95% CI) OS was not reached with pembro + axi and was 35.7 mo (33.3-NR) with sunitinib. Pembro + axi improved PFS (HR, 0.71 [95% CI, 0.60-0.84]; P < 0.001; 24-mo PFS rate, 38% vs 27%) vs sunitinib. For pembro +axi vs sunitinib respectively, median (95% CI) PFS was 15.4 (12.7-18.9) vs 11.1 mo (9.1-12.5); ORR was 60% vs 40% (P < 0.0001); CR rate was 9% vs 3%; and median DOR was 23.5 mo (range 1.4+ to 34.5+) vs 15.9 mo (range 2.3-31.8+). In general, the pembro + axi benefit was observed in all subgroups tested, including IMDC risk and PD-L1 expression subgroups. Post-hoc landmark analysis at 6-mo showed that pts on pembro + axi with ?80% target lesion reduction had OS similar to that of pts with CR per RECIST v1.1 based on Kaplan-Meier curves and HR [95% CI] estimates (0.20 [0.05-0.84] vs. 0.10 [0.01-0.76], respectively) vs pts with 0-30% target lesion reduction. No new safety signals were observed. Conclusions: Pembro + axi continued to demonstrate superior and durable antitumor activity vs sunitinib in pts with first-line aRCC with a 27-mo median follow up; no new safety signals were observed.
    • Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial

      Powles, T.; Plimack, E. R.; Soulières, D.; Waddell, Thomas K; Stus, V.; Gafanov, R.; Nosov, D.; Pouliot, F.; Melichar, B.; Vynnychenko, I.; et al. (2020)
      Background: The first interim analysis of the KEYNOTE-426 study showed superior efficacy of pembrolizumab plus axitinib over sunitinib monotherapy in treatment-naive, advanced renal cell carcinoma. The exploratory analysis with extended follow-up reported here aims to assess long-term efficacy and safety of pembrolizumab plus axitinib versus sunitinib monotherapy in patients with advanced renal cell carcinoma. Methods: In the ongoing, randomised, open-label, phase 3 KEYNOTE-426 study, adults (≥18 years old) with treatment-naive, advanced renal cell carcinoma with clear cell histology were enrolled in 129 sites (hospitals and cancer centres) across 16 countries. Patients were randomly assigned (1:1) to receive 200 mg pembrolizumab intravenously every 3 weeks for up to 35 cycles plus 5 mg axitinib orally twice daily or 50 mg sunitinib monotherapy orally once daily for 4 weeks per 6-week cycle. Randomisation was done using an interactive voice response system or integrated web response system, and was stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk status and geographical region. Primary endpoints were overall survival and progression-free survival in the intention-to-treat population. Since the primary endpoints were met at the first interim analysis, updated data are reported with nominal p values. This study is registered with ClinicalTrials.gov, NCT02853331. Findings: Between Oct 24, 2016, and Jan 24, 2018, 861 patients were randomly assigned to receive pembrolizumab plus axitinib (n=432) or sunitinib monotherapy (n=429). With a median follow-up of 30·6 months (IQR 27·2-34·2), continued clinical benefit was observed with pembrolizumab plus axitinib over sunitinib in terms of overall survival (median not reached with pembrolizumab and axitinib vs 35·7 months [95% CI 33·3-not reached] with sunitinib); hazard ratio [HR] 0·68 [95% CI 0·55-0·85], p=0·0003) and progression-free survival (median 15·4 months [12·7-18·9] vs 11·1 months [9·1-12·5]; 0·71 [0·60-0·84], p<0·0001). The most frequent (≥10% patients in either group) treatment-related grade 3 or worse adverse events were hypertension (95 [22%] of 429 patients in the pembrolizumab plus axitinib group vs 84 [20%] of 425 patients in the sunitinib group), alanine aminotransferase increase (54 [13%] vs 11 [3%]), and diarrhoea (46 [11%] vs 23 [5%]). No new treatment-related deaths were reported since the first interim analysis. Interpretation: With extended study follow-up, results from KEYNOTE-426 show that pembrolizumab plus axitinib continues to have superior clinical outcomes over sunitinib. These results continue to support the first-line treatment with pembrolizumab plus axitinib as the standard of care of advanced renal cell carcinoma.
    • Phase II study of short-course capecitabine plus oxaliplatin (XELOX) followed by maintenance capecitabine in advanced colorectal cancer: XelQuali study.

      Waddell, Thomas K; Gollins, S; Soe, W; Valle, Juan W; Allen, J; Bentley, D E; Morris, J; Lloyd, A; Swindell, Ric; Taylor, M B; et al. (2010-07-30)
      PURPOSE: To evaluate the efficacy, safety and quality of life of a short course of oxaliplatin plus capecitabine (XELOX) followed by single-agent capecitabine in patients with previously untreated, inoperable, metastatic colorectal cancer. METHODS: Patients received intravenous oxaliplatin 130 mg/m(2) on d1 plus oral capecitabine 1,000 mg/m(2) twice daily (bid) on d1-14 every 21 days for four cycles. Patients achieving stable disease (SD) or better than received capecitabine 1,250 mg/m(2) bid on d1-14 every 21 days until disease progression. The primary endpoint was progression-free survival (PFS). RESULTS: Overall, 21/45 (47%) of patients responded to the initial XELOX chemotherapy whilst SD or better was documented in 76%. Median PFS was 6.7 (95% CI 5.7-9.6) months, and median overall survival (OS) was 20.5 (95% CI 13.1-28.1) months. In the 34 patients who then received capecitabine maintenance therapy, the median PFS was 8.1 (95% CI 6.2-11.8) months and median OS was 23.1 (95% CI 17.8-28.5) months. A marked reduction in the vast majority of all grades of adverse event occurred on switching from initial XELOX to maintenance capecitabine chemotherapy including grades 1-2 (77 vs. 47%) and grade 3 (7 vs. 3%) neuropathy, diarrhoea and lethargy. CONCLUSIONS: Short-course XELOX followed by capecitabine maintenance therapy provides an active and well-tolerated treatment option for patients with previously untreated metastatic colorectal cancer. A median OS of more than 20 months is promising and by limiting the number of oxaliplatin infusions, this approach minimises the risk of unwanted cumulative neurotoxicity, is cheaper and more convenient for both patients and healthcare providers.
    • A postcode lottery still exists for cancer patients with 'exceptional circumstances'.

      Clarke, R; Waddell, Thomas K; Gallagher, John T; Lee, K; Radhakrishna, G; Cavet, James; Hawkins, Robert E; Saunders, Mark P (2008-12)
    • PRISM protocol: a randomised phase II trial of nivolumab in combination with alternatively scheduled ipilimumab in first-line treatment of patients with advanced or metastatic renal cell carcinoma

      Buckley, HL; Collinson, FJ; Ainsworth, G; Poad, H; Flanagan, L; Katona, E; Howard, HC; Murden, G; Banks, RE; Brown, J; et al. (2019)
      BACKGROUND: The combination of nivolumab, a programmed death-1 (PD-1) targeted monoclonal antibody, with the cytotoxic T-lymphocyte antigen-4 (CTLA-4) targeted antibody, ipilimumab, represents a new standard of care in the first-line setting for patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC) based on recent phase III data. Combining ipilimumab with nivolumab increases rates of grade 3 and 4 toxicity compared with nivolumab alone, and the optimal scheduling of these agents when used together remains unknown. The aim of the PRISM study is to assess whether less frequent dosing of ipilimumab (12-weekly versus 3-weekly), in combination with nivolumab, is associated with a favourable toxicity profile without adversely impacting efficacy. METHODS: The PRISM trial is a UK-based, open label, multi-centre, phase II, randomised controlled trial. The trial population consists of patients with untreated locally advanced or metastatic clear cell RCC, and aims to recruit 189 participants. Participants will be randomised on a 2:1 basis in favour of a modified schedule of 4 doses of 12-weekly ipilimumab versus a standard schedule of 4 doses of 3-weekly ipilimumab, both in combination with standard nivolumab. The proportion of participants experiencing a grade 3 or 4 adverse reaction within 12?months forms the primary endpoint of the study, but with 12-month progression free survival a key secondary endpoint. The incidence of all adverse events, discontinuation rates, overall response rate, duration of response, overall survival rates and health related quality of life will also be analysed as secondary endpoints. In addition, the potential of circulating and tissue-based biomarkers as predictors of therapy response will be explored. DISCUSSION: The combination of nivolumab with ipilimumab is active in patients with mRCC. Modifying the frequency of ipilimumab dosing may mitigate toxicity rates and positively impact quality of life without compromising efficacy, a hypothesis being explored in other tumour types such as non-small cell lung cancer. The best way to give this combination to patients with mRCC must be similarly established. TRIAL REGISTRATION: PRISM is registered with ISRCTN (reference ISRCTN95351638, 19/12/2017). TRIAL STATUS: At the time of submission, PRISM is open to recruitment and data collection is ongoing.
    • Real-world data (RWD) reveals benefit for adjuvant chemotherapy with docetaxel, oxaliplatin and fluorouracil/leucovorin (FLOT) is limited to those with tumour regression grade (TRG) >= 3 in oesophago-gastric cancer (OGC)

      Hapuarachi, B. S.; Lee, R.; Khan, A.; Woodhouse, L.; Kounnis, V.; Britton, F.; Coyle, J.; Connors, K.; Mariam, Neethu B G; Weaver, Jamie M; et al. (2021)
      Background: Despite potentially curative surgery, long-term survival from OGC remains poor due to high relapse rate. Neoadjuvant (naFLOT) and adjuvant (aFLOT) FLOT is currently standard treatment for resectable OGC based on data from the FLOT-4 trial. We explored whether TRG was associated with FLOT-outcome using RWD. Methods: Pts with OGC treated with naFLOT +/- aFLOT at a tertiary UK centre were identified following institutional board approval. Clinical and laboratory data were extracted from the patient record. TRG was evaluated by a histopathologist. Median overall survival (OS) and median progression-free survival (PFS) were evaluated using Kaplan-Meier and Log-rank tests; time taken from start of naFLOT, and associations between factors with Fisher’s exact (FE) test. Results: 171 pts were identified, median FU 30 mths. 144 (84%) male; median age 66 (32-84); oesophagus 66 (38%), junctional (GOJ) 73 (43%), gastric 32 (19%); stage IB 3 (2%), stage IIB 26 (15%), stage III 91 (53%), stage IVA 47 (28%) and unknown 4 (2%). Pts had median of 2 comorbidities (range 0-6); performance status (PS) 0: 95 (56%), PS 1: 71 (41%), PS 2: 3 (2%) and PS unknown 2 (1%). 132/171 pts completed 4 cycles of naFLOT and this was significantly associated with undergoing surgery (p = 0.02). Those who had surgery (140/171) had significantly improved PFS (not reached (NR) vs. 6 mths; 95% CI 2-10; p < 0.001) and OS (NR vs. 12 mths; 95% CI 6-18; p < 0.001). TRG was reported for 126/140 patients who underwent surgery. TRG 1/2 (42/126) vs. TRG ≥3 was significantly associated with improved PFS (NR vs. 35 mths; 95% CI NR; p < 0.001) and OS (median NR either group; p < 0.001). Pts with TRG 1/2 who commenced aFLOT (≥1 cycle; n = 31/42) or completed 4 cycles of aFLOT (17/31) did not have improved PFS or OS vs. those who did not. Those with TRG ≥3 who commenced aFLOT (≥1 cycle; n = 62/85) had improved PFS (median NR vs. 22 mths; 95% CI 13-31 p = 0.006) and OS (median NR vs. 25 mths; 95% CI 18-32 p = 0.019). Those with TRG ≥3 who completed 4 cycles of aFLOT (n = 38/62) had significantly improved PFS (median NR vs. 25 mths; 95% CI 14-36 p = 0.016) and OS (median NR vs. 36 mths; 95% CI 16-55 p = 0.012). There was no difference in PFS or OS in pts with TRG ≥3 who had a dose reduction at any time during aFLOT. Conclusions: TRG is a predictor of outcome following naFLOT + surgery with superior outcomes in those with TRG 1/2. Our analyses suggest that only pts with TRG >3 following naFLOT + surgery benefit from adjuvant FLOT. Prospective randomised studies are required to confirm whether pts with TRG 1/2 require treatment with aFLOT.