• A phase I/II study of safety and efficacy of the arginase inhibitor INCB001158 plus chemotherapy in patients (Pts) with advanced biliary tract cancers

      Javle, M. M.; Bridgewater, J. A.; Gbolahan, O. B.; Jungels, C.; Cho, M. T.; Papadopoulos, K. P.; Thistlethwaite, Fiona C; Canon, J. L. R.; Cheng, L. L.; Ioannidis, S.; et al. (2021)
      Background: Arginase, secreted in the tumor microenvironment by myeloid suppressor cells, is a major regulator of arginine-mediated immune response. Arginase inhibition by INCB001158 increases arginine, which reverses the immunosuppressive effects of neutrophils and myeloid-derived suppressor cells on T cells. The current standard first-line (1L) treatment for advanced biliary tract cancers (BTC) is gemcitabine/cisplatin chemotherapy. The combination of INCB001158 immunotherapy and standard 1L treatment may provide additional clinical benefit in pts with advanced or metastatic BTC. Methods: This open-label phase 1/2 study evaluated the safety, tolerability, and antitumor activity of INCB001158 in pts with advanced or metastatic solid tumors. In phase I, dose escalation of INCB001158 (50, 75, and 100 mg twice daily [BID]) was used to determine the recommended phase II dose (RP2D) of INCB001158 + gemcitabine/cisplatin. Phase II used a Simon 2-stage design and evaluated objective response rate (ORR; RECIST v1.1), duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS) of INCB001158 RP2D + gemcitabine (1000 mg/m2)/cisplatin (25 mg/m2 Days 1 and 8 of 21-day cycle). Here we report preliminary safety and activity from the cohort of pts with BTC. Results: The phase I dose-escalation group identified a RP2D for INCB001158 of 100 mg BID. At a data cutoff of July 1, 2020, 33 pts with BTC in phase II treated with INCB001158 100 mg BID + gemcitabine/cisplatin were evaluable. Adverse events (AEs) related to INCB001158 and/or chemotherapy occurred in 88% of pts and 73% of pts had AEs related specifically to INCB001158 (Table). Treatment was interrupted due to INCB001158-related TEAEs in 30% of pts (n=10); discontinuation related to INCB001158 occurred in 3% (n=1). Treatment did not result in immune-related or significant additive chemotherapy-associated toxicity. ORR was 24% (8/33; 95% CI, 11.1–42.3) based on confirmed response per investigator’s assessment; stable disease occurred in 42% of pts. Median DOR (95% CI) was 5.8 (4.1–not reached) mo, and the DCR was 67%. Median PFS (95% CI) was 8.5 (5.7–10.1) mo. Conclusions: Preliminary data suggest the combination of INCB001158 100 mg BID + gemcitabine/cisplatin was tolerable and did not result in significant added toxicity. Response rates and PFS suggest that some pts with BTC may benefit from this combination.
    • Longitudinal evaluation of quality of life (QoL) in patients (Pts) with FGFR2-driven cholangiocarcinoma (CCA) treated with pemigatinib

      Valle, Juan W; Bibeau, K.; Cho, Y. H.; Ren, H. B.; Feliz, L.; Lihou, C. F.; Abou-Alfa, G. K.; University of Manchester and Christie Hospital NHS Foundation Trust, Manchester (2021)
      Background: CCA is associated with poor prognosis and reduced QoL. In the phase 2 FIGHT-202 study (NCT02924376) of the selective oral FGFR1–3 inhibitor pemigatinib, 35.5% and 46.7% of pts with previously treated advanced CCA and FGFR2 fusions/rearrangements (RE) had a complete or partial response (CR/PR) and stable disease (SD), respectively; 14.9% had progressive disease (PD) [Abou-Alfa et al., Lancet Oncology 2020;21:671-684]. QoL was an exploratory endpoint. Methods: Pts received pemigatinib 13.5 mg once daily (21-day cycle; 2 weeks on, 1 week off). QoL was assessed longitudinally by best overall response (BOR) per RECIST with the EORTC-QLQ-C30 and the biliary tract cancer-specific EORTC-QLQ-BIL21 questionnaires. QoL scores and longitudinal changes from baseline (BL) were analyzed using descriptive statistics. Treatment-related changes in QoL were a priori expected to be evident by cycle 6 day 1 (week 16). Results: Of 107 pts with FGFR2 RE, 100 (93%) were evaluable for QoL, including36, 48, and 15 with CR/PR, SD, and PD, respectively. From BL to week 16, QLQ-C30 overall health status was maintained in pts with CR/PR and SD and worsened in pts with PD (Table). Emotional functioning remained stable and similar in pts with CR/PR and SD but worsened in pts with PD. All subgroups showed decline in role and social functioning. Pts with CR/PR and SD experienced decreases in QLQ-BIL21 pain and anxiety; all subgroups showed increases in QLQ-BIL21 treatment side effects. Conclusions: In these pts with advanced CCA, those with an SD as BOR had a similar pattern of changes in QoL as those with CR/PR to pemigatinib. Changes in QoL were directionally more favorable in pts with CR/PR or SD than pts with PD.
    • Final results from ClarIDHy, a global, phase III, randomized, double-blind study of ivosidenib (IVO) versus placebo (PBO) in patients (pts) with previously treated cholangiocarcinoma (CCA) and an isocitrate dehydrogenase 1 (IDH1) mutation

      Zhu, A. X.; Macarulla, T.; Javle, M. M.; Kelley, R. K.; Lubner, S. J.; Adeva, J.; Cleary, J. M.; Catenacci, D. V. T.; Borad, M. J.; Bridgewater, J. A.; et al. (2021)
      Background: CCA is a rare cancer for which there are limited effective therapies. IDH1 mutations occur in ~20% of intrahepatic CCAs, resulting in production of the oncometabolite D-2-hydroxyglutarate, which promotes oncogenesis. IVO (AG-120) is a first-in-class, oral, small-molecule inhibitor of mutant IDH1 (mIDH1). ClarIDHy aimed to demonstrate the efficacy of IVO vs PBO in pts with unresectable or metastatic mIDH1 CCA. The primary endpoint was met with significant improvement in progression-free survival (PFS) by independent radiology center (IRC) with IVO vs PBO (hazard ratio [HR] = 0.37, p < 0.0001). Objective response rate (ORR) and stable disease for IVO were 2.4% (3 partial responses) and 50.8% (n = 63) vs 0% and 27.9% (n = 17) for PBO. IVO pts experienced significantly less decline in physical and emotional functioning domains of quality of life at cycle 2 day 1 vs PBO pts (nominal p < 0.05). Methods: Pts with mIDH1 CCA were randomized 2:1 to IVO (500 mg PO QD) or matched PBO and stratified by prior systemic therapies (1 or 2). Key eligibility: unresectable or metastatic mIDH1 CCA based on central testing; ECOG PS 0–1; measurable disease (RECIST v1.1). Crossover from PBO to IVO was permitted at radiographic progression. Primary endpoint: PFS by IRC. Secondary endpoints included overall survival (OS; by intent-to-treat), ORR, PFS (by investigator), safety, and quality of life. The planned crossover-adjusted OS was derived using the rank-preserving structural failure time (RPSFT) model. Results: As of 31 May 2020, ~780 pts were prescreened for an IDH1 mutation and 187 were randomized to IVO (n = 126) or PBO (n = 61); 13 remain on IVO. Median age 62 y; M/F 68/119; 91% intrahepatic CCA; 93% metastatic disease; 47% had 2 prior therapies. 70% of PBO pts crossed over to IVO. OS data were mature, with 79% OS events in IVO arm and 82% in PBO. Median OS (mOS) was 10.3 months for IVO and 7.5 months for PBO (HR = 0.79; 95% CI 0.56–1.12; one-sided p = 0.093). The RPSFT-adjusted mOS was 5.1 months for PBO (HR = 0.49; 95% CI 0.34–0.70; p < 0.0001). Common all-grade treatment emergent adverse events (TEAEs, ≥ 15%) in the IVO arm: nausea 41%, diarrhea 35%, fatigue 31%, cough 25%, abdominal pain 24%, decreased appetite 24%, ascites 23%, vomiting 23%, anemia 18%, and constipation 15%. Grade ≥ 3 TEAEs were reported in 50% of IVO pts vs 37% of PBO pts, with grade ≥ 3 treatment-related AEs in 7% of IVO pts vs 0% in PBO. 7% of IVO pts experienced an AE leading to treatment discontinuation vs 9% of PBO pts. There were no treatment-related deaths. Conclusions: IVO was well tolerated and resulted in a favorable OS trend vs PBO despite a high rate of crossover. These data – coupled with statistical improvement in PFS, supportive quality of life data, and favorable safety profile – demonstrate the clinical benefit of IVO in advanced mIDH1 CCA.
    • Health-related quality of life (HRQoL) of pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced esophageal cancer: The phase III KEYNOTE-590 study

      Mansoor, Was; Kulkarni, A. S.; Kato, K.; Sun, J. M.; Shah, M. A.; Enzinger, P. C.; Adenis, A.; Doi, T.; Kojima, T.; Metges, J. P.; et al. (2021)
      Background: In the randomized, international, double-blind, placebo-controlled KEYNOTE-590 (NCT03189719) study, pembrolizumab (pembro) + chemotherapy (chemo) provided statistically significant and clinically meaningful improvement in OS, PFS, and ORR vs placebo + chemo as first-line therapy for patients (pts) with locally advanced/unresectable or metastatic adenocarcinoma or esophageal squamous cell carcinoma (ESCC) or Siewert type 1 esophagogastric junction adenocarcinoma (EGJ). Here we report HRQoL outcomes in KEYNOTE-590. Methods: 749 pts were randomized 1:1 to pembro 200 mg or placebo Q3W for up to 2y + chemo (cisplatin 80 mg/m2 Q3W [d1; 6 doses] + 5-FU 800 mg/m2 on d1-5 Q3W). EORTC QLQ-C30, EORTC QLQ-OES18, and EQ-5D-5L questionnaires were administered at baseline, every 3 weeks (Q3W) up to week 24, and then Q9W up to 1 year or end of treatment, and at the 30-d safety follow-up visit. HRQoL was assessed in all treated patients who completed ≥1 HRQoL assessment (N = 711: 356 for pembro + chemo; 355 for chemo). Change from baseline to week 18 in EORTC-QLQ-C30 global health status (GHS)/QoL and physical functioning, and in QLQ-OES18 scores were prespecified secondary endpoints. Change from baseline to week 18 in EQ-5D scores was an exploratory endpoint. Time to deterioration (TTD) was evaluated for all endpoints. Least square mean (LSM) change from baseline (95% CI) was compared using a constrained longitudinal data analysis model. TTD was compared using a stratified log rank test and Cox proportional hazards model. P-values are nominal and two-sided. Results: QLQ-C30, QLQ-OES18 and EQ-5D-5L compliance was ≥90% in both arms at baseline and at week 18. There was no significant difference in least squares mean (LSM) change from baseline to week 18 in GHS/QoL status between arms (LSM difference [95% CI] -0.10 [-3.40-3.20]; P = 0.9530). Median TTD in GHS/QoL was similar between arms (HR, 0.86 [95% CI, 0.66-1.13]; P = 0.2864). Outcomes were similar in ESCC PD-L1 CPS ≥10, ESCC, and PD-L1 CPS ≥10 patient populations. LSM change from baseline to week 18 for QLQ-OES18 pain subscale was better for pembro + chemo (-4.78) vs chemo (-1.85 ) (-2.94, -5.86 to -0.02; P = 0.0487). There was no significant difference in LSM change from baseline to week 18 between arms for reflux (-1.19; -4.49-2.10; P = 0.4781) or dysphagia (-2.35; -7.78-3.07; P = 0.3945). VAS LSM change from baseline to week 18 was similar between arms (1.20, -1.61-4.01; P = 0.4016). Conclusions: HRQoL was stable and similar over 18 weeks in the pembro + chemo and chemo arms. Together with superior OS, PFS, and ORR and a manageable safety profile with pembro + chemo, these results support the clinically meaningful benefit of pembro + chemo in patients with advanced esophageal cancer including EGJ adenocarcinoma
    • LEAP-005: A phase II multicohort study of lenvatinib plus pembrolizumab in patients with previously treated selected solid tumors-Results from the gastric cancer cohort

      Chung, H. C.; Lwin, Z.; Gomez-Roca, C.; Longo, F.; Yanez, E.; Alvarez, E. C.; Graham, Donna; Doherty, M.; Cassier, P.; Lopez, J. S.; et al. (2021)
      Background: Lenvatinib, an anti-angiogenic multiple receptor tyrosine kinase inhibitor, in combination with the anti‒PD-1 antibody pembrolizumab, has demonstrated promising antitumor activity with manageable safety in the first- or second-line in a phase 2 trial of patients with advanced gastric cancer. LEAP-005 (NCT03797326) is a phase 2, multicohort, nonrandomized, open-label study evaluating efficacy and safety of lenvatinib plus pembrolizumab in patients with previously treated advanced solid tumors; here, we present findings from the gastric cancer cohort of LEAP-005. Methods: Eligible patients were aged ≥18 years with histologically or cytologically confirmed metastatic and/or unresectable gastric cancer, received at least 2 prior lines of therapy, had measurable disease per RECIST v1.1, ECOG PS of 0‒1, and provided a tissue sample evaluable for PD-L1 expression. Patients received lenvatinib 20 mg once daily plus pembrolizumab 200 mg Q3W for up to 35 cycles of pembrolizumab (approximately 2 years) or until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Treatment with lenvatinib could continue beyond 2 years in patients experiencing clinical benefit. Primary endpoints were ORR (per RECIST v1.1 by blinded independent central review) and safety. Secondary endpoints included disease control rate (DCR; comprising CR, PR, and SD), duration of response (DOR), PFS, and OS. Tumor imaging was performed Q9W from treatment initiation for 54 weeks, then Q12W to week 102, and Q24W thereafter. Results: 31 patients were enrolled in the gastric cancer cohort; 87% were male, 58% were aged < 65 years, and 71% had PD-L1 combined positive score (CPS) ≥1. Median time from first dose to data cutoff (April 10, 2020) was 7.0 months (range, 1.9‒11.9); 19 patients (61%) had discontinued treatment. ORR was 10% (95% CI, 2‒26); 1 patient had CR (3%), and 2 had a PR (6%). 12 patients (39%) had SD. Median DOR was not reached (range, 2.1+ to 2.3+ months). DCR was 48% (95% CI, 30‒67). Median PFS was 2.5 months (95% CI, 1.8‒4.2). Median OS was 5.9 months (95% CI, 2.6‒8.7). 28 patients (90%) had treatment-related AEs, including 13 patients (42%) with grade 3‒5 AEs. 1 patient had a treatment-related AE that led to death (hemorrhage). 8 patients (26%) had immune-mediated AEs: hypothyroidism (n = 5), hyperthyroidism (n = 2), and pneumonitis (n = 1). There were no infusion-related reactions. Conclusions: In patients with advanced gastric cancer who received 2 prior lines of therapy, lenvatinib plus pembrolizumab demonstrated promising antitumor activity and a manageable safety profile. Based on these data, enrollment in the gastric cancer cohort has been expanded to 100 patients
    • Phase II study evaluating trifluridine/tipiracil plus bevacizumab and capecitabine plus bevacizumab in first-line unresectable metastatic colorectal cancer (mCRC) patients who are noneligible for intensive therapy (TASCO1): Results of the final analysis on the overall survival

      Van Cutsem, E.; Danielewicz, I.; Saunders, Mark P; Pfeiffer, P.; Argiles, G.; Borg, C.; Glynne-Jones, R.; Punt, C. J. A.; van de Wouw, A. J.; Fedyanin, M.; et al. (2021)
      Background: Our phase II randomized study was conducted in patients with previously untreated unresectable mCRC not eligible to receive standard oxaliplatin- or irinotecan- based chemotherapy regimens. The results of the primary study analysis were reported earlier and demonstrated a promising efficacy in terms of progression-free survival (PFS) and an acceptable safety profile for the combination of trifluridine/tipiracil + bevacizumab (E. Van Cutsem et al. Ann. Oncol. 2020). Here we present the final end-of-study analysis on the overall survival (OS). Methods: Eligible patients were randomized in 1:1 ratio to receive either trifluridine/tipiracil administered orally at 35 mg/m²/dose bid from days 1-5 and days 8-12, and bevacizumab at 5 mg/kg on days 1 and 15 of a 28-day treatment cycle (TT-B), or capecitabine administered orally at 1250 or 1000 mg/m²/dose bid (according to the patient’s status) from days 1-14 and bevacizumab at 7.5 mg/kg on day 1 of a 21-day treatment cycle (C-B). Cycles were repeated until documented disease progression, unacceptable toxicity, or investigator’s/patient’s decision. Following the treatment discontinuation, all patients were followed for OS until the end-of-study, which was defined as the date of the withdrawal visit for the last patient. In the absence of death confirmation or for patients alive as of the end-of-study date, survival time was censored at the date of their last study follow-up. For the OS analysis the HR and the corresponding 2-sided 80% and 2-sided 95% CIs for TT-B versus C-B were estimated using a Cox proportional hazard model adjusting for the stratification factors based on IWRS data. OS was summarized using Kaplan-Meier curves and further characterized in terms of the median and survival probabilities at 6, 12, 18, and 24 months along with the corresponding 2-sided 80% and 2-sided 95% CI (Brookmeyer and Crowley CI for median and Kalbfleisch and Prentice CI for survival probabilities). Results: From April 2016 to March 2017, 153 patients were randomized and followed until end-of-study on September 1, 2020. Twenty-one patients, 11 from TT-B and 10 from C-B, were alive and censored for the analysis. Median OS was 22.31 months in TT-B and 17.67 months in C-B with HR 0.78 (95% CI, 0.55, 1.10). Survival probability at 18 months in TT-B was 0.62 (95% CI, 0.50, 0.72), and 0.47 (95% CI, 0.35, 0.57) in C-B. Conclusions: Our study demonstrated earlier a median PFS of 9.2 months for TT-B and 7.8 months for C-B when administered to patients with previously untreated unresectable mCRC ineligible for standard combination chemotherapy. The final study analysis performed on OS, the main secondary endpoint, provided further evidence for TT-B as a noteworthy valuable regimen in this population settings.
    • The impact of changes in service delivery in patients with colorectal cancer during the first peak of the COVID-19 pandemic

      Kamposioras, Konstantinos; Lim, Kok Haw Jonathan; Saunders, Mark P; Marti, Kalena; Anderson, Daniel; Cutting, Mark; McCool, Danielle; Connell, Jacqueline; Simpson, Lilly; Hasan, Jurjees; et al. (2021)
      Background: Increased levels of anxiety and distress in both patients and physicians have been reported in response to the significant impact COVID-19 has on cancer service delivery globally. We aimed to investigate how these changes have been perceived by patients diagnosed with colorectal cancer and identify determinants of increased anxiety. Methods: Survey (32-item) of consecutive patients diagnosed with colorectal cancer attending a large tertiary comprehensive cancer centre in the United Kingdom (18 May to 1 July 2020). Self-reported GAD-7 (both paper/electronic forms) was used as a screening tool for anxiety. Statistical analyses of associations:Chi-square, Fisher’s exact, and uni- and multi-variable analyses were performed using SPSS v19 and R. Results: A total of 143 patients (response rate 67%), 82% male, and median age of 61-70 years were included. Majority of patients had telephone consultation (78%), including 40% who had scan results discussed over the phone; with favourable feedback received with both respectively. Twenty-three patients (18%) were considered to have anxiety, with 7 (6%) scoring for moderate or severe anxiety. Three items asked patients if they had concerns about getting COVID-19, were worried that COVID-19 would have effect on mental health, and affect their experience of cancer care. Patients answering positively to any of these items were most likely to have anxiety; multivariate analysis – OR 2.361 (95% CI 1.187-4.694, p=0.014), 3.219 (95% CI 1.401-7.395, p=0.006) and 3.206 (95% CI 1.036-9.920, p=0.043), respectively. Majority of the patients did not feel that they needed support during the pandemic period and hence the available well-being services were not used. Patients felt that friends and family had been very supportive but less so the primary care services (p<0.05). However, they felt they were supported by the clinical team. Conclusions: At our centre, during the first-peak of COVID-19 pandemic in the UK, patients with colorectal cancer did not display increased rates of significant anxiety. The findings of this survey suggests that some service changes implemented, including increased telephone follow-up, may have already improved the overall experience of cancer care. Importantly, patients were much more concerned about their cancer treatment than COVID-19, emphasising the need to continue to provide comprehensive cancer care even if we get a “2nd wave” of COVID-19.
    • Phase III study of NUC-1031+cisplatin vs gemcitabine plus cisplatin for first-line treatment of patients with advanced biliary tract cancer (NuTide:121)

      Knox, J. J.; McNamara, Mairead G; Goyal, L.; Cosgrove, D.; Springfeld, C.; Sjoquist, K. M.; Park, J. O.; Verdaguer, H.; Braconi, C.; Ross, P. J.; et al. (2021)
      Background: Biliary tract cancer (BTC) carries a poor prognosis and no first-line treatments are approved. The accepted global standard of care is gemcitabine + cisplatin (GemCis). NUC-1031 is a phosphoramidate transformation of gemcitabine designed to overcome key cancer resistance mechanisms that are associated with gemcitabine. Promising efficacy has been observed with single-agent NUC-1031 in a phase I study in advanced solid tumors and in the phase Ib ABC-08 study of NUC-1031 + cisplatin for first-line treatment of advanced BTC. Of 14 patients enrolled in 2 cohorts (NUC-1031 625 mg/m2 or 725 mg/m2 + cisplatin 25 mg/m2 on Days 1 and 8 of 21-day cycle), 1 had a CR and 6 had PRs, resulting in an unconfirmed ORR of 50%. This represents an approximate doubling of ORR over SoC. The combination was well-tolerated with no unexpected AEs or DLTs. The RP2D of NUC-1031 with cisplatin was 725 mg/m2. The tolerability profile, together with encouraging efficacy, suggested NUC-1031 + cisplatin may represent a more effective therapy than GemCis for BTC and led to initiation of a global registrational study. Methods: NuTide:121 is a Phase III, open-label, randomized study of NUC-1031 + cisplatin vs GemCis for first-line treatment of advanced BTC. Patients ≥18 years with histologically- or cytologically-confirmed BTC (including cholangiocarcinoma, gallbladder, or ampullary cancer), who have had no prior systemic chemotherapy for locally advanced/metastatic disease, are eligible. A total of 828 patients are being randomized (1:1) to either 725 mg/m2 NUC-1031 or 1000 mg/m2 gemcitabine, both with 25 mg/m2 cisplatin, administered on days 1 and 8 of 21-day cycles. Primary objectives are OS and ORR. Secondary objectives include PFS, safety, PK and patient-reported quality of life. In addition to the final analysis, three interim analyses, including two designed to support accelerated approval, are planned. The study has passed an initial safety analysis, with no protocol changes required. NuTide:121 is being conducted at approximately 130 sites across North America, Europe and Asia Pacific countries.
    • Early safety assessment of durvalumab after sCRT in patients with stage III, unresectable NSCLC (PACIFIC-6)

      Garassino, M. C.; Mazieres, J.; Reck, M.; Delmonte, A.; Bischoff, H. G.; Bernabe, R.; Perez, I. D.; Sawyer, W.; Trunova, N.; Faivre-Finn, Corinne; et al. (2021)
      Background: In the ph III PACIFIC trial, durvalumab after concurrent chemoradiotherapy (cCRT) significantly improved survival outcomes in pts with Stage III, unresectable NSCLC with manageable safety. As many pts are ineligible for cCRT, we aimed to assess durvalumab after sequential (s)CRT in pts with Stage III, unresectable NSCLC in the ph II PACIFIC-6 trial (NCT03693300). Methods: Up to 120 pts with ECOG PS ≤2 and no progression after sCRT will receive durvalumab 1500 mg IV q4w ≤24 months or until progression, unacceptable toxicity or consent withdrawal. The primary endpoint is assessment of safety/tolerability, defined by gr 3/4 treatment-related AEs occurring within 6 months. Pre-specified early assessment was planned after ≥50 pts in a PS 0/1 cohort (∼100–120 expected) had received durvalumab ≥6 months. Results: As of August 24, 2020, 50 pts with ECOG PS 0/1 (46%/54%) had received durvalumab for a median 24.0 weeks. Median agewas 67.0 years; 64% were male; 64% had adenocarcinoma histology; 38%/52%/ 10% had Stage IIIA/B/C disease; and 48%/52% had PD-L1 tumor cell expression ≥/< 1%. Many pts had past/present medical conditions, including vascular (62%), metabolism (54%) and respiratory (50%) disorders. Pts had received a median 4 CT cycles, with 68% receiving a total RT dose of ≥54 to ≤60 Gy and 32% receiving >60 to ≤66 Gy. In most pts (84%), CT and RT did not overlap. Best response to prior sCRT (RECIST 1.1) included PR (74%) and SD (18%). In all, 88% had any AEs and 12% had gr 3/4 AEs; 70% had any possibly related AEs (PRAEs) and 4% had gr 3/4 PRAEs (including 2% with the gr 3/4 PRAE pneumonitis). 22% had SAEs (10% PRSAEs) and 2 pts had fatal AEs (1 pt fatal PRAE). 72% had AESIs, including pneumonitis (32%) and dermatitis/rash (28%). 9/25 pts who discontinued did so due to AEs, most commonly pneumonitis (n = 8). Conclusions: Based on early assessment, durvalumab after sCRT appears to have a similar safety profile to that with durvalumab after cCRT in PACIFIC pts with Stage III, unresectable NSCLC. Full cohort results for safety primary analysis in the near future are awaited
    • Survival data from EMPOWER-Lung 4: Phase II study of cemiplimab plus ipilimumab in the second-line (2L) treatment of advanced non-small cell lung cancer (NSCLC)

      Shim, B. Y.; Lee, S.; Carpeno, J. D.; Chiu, C. H.; Cobo, M.; Kim, H. R.; Ryu, J. S.; Tarruella, M. M.; Summers, Yvonne J; Thomas, C. A.; et al. (2021)
      Background: EMPOWER-Lung 4 is a phase II study evaluating cemiplimab monotherapy, and combination therapy with cemiplimab + ipilimumab, as 2L treatment in patients (pts) with advanced NSCLC and programmed cell death-ligand 1 (PD-L1) <50%.We previously reported on this study, showing that numerically better objective response rates (ORR) were observed with cemiplimab + ipilimumab vs cemiplimab monotherapy. Here, we present follow-up data including survival outcomes not previously reported. Methods: Pts received cemiplimab 350 mg every 3 weeks (Q3W) (Arm A); or cemiplimab 350 mg Q3W plus ipilimumab 50 mg every 6 weeks (Arm B); or cemiplimab 1050 mg Q3W (Arm C), for up to 108 weeks or until progression. Primary endpoint was ORR per independent review committee (IRC). Data cut-off was 30 Jun 2020. Results: Of 28 pts enrolled, 27 received treatment (Arm A, n = 8;ArmB, n = 11; and Arm C, n = 8). Median duration of treatment exposurewas 10.8 (Arm A), 17.9 (Arm B) and 10.8 (Arm C)weeks. Median follow-upwas 2.6 (Arm A), 17.4 (Arm B) and 3.9 (Arm C) months. ORR (95% confidence interval [CI]) remained unchanged since the previous report: 0% (0.0– 36.9%) in Arm A, 45.5% (16.7–76.6%) in Arm B, and 11.1% (0.3–48.2%) in Arm C, with a median duration of response not reached (NR) in Arm B and 11.2 months in Arm C. Median overall survival (OS) (95% CI) per IRC was 5.1 months (1.7–not evaluable [NE]) in Arm A, NR (2.2–NE) in Arm B and 8.4 months (0.3–NE) in Arm C. Median progression-free survival (PFS)(95%CI) per IRCwas 2.0months (0.7–8.3) inArmA,NR(1.2–NE)in ArmBand 1.8 months (0.3–12.7) inArmC. Grade≥3 treatment-emergent adverse events (AEs) occurred in 25.0% (Arm A), 72.7% (Arm B) and 75.0%(ArmC) of pts. Across all arms, increased alanine aminotransferase was the only Grade ≥3 immune-related AE reported in >1 pt (n = 2 [18.2%]; both in Arm B). Conclusions: This follow-up analysis which includes OS/PFS data shows that combination of ipilimumab 50 mg with cemiplimab 350 mg provides additional survival improvement in pts with advanced NSCLC and PD-L1 <50%. Moreover, consistency in ORR with the previous analysis demonstrates durability of responses to cemiplimab 350 mg + ipilimumab 50 mg.
    • RAS precision medicine trans-atlantic partnership: multi-centre pooled analysis of RAS pathway mutations in advanced NSCLC

      Adderley, Helen; Aldea, M.; Aredo, J.; Carter, Matthew; Church, Matt; Blackhall, Fiona H; Krebs, Matthew G; Wakelee, H. A.; Besse, B.; Planchard, D.; et al. (2021)
      Introduction: The most common histological subtype of non-small cell lung cancer (NSCLC) is adenocarcinoma (50-55% of patients), of which the most common oncogenic driver is KRAS mutation (w30% internationally). Genetic data has altered the taxonomy of NSCLC over the past 10 years, highlighting subgroups such as EGFR mutation, which have improved prognosis and are susceptible to targeted therapies. Despite its frequency, targeting RAS has historically been limited by pre-clinical and clinical failures. Emerging preclinical/ clinical data suggests there is value looking beyond RAS mutation, analysing subtypes- represented by a limited number of variations in its mutational isoforms, codons and alleles. Through international collaboration our partnership aims to extend existing knowledge of RAS precision medicine in NSCLC, evaluating biological, clinical and treatment effects at subtype level. Methods: For this analysis, the first 309/384 patients with stage IIIb/IV RAS- and/ or NF1-mutant NSCLC were identified from the Christie NHS Foundation Trust and the Gustave Roussy Cancer Centre between August 2008 and July 2020. DNA was extracted from archival FFPE samples, plasma or both to identify mutations using targeted next generation sequencing. Molecular, clinical, pathological and outcome data were collected on all patients and Kaplan-Meier survival analysis was performed to test for survival differences between subtypes based on treatment arms. For clinical characteristics, Mann-Whitney and Fisher’s exact tests were used for statistical comparisons in continuous and dichotomous datasets, respectively. Results: Of 309 patients analysed, 151 patients were from the Christie NHS Foundation Trust and 158 patients from the Gustave Roussy Cancer Centre. Mean age was 63, range 19-92. 30 patients (10%) had stage IIIb disease with the remainder stage IV, 292 patients (94.5%) demonstrated non-squamous histology vs. 16 (5%) squamous vs 1 (0.5%) adenosquamous. Median PD-L1 status across the cohort was 20%. 209 patients (68%) had a mutation identified by tissue analysis, 38 patients (12%) by plasma and 62 (20%) by both. The most common RAS mutation identified was KRAS in 259 patients (84%), followed by NRAS in 13 patients (4%) and HRAS in 7 patients (2%). Amongst the KRAS mutant population, 111 pts (43%) harboured a mutation in G12C, followed by 52 (20%) G12D and 41 (16%) G12V. Codon 61 was most commonly mutated within this subgroup 16/259 (6%). 40 patients (13%) were identified as carrying a mutation in NF1; 35 non-squamous histology, 4 squamous and 1 adenosquamous. Progression free survival following first line chemotherapy plus immunotherapy or immunotherapy alone was variable across KRAS-, NRAS- and NF1-mutant subgroups (8.3 vs. 14.9 vs. 10.2 months; p¼0.86). Median PD-L1 status was found to be 63% vs. 100% vs. 79% respectively. Analysis of RAS codon and allelic subgroups, including their therapeutic vulnerabilities beyond immunotherapy, will be presented following further analysis. Conclusion: The RAS precision medicine Trans-Atlantic partnership is designed to evaluate prognostic/predictive value of RAS and NF1 mutations in advanced NSCLC, focusing specifically on signal seeking for therapeutic vulnerabilities in mutant RAS isoforms, codons, and allelic subtypes. Ongoing analysis is planned to expand the dataset and inform the optimal sequence of therapy for subtypes of RAS- and NF1-mutant patients.
    • Phase I study of AMG 757, a delta-like ligand 3 (DLL3) targeting, half-life extended bispecific T-cell engager immuno-oncology therapy, in small cell lung cancer (SCLC)

      Paz-Ares, L.; Owonikoko, T. K.; Johnson, M.; Govindan, R.; Izumi, H.; Lai, V.; Borghaei, H.; Boyer, M.; Boosman, R. J.; Hummel, H. D.; et al. (2021)
      Background: AMG 757 simultaneously binds DLL3 on SCLC cells and CD3 on T cells leading to T cell- mediated tumor lysis. Data from an ongoing phase I study of AMG 757 in SCLC are reported. Methods: Safety and efficacy were evaluated in a phase I trial of AMG 757 for patients (pts) with relapsed/refractory SCLC after >= 1 platinum-based regimen (NCT03319940). AMG 757 was administered intravenously (9 dose levels (DLs); dose range: 0.003−30 mg q2w, ± step dosing). Results: As of 03 Nov 2020, 52 pts (median age, 64 [32−80] y; median prior lines of therapy, 2 [1−6]) were enrolled. 79% (41/52) of pts reported treatment (tx)-related adverse events (TRAEs) (Grade [Gr] >= 2, 29/52 [56%], Gr >= 3, 12/52 [23%], Gr >= 4, 4/52 [8%]). TRAEs accounted for 1 tx discontinuation and 1 death (Gr 5 pneumonitis, DL, 0.3 mg). Cytokine release syndrome (CRS; 44%; Lee criteria (2014): Gr 2, 5/52 [10%], Gr 3, 1/52 [2%], no Gr >= 4) was the most common TRAE and typically occurred in cycle 1. Median time to onset of CRS was 9 (3−52) h following an AMG 757 dose; median duration was 60 (3−197) h. Fever (31%), tachycardia (19%), and nausea (14%) were the most common CRS-related symptoms. Significant increases in cytokine (IL-8, MCP-1, IFN-g, IL-10, IL-6, MIP-1a, MIP-1b, TNF-a) levels from baseline in the 24 h following the first AMG 757 dose in cycle 1 were observed in pts experiencing CRS vs. pts who did not experience CRS symptoms. CRS did not result in tx discontinuation or deaths and was managed with supportive care, corticosteroids, and/or anti-IL-6R. 14% (7/51) of pts achieved a confirmed partial response (PR) (modified RECIST 1.1) in 4 DLs (0.3 mg [8% of PR], 1 mg [13%], 3 mg [33%], and 10 mg [20%]). Stable disease was seen in 24% (12/51). Median time to response was 1.8 months; the estimated duration of response was > 6 months in 83% (95% CI: 27%, 98%) of pts with a confirmed PR. An unconfirmed PR was noted in an additional pt (30 mg DL). Conclusions: AMG 757 showed an acceptable safety profile and preliminary evidence for efficacy in pts with SCLC. The most common TRAE—CRS—occurred early in the dosing cycle, did not recur, was typically mild in severity, and manageable. The maximum tolerated dose has not been reached. Dose-finding for monotherapy is ongoing.
    • An autoethnographic study exploring the role of the lung cancer nurse specialist in the national optimal lung cancer pathway

      Bobat, A.; Anderson, V.; Barnett, N.; Beattie, V.; Bostock, Layla; Clayton, K.; Cole, T.; Foreman, H.; Holden, S.; Kefyalew, S.; et al. (2021)
      Introduction: Background: The National Optimal Lung Cancer Pathway (NOLCP) is a pathway hospitals in the UK are expected to follow which advocates a standardised care pathway. The pathway is aimed at improving lung cancer care to enable time to treatment within 49 days. The Lung Cancer Nurse Specialist is a core member of the Multidisciplinary Team providing expert knowledge, specialist assessment and advanced communication. They also act as an advocate for patients on the NOLCP. The aim of study was to explore the role of Lung Cancer Nurse Specialist in the NOLCP and the Lung Cancer Specialist Nurse’s experience of the “meet the Lung CNS “ aspect of the NOLCP. Methods: An autoethnographic study of 16 practicing Lung Cancer Nurse Specialist’s from different centres across the country who reflected on the first meeting with two patients on the NOLCP. Written reflections were subjected to thematic analysis and Gibbs reflective model was used to complete the reflections. Results: Four key themes were identified: 1. Co-ordination of complex care. This is delivering care in accordance with the NOLCP, avoiding delays and ensuring right care, right time in the right place. 2. Relationship building and advanced communication. Utilising specialised knowledge along woth advanced listening and communication skills. Being accessible and providing accurate information and advice 3. Specialist patient assessment and management. This involves the undertaking of specialist holistic assessments to support the treatment and management of lung cancer and its symptoms. 4. Support and management of emotions and expectations. Providing emotional support and management of unrealistic expectations for patients and relatives, as well as themselves and the wider healthcare community These four themes were underpinned by a fifth cross-cutting theme which was effective utilisation of resources. Conclusion: Lung Cancer Nurse Specilaists are pivotal in the delivery of high quality lung cancer care. Through the provision of specialist and expert nursing care, Lung Cancer Nurse Specialists co-ordinate complex care, undertake holistic patient assessment and support and management expectations. This is achieved through successful relationship building and advanced communication skills and appropriate and effective utilisation of resources. Recommendations Clarification of the Lung Cancer Nurse Specialist role is required both locally & nationally. Implementation of the NOLCP will add increased demand on Lung Cancer Nurse Specialist services which are already underresourced. Adequate provision must be made to meet this requirement.
    • The ARIA Study:activity of next-generation ALK TKIs based on ALK resistance mutations detected by liquid biopsy in ALK positive NSCLC patients

      Mezquita, L.; Swalduz, A.; Auclin, E.; Carter, Matthew; Steendam, C.; Aldea, M.; Scheffler, M.; Corral, J.; Viteri, S.; Segui, E.; et al. (2021)
      Introduction: Detection of resistance mechanisms to tyrosine kinase inhibitors (TKI), in particular ALK mutations (ALKm), could help to select the subsequent treatment in ALK-positive NSCLC patients. Liquid biopsy can identify these ALKm from ctDNA in up to 29% of patients after 2nd-generation TKI-failure. We assessed the activity of next-gen TKIs based on the presence of ctDNA ALKm. Methods: Patients with ALK-positive advanced NSCLC pretreated with 1st and/or 2nd-generation ALK-TKI were selected in 9 European centers. Liquid biopsy was collected immediately before starting brigatinib or lorlatinib. ALKm were defined by commercial or homemade next-generation sequencing run on ctDNA and covering ALK exon 22/23/25. We correlated the activity of brigatinib or lorlatinib based on three ctDNA molecular groups: presence ALKm (if one: single; if 2: complex); other mutations and no detectable mutations. We assessed progression-free survival (PFS), objective response rate (ORR), intracranial ORR according to the clinical routine of each center and overall survival (OS). Results: 62 patients were identified, 58 evaluable at cutoff data (Jul-20): 16 before brigatinib and 42 before lorlatinib. Median age was 53 [27-80], 64% were female, 67% nonsmoker; 97% with adenocarcinoma; 7% and 10% with isolated thoracic and brain disease, respectively. The median (m) number of TKIs was 3 [2-7]; 90% received 2nd-generation TKIs. The mFU since liquid biopsy was 24.8 months. ALKm were detected in 28% (3 brigatinib; 13 lorlatinib), 9 single and 7 complex; others were detected in 17% (n¼10) and none in 55% (n¼32). The most common mutation was G1202R (7 before lorlatinib), followed by G1269A and F1174L in 3 cases each, all pretreated with 2nd-generation TKIs. The TKI outcomes according to the ctDNA molecular groups is summarized in table 1. In the ALKm group, lorlatinib showed an ORR of 46% and 56% of intracranial ORR with mPFS of 6.5 months (7¼single/ 6¼complex) while no responses were observed in the 3 cases treated with brigatinib, with mPFS of 3.5 months (2¼single/1¼complex). Those 7 cases harboring the G1202Rmut (4¼complex) had an ORR of only 14% but an intracranial ORR of 50%; mPFS was 3.6 mo. No differences were observed among ctDNA molecular groups. Conclusion: In our study, lorlatinib showed activity in heavily-pretreated patients with ALK-positive NSCLC, regardless the ctDNA molecular groups. Poor outcomes were observed for brigatinib in 3 heavily-pretreated patients with ctDNA ALKm. The recent use of 2ndgen TKI upfront calls for similar studies to confirm if ctDNA may be a biomarker for guiding the sequential therapy.
    • Local, regional and pulmonary failures in the randomised PET-boost trial for NSCLC patients

      Cooke, S.; De Ruysscher, D.; Reymen, B.; Lambrecht, M.; Persson, G. F.; Faivre-Finn, Corinne; Dieleman, E.; Van Diessen, J.; Sikorska, K.; Lalezari, F.; et al. (2021)
      Introduction: In the phase II PET-Boost trial (NCT01024829), patients with stage II-III non-small cell lung cancer (NSCLC) were treated with hypofractionated dose escalation to either the primary tumour (PT) as a whole (armA) or the high FDG-uptake region inside the PT (>50%SUVmax) (armB). Results on Freedom From Local Failure at 1-year (primary endpoint), and overall survival (a secondary endpoint) were reported previously (Cooke et al,ESTRO,2020). Here we report on local and regional failure. Methods: Patients with stage II-III NSCLC were randomised to armA or armB, after a treatment plan was made for both arms that were normalized to the mean lung dose. Concurrent/ sequential/no chemotherapy was allowed. Followup chest CT-scans - scheduled at 3/6/12/18 months - were centrally reviewed by a thoracic radiologist. Definitions: local failure (LF): 20% growth of PT. Regional failure (RF): lymph node (LN) failure either in-field (IF) or out-of-field (OF) on CT-scan. Kaplan Meier analysis was performed to assess LF and RF rates at 2 years. Analysis of distant metastases is on-going. Results: Between April 2010 and Sep 2017, 107 patients were randomised. 82% had stage III disease and 80% had N 1 disease. Most patients received concurrent-chemoradiotherapy (72%). In arms A and B, median GTV-PT was 100 and 115cm3, median GTV-LN was 18 and 20cm3, median fraction dose was 3.25Gy to PTVwhole PT and 3.50Gy to PTV50%SUVmax, resulting in total planned physical dose 78.0 and 84.0 Gy, in 24 fractions (median OTT 34 days in both arms). Median follow-up for CT-scans in central review was 12.6months. In armsA and B respectively, loco-regional failure occurred in 12 and 15 patients, of which 2 and 4 had LF-without-RF, while 9 and 10 had RF-without- LF. One patient in armA had LF with synchronous RF, while in armB one patient had non-synchronous LF and RF. Analysis of all RF’s (10 and 11 total) showed 3 and 4 IF, 3 and 5 OF, 3 and 0 IF as well as OF (missing n¼3). In arms A and B respectively, the 2-year cumulative incidence of LF was 11% and 18%, and for RF 28% and 25% Conclusion: In this randomised, phase II trial dose escalation to the whole PT or 50%SUVmax in NSCLC patients led to excellent local control rates in both treatment arms. The 2-year local failure rate was below 20% and regional failures rate about 27%. In future trials, dose escalation on the PT, sparing central structures as much as possible, may be considered.
    • A phase 1 Study of AMG 757, half-life extended bispecific t-cell engager (BiTE (R))immune therapy against DLL3, in SCLC

      Owonikoko, T.; Boyer, M.; Johnson, M.; Govindan, R.; Rodrigues, L.; Blackhall, Fiona H; Boosman, R.; Champiat, S.; Hummel, H.; Lai, W. V.; et al. (2021)
      Introduction: Delta-like ligand 3 (DLL3), an inhibitory Notch ligand that is highly expressed in small cell lung cancer (SCLC) compared to normal tissues, is a potential therapeutic target.1 AMG 757, a half-life extended BiTE® immune therapy, binds DLL3 on tumor cells and CD3 on T cells, leading to T cell-dependent killing of tumors. Emerging data from the ongoing phase 1 study of AMG 757 in SCLC are reported (NCT03319940). Methods: AMG 757 (0.003e10.0 mg) was administered intravenously every two weeks with/without step dose. Eligible patients had SCLC that progressed or recurred following 1 platinumbased regimen. Antitumor activity was assessed using modified RECIST 1.1. Tumor DLL3 expression was assessed by immunohistochemistry. T-cell activation and cytokine profiles pre and post AMG 757 treatment were evaluated. Results: As of 7 August 2020, 40 patients (median age [range], 64 years [44e80]; ECOG PS: 0-1, n¼39 [97.5%], median prior lines: 2.0 [1e6]; prior PD-1/PD-L1 treatment: n¼17 [42.5%]) enrolled at eight dose levels (DL) received 1 AMG 757 dose. Median treatment duration was 6.1 weeks (0.1e59.4). Adverse events occurred in 39 (97.5%) patients, resulting in discontinuation in 4 (10.0%); 32 (80.0%) were treatment-related, including 7 (17.5%) grade 3 and 1 (2.5%) grade 5 (pneumonitis; DL5 [0.3 mg]). Cytokine release syndrome (CRS) was reported in 18 (45.0%) patients; grade 2 CRS in 5 (12.5%); no grade 3 CRS. CRS presented mainly as fever ± hypotension, was reversible, did not lead to treatment interruption or discontinuation, occurred mostly within 24 hours of the first two doses of AMG 757, and was managed with supportive care, corticosteroids, and/or anti-IL-6 treatment. AMG 757 showed dose proportional increase in exposures. Confirmed partial response (PR) was reported for 6 (15.8%) patients (1/12 [8.3%] in DL5, 1/8 [12.5%] in DL6, 3/7 [42.9%] in DL7, and 1/7 [14.3%] in DL8 [Figure]). Stable disease was reported for 11 (28.9%). One patient has ongoing unconfirmed PR in DL8. Evaluation of DL8 is ongoing. Patients with confirmed PR had a median of 2 (1e4) prior lines of therapy and duration of response of 1.9+ to 9.4+ months. DLL3 expression at any level was observed in 31/32 (96.9%) patient tumor samples, with overall H-score 40e300. Tumor shrinkage occurred across a wide range of DLL3 expression (H-score, 55e300). Conclusion: AMG 757 has acceptable safety at doses of up to 10 mg and shows anti-tumor activity in patients with SCLC. Dose escalation is ongoing. References: 1. Leonetti A, et al. Cell Oncol (Dordr). 2019;42(3):261-273.
    • Phase 1/2 TRIDENT-1 study of repotrectinib in patients with ROS1+ or NTRK plus advanced solid tumors

      Cho, B. C.; Doebele, R. C.; Lin, J.; Nagasaka, M.; Baik, C.; Van der Wekken, A.; Velcheti, V.; Lee, K. H.; Liu, S.; Solomon, B.; et al. (2021)
      Introduction: Repotrectinib is a next-generation ROS1/TRK TKI with >90-fold greater potency than crizotinib and entrectinib against ROS1 and >100-fold greater potency than larotrectinib against TRK in engineered Ba/F3 cell proliferation assays. In the Phase 1 portion of TRIDENT-1 study, repotrectinib demonstrated encouraging overall clinical activity in patients (pts) with ROS1 fusion+ NSCLC and TRK fusion+ solid tumors, especially in those pts with ROS1+ NSCLC who are TKI naive. Methods: In Phase 1 portion of the study, the Recommended Phase 2 Dose (RP2D) for repotrectinib was determined to be 160 mg QD for 14 days followed by 160 mg BID if tolerated. Currently, this global trial (Clinical trial information: NCT03093116) is actively enrolling pts whose cancers harbor a ROS1 or NTRK1/2/3 fusion in six phase 2 expansion cohorts (see table). The primary endpoint for the Phase 2 portion is confirmed overall response rate (cORR) by Blinded Independent Central Review (BICR) using RECIST v1.1. An early interim analysis on 39 pts enrolled in Phase 2 was conducted using investigator assessment. Results: Phase 1: Utilizing a 22 July 2019 data cutoff, cORR was 91% by BICR in 11 ROS1 TKI-naïve pts with 5 responses ongoing. The median duration of response (DOR) for the 10 confirmed responders was 23.1 months (95% CI: 5.6enot reached [NR]) and median progression-free survival (PFS) was 24.6 months (95% CI: 7.2 e NR). As of 6 April 2020, with an additional 8.5 months of follow-up, 4 of the 5 previously responding TKI-naïve pts remained in a partial response (PR) per physician assessment data and 7 TKI-naïve pts remained on treatment, range (17.3+ - 34.2+ months). Phase 2: The early Phase 2 TRIDENT-1 dataset utilizing a July 10, 2020 data cutoff includes the first 39 treated pts across six cohorts who have had at least one post-baseline scan. Conclusion: Repotrectinib was well tolerated and continues to demonstrate encouraging overall clinical activity in pts with ROS1 fusion-positive NSCLC and TRK fusion-positive solid tumors. Keywords: repotrectinib TKI-naive response.
    • International Delphi consensus on radical thoracic re-irradiation for non-small cell lung cancer (NSCLC)

      Rulach, R.; Guckenberger, M.; De Ruysscher, D.; Palma, D.; Louie, A.; Ball, D.; Hanna, G.; Siva, S.; Salem, Ahmed; Videtic, G.; et al. (2021)
      Introduction: Local recurrence or second lung primaries are common indications for radical thoracic re-irradiation (re-RT), affecting approximately 700 patients in the UK annually. Re-RT is usually the only suitable curative-intent treatment but prospective evidence on toxicity, dose constraints, and optimal treatment technique is lacking. We performed a Delphi process to identify areas of consensus in re-RT for NSCLC. Methods: An international panel of 15 radiation oncologists specialising in lung cancer participated in an initial survey on 23/09/2019 to capture their definition of re-RT, suitable patients, re-RT technique and dose constraints used. The most common responses to questions from the first survey were used to make statements which participants voted on in subsequent rounds using a 5-point Likert scale. Consensus was achieved once 75% of participants agreed with a statement. For the statements which did not reach consensus, respondents provided additional evidence/ comments to refine them. In total, four surveys were performed using a web-based survey programme. Results: All respondents completed three rounds of the survey, with the final round currently in progress. Consensus was achieved within two rounds regarding re-RT indications, patient eligibility and work-up (Table 1). In addition, agreementwas reached to use stereotactic ablative body radiotherapy (SABR) if possible for re-RT. Dose constraints, due to the lack of supportive data, required three rounds to develop agreement. Several volumetric lung constraints were suggested, but due to post-radiotherapy fibrosis, it was concluded that there was insufficient evidence to form recommendations (Table 2). Areas of controversy were how much overlap was significant when performing re-RT, what were the minimum lung function requirements and the minimum safe interval between treatments. Conclusion: This Delphi process with international experts has developed key recommendations on the criteria for suitable re-RT patients, dose constraints and preferred technique. These statements can be used to develop prospective trials to provide better evidence for re-RT.
    • A phase II study of the oral selective AXL inhibitor bemcentinib with pembrolizumab in patients with advanced NSCLC

      Krebs, Matthew G; Helland, A.; Costa, E. C.; Aperribay, E. A.; Gomez, M. D.; Perez, J. T.; Thompson, J.; Strauss, J.; Granados, A. L. O.; Felip, E.; et al. (2021)
      Background: The RTK AXL is implicated in epithelial-to-mesenchymal transition, negative regulation of anti-tumour immunity and resistance to multiple therapies including immune checkpoint inhibitors. Bemcentinib (BGB324) is a first-in-class, oral, highly selective and potent AXL inhibitor which has been demonstrated to enhance anti-PD1 therapy. The combination of bemcentinib and pembrolizumab was well tolerated and showed promising efficacy in previously treated IOnaïve NSCLC patients (Cohort A, NCT03184571), particularly in those with AXL positive disease, including PD-L1 negative patients. The novel combination is now being assessed in patients refractory to anti-PD-(L)1 therapy, considering the emerging need in this population and AXL’s role as a mediator of resistance. Method: This is an open-label, single-arm, 2-stage phase II study (Cohort B, NCT03184571) to evaluate the safety and efficacy of bemcentinib (200mg/d) in combination with pembrolizumab (200mg/q3wk) in patients post anti-PD-(L)1 therapy. The primary endpoint is overall response rate (ORR), and additional endpoints include efficacy by biomarker expression, duration of response (DoR), disease control rate (DCR), progression free survival (PFS), overall survival (OS), and safety. Clinical efficacy endpoints are based on tumour imaging evaluable by RECIST v1.1. Eligible patients received a maximum of 2 prior lines of therapy, with the most recent course having included a PD-(L)1 inhibitor. To be eligible, patients must have exhibited disease control (CR/PR/SD) for at least 6 months on prior PD-(L)1 inhibitor therapy with disease progression occurring within 12 weeks since last dose. Bemcentinib will be administered as a loading dose of 400mg on days 1, 2 and 3 followed by a dose of 200mg once daily. A fixed dose of 200 mg pembrolizumab will be given by intravenous infusion over 30 minutes every 3 weeks. Bemcentinib and pembrolizumab will be given until disease progression, unacceptable dose toxicity, or for a maximum of 35 cycles. Tumour specimens will be analysed for PD-L1 expression (22C3 pharmDx), AXL by IHC, and infiltrating immune cells. The prespecified efficacy threshold for continuation into the second stage is 1 objective response among the first 13 patients, at which point up to a further 16 patients may be evaluated, for a total of 29 patients. Result: Section not applicable Conclusion: Section not applicable
    • An adaptive, biomarker-directed platform study of durvalumab in combination with targeted therapies in advanced urothelial cancer

      Powles, T.; Carroll, D.; Chowdhury, S.; Gravis, G.; Joly, F.; Carles, J.; Fléchon, A.; Maroto, P.; Petrylak, D.; Rolland, F.; et al. (2021)
      Durvalumab is a programmed death-ligand 1 (PD-L1) inhibitor with clinical activity in advanced urothelial cancer (AUC)1. AUC is characterized by several recurrent targetable genomic alterations2-5. This study ( NCT02546661 , BISCAY) combined durvalumab with relevant targeted therapies in biomarker-selected chemotherapy-refractory AUC populations including: (1) fibroblast growth factor receptor (FGFR) inhibitors in tumors with FGFR DNA alterations (FGFRm); (2) pharmacological inhibitor of the enzyme poly-ADP ribose polymerase (PARP) in tumors with and without DNA homologous recombination repair deficiency (HRRm); and (3) TORC1/2 inhibitors in tumors with DNA alteration to the mTOR/PI3K pathway3-5.This trial adopted a new, biomarker-driven, multiarm adaptive design. Safety, efficacy and relevant biomarkers were evaluated. Overall, 391 patients were screened of whom 135 were allocated to one of six study arms. Response rates (RRs) ranged 9-36% across the study arms, which did not meet efficacy criteria for further development. Overall survival (OS) and progression-free survival (PFS) were similar in the combination arms and durvalumab monotherapy arm. Biomarker analysis showed a correlation between circulating plasma-based DNA (ctDNA) and tissue for FGFRm. Sequential circulating tumor DNA analysis showed that changes to FGFRm correlated with clinical outcome. Our data support the clinical activity of FGFR inhibition and durvalumab monotherapy but do not show increased activity for any of the combinations. These findings question the targeted/immune therapy approach in AUC.