• Drug development and clinical trial design in pancreatico-biliary malignancies.

      Harrington, J; Carter, Louise; Basu, B; Cook, Natalie; Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge, UK (2018-01-08)
      Pancreatico-biliary (P-B) tumors arise from the pancreas, bile duct, and ampulla of Vater. Despite their close anatomical location, they have different etiology and biology. However, they uniformly share a poor prognosis, with no major improvements observed in overall survival over decades, even in the face of progress in diagnostic imaging and surgical techniques, and advances in systemic and loco-regional radiation therapies. To date, cytotoxic treatment has been associated with modest benefits in the advanced disease setting, and survival for patients with stage IV disease has not exceeded a year. Therefore, there is a pressing need to identify better treatments which may impact more significantly. Frequently, encouraging signals of potential efficacy for novel agents in early phase clinical trials have been followed by disappointing failures in larger phase III trials, raising the valid question of how drug development can be optimized for patients with pancreatic adenocarcinoma and biliary tract malignancies. In this article we summarize the current therapeutic options for these patients and their limitations. The biological context of these cancers is reviewed, highlighting features that may make them resistant to standard chemotherapeutics and could be potential therapeutic targets. We discuss the role of early phase clinical trials, defined as phase I and non-randomised phase II trials, within the clinical context and current therapeutic landscape of P-B tumors and postulate how translational studies and trial design may enable better realization of emerging targets together with a proposed model for future patient management. A detailed summary of current phase I clinical trials in P-B tumors is provided.
    • Druggable molecular alterations in bile duct cancer: potential and current therapeutic applications in clinical trials

      Bourien, H.; Lamarca, Angela; McNamara, Mairead G; Hubner, Richard A; Valle, Juan W; Edeline, J; Department Of Medical Oncology, Centre Eugène Marquis, Rennes, France, France (2021)
      Introduction: Cholangiocarcinomas (CCA) are rare tumors that are associated with a variety of molecular alterations. Many of these alterations are now actionable using drugs currently in development, and CCA may be a perfect example of application of a precision oncology approach. However, development of drugs in CCA faces the challenge of targeting rare alterations in a rare disease.Areas covered: In this review, we present the current data on targeted therapies in development for CCA, focusing on IDH1, FGFR2, BRAF, and HER2 alterations. We also discuss rationale for targeting other alterations, currently without specific development in CCA. We searched PubMed and google scholar in February 2021 for relevant articles and presentation in recent congress regarding the literature on molecular alterations, drugs in cholangiocarcinomas and biliary tract cancers.Expert opinion: Despite a strong rationale and promising early results, applying a precision oncology approach in CCA for everyday patients is still exposed to significant challenges: obtaining the molecular portrait of these tumors due to difficulties with biopsy access, complexities of drug development in subgroups of these relatively rare tumors, and sub-optimal access to drugs outside clinical trials.
    • Dual RAF/MEK inhibitor VS-6766 for treatment of KRAS mutant NSCLC: novel combinations targeting G12C or G12V variants

      Coma, S.; Chowdhury, S.; Musteanu, M.; Stewart, A.; Pickard, L.; Krebs, Matthew G; Minchom, A.; Banerji, U.; Barbacid, M.; Pachter, J.; et al. (2021)
      Introduction:KRAS is mutated in 25% of non-small cell lung cancer(NSCLC) adenocarcinoma, with KRAS G12C and G12V mutationsoccurring inw13% andw7% of patients, respectively. Whereas G12Cinhibitors (G12Ci) sotorasib (AMG 510) and adagrasib (MRTX849) havedemonstrated promising antitumor activity in patients with KRAS G12Cmutant (mt) NSCLC, KRAS G12V mt NSCLC remains an unmet need. VS-6766 is a unique dual RAF/MEK inhibitor which has shown singleagent activity against KRAS G12V mt NSCLC (Guo Lancet Oncology2020).Methods:We assessed synergistic antitumor effects of VS-6766with G12C or focal adhesion kinase (FAK) inhibitors in KRAS G12C orG12V NSCLC preclinical models, respectively.Results:In KRAS G12Cmt NSCLC, emerging data suggest that G12Ci monotherapy may beinsufficient for maximal depth or duration of response, and combina-tions with agents that target additional nodes in the RAS pathway(vertical blockade) may be necessary. In 3D proliferation assays, VS-6766 was synergistic with both sotorasib and adagrasib in reducingviability of a panel of KRAS G12C mt NSCLC cell lines. Accordingly, VS-6766 effectively suppressed pERK across KRAS G12C mt NSCLC celllines as a single agent, and the combination of VS-6766 + G12Ci showedimproved depth and duration of inhibition relative to G12Ci alone. InKRAS G12C mt NSCLC xenograft models (H2122, H358), combinationwith VS-6766 (0.3 mg/kg QD) augmented tumor growth inhibition bysotorasib, whereas trametinib (0.3 mg/kg QD) was much less effectivein augmenting sotorasib efficacy. Strikingly, triple combination of VS-6766, sotorasib and FAK inhibitor conferred tumor reductions of 35% in all mice in both models. In KRAS G12V mt NSCLC, CRAFsignaling was essential for tumor progression in a genetically engi-neered mouse tumor model (Sanclemente Cancer Cell 2018), providingrationale for testing the RAF/MEK inhibitor VS-6766 in KRAS G12V mtNSCLC. As RAF and MEK inhibition have been reported to activate FAKas a potential resistance mechanism, the combination of VS-6766 withthe FAK inhibitor defactinib has been studied. In 3D proliferation as-says in vitro, VS-6766 was synergistic with defactinib in reducingviability of KRAS mt cell lines with the broadest synergy observed inKRAS G12V mt cell lines, as compared with G12C and G12D cell lines. Ina KRAS G12V mt/TP53 null NSCLC model, which has previously beenshown to be CRAF dependent, VS-6766 monotherapy induced statisti-cally significant tumor regression, while trametinib at the same dosedid not. FAK inhibition further augmented the tumor regressioninduced by VS-6766. These preclinical data correlate well with theclinical observation of partial responses in patients with KRAS G12V mtNSCLC treated with VS-6766 monotherapy (Guo Lancet Oncology2020) or in combination with defactinib. Furthermore, this combina-tion regimen of VS-6766 with defactinib exhibited a manageable safetyprofile with no patients discontinuing for adverse events (Krebs AACR2021).Conclusion:These results support the ongoing registration-directed study evaluating VS-6766±defactinib for treatment ofrecurrent KRAS G12V mt NSCLC (NCT04620330) and provide rationalefor the clinical evaluation of VS-6766 in combination with a G12C in-hibitor for treatment of KRAS G12C mt NSCLC.
    • Dual repair modulation reverses Temozolomide resistance in vitro.

      Barvaux, Vincent A; Ranson, Malcolm R; Brown, Robert; McElhinney, R Stanley; McMurry, T Brian H; Margison, Geoffrey P; Paterson Institute for Cancer Research and Christie Hospital, Manchester, United Kingdom. (2004-02)
      Temozolomide is an alkylating agent that mediates its cytotoxic effects via O(6)-methylguanine (O(6)-meG) adducts in DNA and their recognition and processing by the postreplication mismatch repair system (MMR). O(6)-meG adducts can be repaired by the DNA repair protein O(6)-alkylguanine-DNA-alkyltransferase (MGMT), which therefore constitutes a major resistance mechanism to the drug. Resistance to Temozolomide can also be mediated by loss of MMR, which is frequently mediated by methylation of the hMLH1 gene promoter. Methylation of hMLH1 can be reversed by treatment of cells with 5-aza-2'-deoxycytidine, while the MGMT pseudosubstrate O(6)-(4-bromothenyl)guanine (PaTrin-2) can deplete MGMT activity. Using a drug-resistant cell line which expresses MGMT and has methylated hMLH1, we show that while either of these treatments can individually sensitize cells to Temozolomide, the combined treatment leads to substantially greater sensitization. The increased sensitization is not observed in matched MMR proficient cells.
    • Dual-energy computed tomography: Survey results on current uses and barriers to further implementation

      Hodgson, K. E.; Larkin, E. A.; Aznar, Marianne Camille; Vasquez Osorio, Eliana; University Hospitals Birmingham NHS Foundation Trust, Birmingham, England (2021)
      Objective: To gauge the current availability of dual-energy computed tomography (DECT) scanners in the UK, establish available technologies, look broadly at current clinical uses in adults and paediatrics, and identify barriers to implementation and potential ways to increase use. Methods: A survey was distributed amongst 10 radiology departments and shared on two national professional co-operation mail bases; the survey ran from 20th July to 9th December 2020. It explored current DECT utilisation in adults and paediatrics as well as barriers to use and suggestions to overcome those barriers. Results: The survey demonstrated DECT availability on 39 (40%) of the 98 CT scanners, but there was limited clinical use in adults and paediatrics. Eighteen (72%) of the 25 respondents had access to at least one DECT scanner, with 14 (56%) having adult DECT protocols in clinical use; <10% head examinations and <50% for other anatomical areas. Only two (8%) respondents had DECT paediatric protocols in clinical use; <10% examinations for all anatomical areas.The main barriers to implementation identified were lack of experience with DECT (8 (44%) users (adult) and 10 (56%) users (paediatric)) and no clinical protocols available (6 (33%) users (adult and paediatric)).Understanding DECT benefits and establishing suitable protocols were the most popular suggestions for increased implementation (10 (40%) of 25 respondents). Conclusion: DECT scanners are available, but clinical use is limited for both adults and paediatrics. The main barriers identified were lack of experience with DECT and the availability of suitable protocols. Further work identified to help implementation included better education on the benefits of DECT, provision of clinical protocols and ensuring a multidisciplinary approach. Advances in knowledge: Barriers to implementation of clinical DECT protocols were identified, together with potential solutions to overcome these and enable further implementation.
    • Dual-specificity protein phosphatase DUSP4 regulates response to MEK inhibition in BRAF wild-type melanoma

      Gupta, Avinash; Towers, C; Willenbrock, F; Brant, R; Hodgson, DR; Sharpe, A; Smith, P; Cutts, A; Schuh, A; Asher, R; et al. (2019)
      BACKGROUND: Aiming to improve treatment options for BRAF wild-type melanoma, we previously conducted the DOC-MEK study of docetaxel with MEK inhibitor (MEKi) selumetinib or placebo, revealing trends to prolongation of progression-free survival (hazard ratio 0.75, P?=?0.130), and improved response rates (32% vs 14%, P?=?0.059) with docetaxel plus selumetinib. NRAS status did not associate with outcome. Here, the aim was to identify novel biomarkers of response to MEKi. METHODS: A MEK 6 gene signature was quantified using NanoString and correlated with clinical outcomes. Two components of the gene signature were investigated by gene silencing in BRAF/NRAS wild-type melanoma cells. RESULTS: In melanomas of patients on the selumetinib but not the placebo arm, two gene signature components, dual-specificity protein phosphatase 4 (DUSP4) and ETS translocation variant 4 (ETV4), were expressed more highly in responders than non-responders. In vitro, ETV4 depletion inhibited cell survival but did not influence sensitivity to MEKi selumetinib or trametinib. In contrast, DUSP4-depleted cells showed enhanced cell survival and increased resistance to both selumetinib and trametinib. CONCLUSIONS: ETV4 and DUSP4 associated with clinical response to docetaxel plus selumetinib. DUSP4 depletion induced MEKi resistance, suggesting that DUSP4 is not only a biomarker but also a mediator of MEKi sensitivity.
    • DUETTE: A randomized phase II study to assess a second maintenance treatment with olaparib (ola) or ola plus ceralasertib (cer), in patients (pts) with platinum-sensitive relapsed (PSR) epithelial ovarian cancer who have previously received PARP inhibitor maintenance treatment (NCT04239014)

      Oza, A. M.; Pierce, A.; Lau, A.; Kurian, N.; Parr, G.; Lao-Sirieix, S. H.; Ah-See, M. L. W.; Dean, Emma J; Loembe, B.; Princess Margaret Cancer Centre, Toronto, ON, Canada (2020)
      Background: Ovarian cancer is the leading cause of death from gynecological cancers in the USA, and the fifth most common cause of cancer death in women. Ola is a PARPi approved for first-line maintenance treatment of BRCA-mutated advanced ovarian cancer in women who achieve a complete or partial response to platinum-based chemotherapy. Ola is also efficacious in combination with bevacizumab in the same population, independent of BRCA mutation status. Cer is a potent, oral, selective inhibitor of ATR. ATR is a critical DDR kinase that is activated in response to replication stress and stalled replication forks. There is no second maintenance standard of care for patients with PSR ovarian cancer who have previously received a PARPi in the maintenance setting. Pre-clinical models have shown that several mechanisms of PARPi resistance may be overcome by ATR inhibition, such as BRCA reversion, replication fork protection and DDR rewiring. DUETTE will select pts with tumor response or stable disease after second or third-line platinum-based treatment, with the expectation to enrich for non-BRCA reversion PARPi resistance mechanisms. The study will address the role of a second maintenance treatment following prior 1L or 2L maintenance, an emerging population of unmet need, and includes translational studies that aim to further our knowledge of clinical PARPi resistance mechanisms and predictors of treatment response. Methods: DUETTE is a global, multi-center, phase II study. 192 pts with PSR epithelial ovarian cancer who have previously received PARPi maintenance treatment, will be retreated with platinum and those who have not progressed after ≥ 4 cycles will be randomized (1:1:1) to 3 treatment arms: Arm 1, open-label: cer 160 mg once daily (qd) days 1 to 7 plus ola 300 mg twice daily (bd); Arm 2, blinded: ola monotherapy 300 mg bd and Arm 3, blinded: ola-placebo. Treatment is administered in 28-day cycles. All pts will be stratified by BRCA status (mutation or wildtype) and response to most recent line of platinum-based chemotherapy (CR/PR or SD). The primary endpoint is to assess the efficacy of maintenance ola monotherapy and cer+ola combination therapy compared with placebo by PFS using blinded, independent central review. Secondary endpoints are overall survival, PFS2, ORR, DoR, safety and tolerability. Enrolment is planned to start in April 2020.
    • Duodenal neuroendocrine tumour associated with minimal change glomerulonephritis

      Montague, E; Hockenhull, Kimberley; Lamarca, Angela; Al-Sayed, Tamer; Hubner, Richard A; Medical Oncology, Christie NHS Foundation Trust, Manchester, UK (2019)
      Paraneoplastic glomerular disease is an increasingly well-recognised entity, and a wide range of both solid and haematological malignancies have been implicated. The most common glomerular disease associated with cancer is membranous nephropathy. Only a few case reports have described an association between neuroendocrine tumours (NETs) and glomerulonephritis and only one paediatric case in relation to minimal change disease. A 76-year-old woman with a well-differentiated duodenal NET presented with nephrotic syndrome and renal biopsy was suggestive of minimal change glomerulonephritis. Standard therapy with corticosteroids brought little benefit, but a dramatic improvement was seen following initiation of systemic anticancer therapy with lanreotide, a somatostatin analogue. Less than 1?month after initiation of lanreotide, the patient was no longer in a nephrotic state, and after a further 2 months of follow-up had shown no sign of relapse.
    • Durable responses and low toxicity after fast off-rate CD19 chimeric antigen receptor-t therapy in adults with relapsed or refractory b-cell acute lymphoblastic leukemia

      Roddie, C.; Dias, J.; O'Reilly, M. A.; Abbasian, M.; Cadinanos-Garai, A.; Vispute, K.; Bosshard-Carter, L.; Mitsikakou, M.; Mehra, V.; Roddy, H.; et al. (2021)
      Purpose: Prognosis for adult B-cell acute lymphoblastic leukemia (B-ALL) is poor, and there are currently no licensed CD19 chimeric antigen receptor (CAR) therapeutics. We developed a novel second-generation CD19-CAR (CAT19-41BB-Z) with a fast off rate, designed for more physiologic T-cell activation to reduce toxicity and improve engraftment. We describe the multicenter phase I ALLCAR19 (NCT02935257) study of autologous CAT19-41BB-Z CAR T cells (AUTO1) in relapsed or refractory (r/r) adult B-ALL. Methods: Patients age ≥ 16 years with r/r B-ALL were eligible. Primary outcomes were toxicity and manufacturing feasibility. Secondary outcomes were depth of response at 1 and 3 months, persistence of CAR-T, incidence and duration of hypogammaglobulinemia and B-cell aplasia, and event-free survival and overall survival at 1 and 2 years. Results: Twenty-five patients were leukapheresed, 24 products were manufactured, and 20 patients were infused with AUTO1. The median age was 41.5 years; 25% had prior blinatumomab, 50% prior inotuzumab ozogamicin, and 65% prior allogeneic stem-cell transplantation. At the time of preconditioning, 45% had ≥ 50% bone marrow blasts. No patients experienced ≥ grade 3 cytokine release syndrome; 3 of 20 (15%) experienced grade 3 neurotoxicity that resolved to ≤ grade 1 within 72 hours with steroids. Seventeen of 20 (85%) achieved minimal residual disease-negative complete response at month 1, and 3 of 17 underwent allogeneic stem-cell transplantation while in remission. The event-free survival at 6 and 12 months was 68.3% (42.4-84.4) and 48.3% (23.1%-69.7%), respectively. High-level expansion (Cmax 127,152 copies/µg genomic DNA) and durable CAR-T persistence were observed with B-cell aplasia ongoing in 15 of 20 patients at last follow-up. Conclusion: AUTO1 demonstrates a tolerable safety profile, high remission rates, and excellent persistence in r/r adult B-ALL. Preliminary data support further development of AUTO1 as a stand-alone treatment for r/r adult B-ALL.
    • Duration of adjuvant chemotherapy for stage III colon cancer.

      Grothey, A; Sobrero, A; Shields, A; Yoshino, T; Paul, J; Taieb, J; Souglakos, J; Shi, Q; Kerr, R; Labianca, R; et al. (2018)
      Since 2004, a regimen of 6 months of treatment with oxaliplatin plus a fluoropyrimidine has been standard adjuvant therapy in patients with stage III colon cancer. However, since oxaliplatin is associated with cumulative neurotoxicity, a shorter duration of therapy could spare toxic effects and health expenditures.
    • Duration of adjuvant doublet chemotherapy (3 or 6 months) in patients with high-risk stage II colorectal cancer

      Iveson, T. J.; Sobrero, A. F.; Yoshino, T.; Souglakos, I.; Ou, F. S.; Meyers, J. P.; Shi, Q.; Grothey, A.; Saunders, Mark P; Labianca, R.; et al. (2021)
      Purpose: As oxaliplatin results in cumulative neurotoxicity, reducing treatment duration without loss of efficacy would benefit patients and healthcare providers. Patients and methods: Four of the six studies in the International Duration of Adjuvant Chemotherapy (IDEA) collaboration included patients with high-risk stage II colon and rectal cancers. Patients were treated (clinician and/or patient choice) with either fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX) and randomly assigned to receive 3- or 6-month treatment. The primary end point is disease-free survival (DFS), and noninferiority of 3-month treatment was defined as a hazard ratio (HR) of < 1.2- v 6-month arm. To detect this with 80% power at a one-sided type one error rate of 0.10, a total of 542 DFS events were required. Results: 3,273 eligible patients were randomly assigned to either 3- or 6-month treatment with 62% receiving CAPOX and 38% FOLFOX. There were 553 DFS events. Five-year DFS was 80.7% and 83.9% for 3-month and 6-month treatment, respectively (HR, 1.17; 80% CI, 1.05 to 1.31; P [for noninferiority] .39). This crossed the noninferiority limit of 1.2. As in the IDEA stage III analysis, the duration effect appeared dependent on the chemotherapy regimen although a test of interaction was negative. HR for CAPOX was 1.02 (80% CI, 0.88 to 1.17), and HR for FOLFOX was 1.41 (80% CI, 1.18 to 1.68). Conclusion: Although noninferiority has not been demonstrated in the overall population, the convenience, reduced toxicity, and cost of 3-month adjuvant CAPOX suggest it as a potential option for high-risk stage II colon cancer if oxaliplatin-based chemotherapy is suitable. The relative contribution of the factors used to define high-risk stage II disease needs better understanding.
    • Duration of remission to ICI 182,780 compared to megestrol acetate in tamoxifen resistant breast cancer

      Robertson, J F R; Howell, Anthony; De Friend, D J; Blamey, R W; Department of Surgery, City Hospital, Nottingham (1997)
    • Duration of response to loncastuximab tesirine in relapsed/refractory diffuse large B-cell lymphoma by demographic and clinical characteristics: Subgroup analyses from LOTIS 2

      Caimi, P.; Ai, W. Y. Z.; Alderuccio, J. P.; Ardeshna, K.; Hamadani, M.; Hess, B. T.; Kahl, B. S.; Radford, John A; Solh, M. M.; Stathis, A.; et al. (2021)
      Background: Outcomes for patients with refractory/relapsed diffuse large B-cell lymphoma (R/R DLBCL) are poor, particularly for those with high-risk clinical characteristics. There remains an unmet need for new treatment options for these patients. Loncastuximab tesirine (Lonca) is an antibody-drug conjugate comprising a humanized anti-CD19 antibody conjugated to a potent pyrrolobenzodiazepine dimer toxin. LOTIS 2 was a pivotal Phase 2 study that demonstrated substantial single-agent anti-cancer activity of Lonca in patients with R/R DLBCL. Efficacy and safety data were presented at ASH 2020 (Caimi et al, ASH 2020; abstract 1183). Here we present subgroup analyses of duration of response (DoR) to Lonca by demographic and clinical characteristics. Methods: Adult patients with R/R DLBCL who had received ≥2 prior therapies were enrolled in this Phase 2, multicenter, single-arm, open-label study of single-agent Lonca (150 µg/kg every 3 weeks for 2 doses, followed by 75 µg/kg thereafter for up to 1 year). The primary analysis has previously been reported, with a primary endpoint of overall response rate (ORR). Patients are being followed-up every 12 weeks for up to 3 years. DoR was a key secondary efficacy endpoint, defined as time from the first documentation of response (central review) to disease progression or death. We analyzed pre-specified demographic and clinical characteristic subgroups for DoR. Results: As of data cut-off (August 6, 2020), ORR in the total population (N = 145) was 48.3% (24.8% had complete response [CR] and 23.4% had partial response [PR]). Median DoR (mDoR) for the 70 responders was 12.58 months. mDoR for patients with CR and PR was 13.37 months and 5.68 months, respectively. Overall, subgroups with high-risk characteristics for poor prognosis had a DoR comparable to the whole study population. mDoR for patients with double-/triple-hit DLBCL was 13.37 months, with advanced stage disease was 12.58 months, and with transformed disease was 12.58 months. The mDoR for older patients was longer than for younger patients (≥75 years, 13.37 months; 65 to < 75 years, 12.58 months; < 65 years, 9.26 months). Patients with DLBCL refractory (defined as no response to therapy) to first-line, most recent line, and all prior lines of therapy had mDoRs of 9.63 months, 9.26 months, and 9.63 months, respectively. Conclusions: Durable responses were observed with the recommended Phase 2 dose regimen of Lonca in heavily pre-treated patients and those at high risk of poor prognosis, including older patients and those with double-/triple-hit, advanced stage, transformed, and primary refractory DLBCL. Updated DoR data will be presented at the meeting.
    • Durvalumab (MEDI 4736) in combination with extended neoadjuvant regimens in rectal cancer: a study protocol of a randomised phase II trial (PRIME‑RT)

      Hanna, C R; O'Cathail, S M; Graham, J S; Saunders, Mark P; Samuel, L; Harrison, M; Devlin, L; Edwards, J; Gaya, D R; Kelly, C A; et al. (2021)
      Background: Advances in multi-modality treatment of locally advanced rectal cancer (LARC) have resulted in low local recurrence rates, but around 30% of patients will still die from distant metastatic disease. In parallel, there is increasing recognition that with radiotherapy and systemic treatment, some patients achieve a complete response and may avoid surgical resection, including in many cases, the need for a permanent stoma. Extended neoadjuvant regimes have emerged to address these concerns. The inclusion of immunotherapy in the neoadjuvant setting has the potential to further enhance this strategy by priming the local immune microenvironment and engaging the systemic immune response. Methods: PRIME-RT is a multi-centre, open label, phase II, randomised trial for patients with newly diagnosed LARC. Eligible patients will be randomised to receive either: short course radiotherapy (25 Gray in 5 fractions over one week) with concomitant durvalumab (1500 mg administered intravenously every 4 weeks), followed by FOLFOX (85 mg/m2 oxaliplatin, 350 mg folinic acid and 400 mg/m2 bolus 5-fluorouracil (5-FU) given on day 1 followed by 2400 mg/m2 5-FU infusion over 46-48 h, all administered intravenously every 2 weeks), and durvalumab, or long course chemoradiotherapy (50 Gray to primary tumour in 25 fractions over 5 weeks with concomitant oral capecitabine 825 mg/m2 twice per day on days of radiotherapy) with durvalumab followed by FOLFOX and durvalumab. The primary endpoint is complete response rate in each arm. Secondary endpoints include treatment compliance, toxicity, safety, overall recurrence, proportion of patients with a permanent stoma, and survival. The study is translationally rich with collection of bio-specimens prior to, during, and following treatment in order to understand the molecular and immunological factors underpinning treatment response. The trial opened and the first patient was recruited in January 2021. The main trial will recruit up to 42 patients with LARC and commence after completion of a safety run-in that will recruit at least six patients with LARC or metastatic disease. Discussion: PRIME-RT will explore if adding immunotherapy to neoadjuvant radiotherapy and chemotherapy for patients with LARC can prime the tumour microenvironment to improve complete response rates and stoma free survival. Sequential biopsies are a key component within the trial design that will provide new knowledge on how the tumour microenvironment changes at different time-points in response to multi-modality treatment. This expectation is that the trial will provide information to test this treatment within a large phase clinical trial.
    • Durvalumab after chemo-radiotherapy in stage III non-small cell lung cancer.

      Chiramel, Jaseela; Tay, R; Califano, Raffaele; Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK (2018-04)
    • Durvalumab after chemoradiotherapy in stage III NSCLC: 4-year survival update from the phase III PACIFIC trial

      Faivre-Finn, Corinne; Vicente, D.; Kurata, T.; Planchard, D.; Paz-Ares, L.; Vansteenkiste, J. F.; Spigel, D. R.; Garassino, M. C.; Reck, M.; Senan, S.; et al. (2020)
      Background: In the phase III PACIFIC trial of patients (pts) with unresectable Stage III NSCLC without disease progression after concurrent chemoradiotherapy (cCRT), durvalumab significantly improved progression-free survival (PFS; stratified HR 0.52, 95% CI 0.42e0.65; P<0.0001; median 16.8 vs 5.6 months; data cutoff [DCO], 13 Feb 2017) and overall survival (OS; stratified HR 0.68, 95% CI 0.53e0.87; P¼0.0025; median not reached vs 28.7 months; DCO, 22 Mar 2018) vs placebo (pbo), with manageable safety. We report updated, exploratory analyses of survival outcomes at 4 years, including the first estimate of median OS for the durvalumab arm. Methods: Pts with WHO PS 0/1 (any tumour PD-L1 status) who had received _2 cycles of platinum-based cCRT (RT dosage typically 60e66 Gy in 30e33 fractions) were enrolled and randomised (2:1), 1e42 days post-cCRT, to IV durvalumab 10 mg/ kg or pbo (q2w for _12 months), stratified by age, sex, and smoking history. Primary endpoints were PFS (blinded independent central review; RECIST v1.1) and OS (both measured from the time of randomisation). HRs and 95% CIs were estimated using a stratified log-rank test in the ITT population. Medians and OS/PFS rates at 48 months were estimated by KaplaneMeier method. Results: In total, 709/713 randomised patients received durvalumab (n/N¼473/476) and pbo (n/N¼236/237). The last pt had completed study treatment in May 2017, almost 3 years prior to the current DCO. As of 20 Mar 2020 (current DCO; median follow up, 34.2 months [range, 0.2e64.9]), updated PFS (stratified HR 0.55, 95% CI 0.44e0.67; median 17.2 vs 5.6 months) and OS (stratified HR 0.71, 95% CI 0.57e0.88) remained consistent with previous reports. Median OS for the durvalumab arm was determined for the first time: 47.5 months (pbo, 29.1 months). The 48-month OS rates were 49.6% vs 36.3% for durvalumab vs pbo, and PFS rates were 35.3% vs 19.5% respectively. Updates to treatment effects for pt subgroups will be reported. Conclusions: These updated analyses of PFS and OS demonstrate durable benefit with durvalumab after cCRT. Approximately half of patients randomised to durvalumab in PACIFIC remain alive at 4 years, and about a third remain both alive and progression free, almost 3 years after the last pt completed study treatment.
    • Durvalumab impact in the treatment strategy of stage III non-small cell lung cancer (NSCLC): an EORTC Young Investigator Lung Cancer Group Survey

      Levra, MG; Benet, J; Hasan, B; Berghmans, T; Bruni, A; Dingemans, A; Levra, NG; Edwards, J; Faivre-Finn, Corinne; Girard, N; et al. (2019)
    • A dyad of lymphoblastic lysosomal cysteine proteases degrades the antileukemic drug L-asparaginase.

      Patel, Naina; Krishnan, Shekhar; Offman, Marc N; Krol, Marcin; Moss, Catherine X; Leighton, Carly; Van Delft, Frederik W; Holland, Mark; Liu, Jizhong; Alexander, Seema; et al. (2009-07)
      l-Asparaginase is a key therapeutic agent for treatment of childhood acute lymphoblastic leukemia (ALL). There is wide individual variation in pharmacokinetics, and little is known about its metabolism. The mechanisms of therapeutic failure with l-asparaginase remain speculative. Here, we now report that 2 lysosomal cysteine proteases present in lymphoblasts are able to degrade l-asparaginase. Cathepsin B (CTSB), which is produced constitutively by normal and leukemic cells, degraded asparaginase produced by Escherichia coli (ASNase) and Erwinia chrysanthemi. Asparaginyl endopeptidase (AEP), which is overexpressed predominantly in high-risk subsets of ALL, specifically degraded ASNase. AEP thereby destroys ASNase activity and may also potentiate antigen processing, leading to allergic reactions. Using AEP-mediated cleavage sequences, we modeled the effects of the protease on ASNase and created a number of recombinant ASNase products. The N24 residue on the flexible active loop was identified as the primary AEP cleavage site. Sole modification at this site rendered ASNase resistant to AEP cleavage and suggested a key role for the flexible active loop in determining ASNase activity. We therefore propose what we believe to be a novel mechanism of drug resistance to ASNase. Our results may help to identify alternative therapeutic strategies with the potential of further improving outcome in childhood ALL.
    • Dynamic contrast-enhanced MRI for prostate cancer localization.

      Jackson, Andrew; Reinsberg, S A; Sohaib, S A; Charles-Edwards, E M; Jhavar, S; Christmas, T J; Thompson, A C; Bailey, M J; Corbishley, C M; Fisher, C; et al. (2009-02)
      Radiotherapy dose escalation improves tumour control in prostate cancer but with increased toxicity. Boosting focal tumour only may allow dose escalation with acceptable toxicity. Intensity-modulated radiotherapy can deliver this, but visualization of the tumour remains limiting. CT or conventional MRI techniques are poor at localizing tumour, but dynamic contrast-enhanced MRI (DCE-MRI) may be superior. 18 patients with prostate cancer had T(2) weighted (T2W) and DCE-MRI prior to prostatectomy. The prostate was sectioned meticulously so as to achieve accurate correlation between imaging and pathology. The accuracy of DCE-MRI for cancer detection was calculated by a pixel-by-pixel correlation of quantitative DCE-MRI parameter maps and pathology. In addition, a radiologist interpreted the DCE-MRI and T2W images. The location of tumour on imaging was compared with histology, and the accuracy of DCE-MRI and T2W images was then compared. Pixel-by-pixel comparison of quantitative parameter maps showed a significant difference between the benign peripheral zone and tumour for the parameters K(trans), v(e) and k(ep). Calculation of areas under the receiver operating characteristic curve showed that the pharmacokinetic parameters were only "fair" discriminators between cancer and benign gland. Interpretation of DCE-MRI and T2W images by a radiologist showed DCE-MRI to be more sensitive than T2W images for tumour localization (50% vs 21%; p = 0.006) and similarly specific (85% vs 81%; p = 0.593). The superior sensitivity of DCE-MRI compared with T2W images, together with its high specificity, is arguably sufficient for its use in guiding radiotherapy boosts in prostate cancer.