• The ECHELON-2 Trial: 5-year results of a randomized, double-blind, phase 3 study of brentuximab vedotin and CHP (A plus CHP) versus CHOP in frontline treatment of patients with CD30-positive peripheral T-cell lymphoma

      Iyer, S.; Trumper, L.; O'Connor, O. A.; Pro, B.; Illidge, Timothy M; Advani, R.; Bartlett, N. L.; Christensen, J. H.; Morschhauser, F.; Domingo-Domenech, E.; et al. (2021)
      Objective: Brentuximab vedotin (BV) plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) signifi cantly prolonged progression-free survival (PFS) and overall survival (OS) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in patients with systemic anaplastic large-cell lymphoma (sALCL) or other CD30-positive peripheral T-cell lymphomas (PTCL) in ECHELON-2 (Horwitz S et al., Lancet 2019). We report updated results; median follow-up was 47.6 months for PFS and 66.8 months for OS. Design: This phase 3, double blind study (NCT01777152) randomized patients aged 18 years with previously untreated CD30-positive PTCL (targeting 75% ± 5% with sALCL) to A+CHP or CHOP for 6 or 8 cycles. Primary endpoint of PFS was assessed per investigator in this updated analysis. Key secondary endpoints included OS and PFS in sALCL. BV or BV-containing regimens were permitted as subsequent/ retreatment therapies. Results: 452 patients were enrolled (226 patients in each arm); 316 (70%) patients had sALCL. Patients with advanced disease were included (stage III [27%] and stage IV [53%]; International Prognostic Index 2 [78%]). Data continues to favor A+CHP: HRs were 0.70 (95% CI: 0.53–0.91, P=0.0077) for PFS per investigator and 0.72 (95% CI: 0.53–0.99, P=0.0424) for OS. 5-year PFS was 51.4% (95% CI: 42.8–59.4) with A+CHP versus 43.0% (95% CI: 35.8–50.0) with CHOP; median PFS was 62.3 months (95% CI: 42.0–not evaluable) with A+CHP and 23.8 months (95% CI: 13.6–60.8) with CHOP. 5-year OS was 70.1% (95% CI: 63.3–75.9) and 61.0% (95% CI: 54.0–67.3) with A+CHP and CHOP, respectively. Median OS was not reached in either arm. PFS favored A+CHP (HR: 0.55 [95% CI: 0.39–0.79]) in sALCL. 29 (13%) and 54 (24%) patients with A+CHP and CHOP received subsequent BV, respectively. Treatment-emergent peripheral neuropathy (PN), resolved/improved in 72% (n=84/117) and 78% (n=97/124) of patients with PN on A+CHP and CHOP, respectively; 98% and 97% of ongoing PN events were grade 1/2 with A+CHP and CHOP, respectively. Conclusions: At this important 5-year milestone, A+CHP still provides clinically meaningful improvement in both PFS and OS versus CHOP, with a manageable safety profi le, including continued resolution/improvement of PN.
    • Incidence, onset, and management of edema and effusion in patients treated with loncastuximab tesirine for R/R DLBCL in the LOTIS clinical trial program

      Alderuccio, J. P.; Ardeshna, K.; Hess, B.; Radford, John A; Lunning, M.; Ungar, D.; Burke, M.; Wang, L. Q.; Solh, M.; Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA (2021)
      Context: Loncastuximab tesirine (Lonca), an antibody-drug conjugate (ADC) comprising an anti-CD19 antibody conjugated to a pyrrolobenzodiazepine (PBD) dimer cytotoxin, is the fi rst FDA approved PBD-containing ADC. Lonca is indicated for relapsed/ refractory DLBCL after ≥2 systemic treatments. Several TEAEs, including edema and effusions, appear to be PBD-related (Saber, et al 2019). Objective: To further characterize edema and effusion by assessing the time to onset, duration, and management in the pivotal LOTIS-2 clinical trial (NCT03589469). Methods: Key safety outcomes: median time to onset and median duration of edema and effusion (April 6, 2020 cutoff date). Missing AE end dates were imputed using the date of new anticancer therapy (NAT), the end of study (EOS), or data cutoff. Partial AE end dates were imputed using the last month or last day of the month bounded by EOS/data cutoff (when EOS is not reached) or NAT date. All AE start dates are complete or partial, with day imputed to the fi rst day of the month, bounded by fi rst dose date. After AE start/ end date imputation, duration was calculated at the patient level. Results: In LOTIS-2 (N=145), dexamethasone pre-medication was administered to reduce the risk of PBD toxicities, based on outcomes from the phase 1, dose-fi nding study (LOTIS-1; NCT02669017). Edema occurred in 27.6% of patients; median time to onset was 40.0 days (range 1–277). Median duration: 50.5 days (2-407). Grade 3 edema occurred in 3.4% of patients. Median time to onset: 106.0 days (9–183); median duration: 5.0 days (3–112).Effusions occurred in 11.0% of patients; median time to onset was 51.5 days (3–203). Median duration: 19.5 days (4–252). Grade 3 effusion occurred in 2.7% of patients. Median time to onset: 118.0 days (17– 277); median duration: 20.5 days (6-82). Five patients (12.5%) with edema and one patient (6.3%) with effusion underwent Lonca re-challenge; diuretics, primarily spironolactone, were commonly used to manage edema and effusion. Conclusions: Edema and effusions in LOTIS-2 were generally reversible and manageable, with dose delays or modifi cations recommended for Grade ≥2 events. Grade ≥3 edema or effusion was uncommon and typically developed later in therapy
    • LOTIS-2 follow-up analysis: updated results from a phase 2 study of loncastuximab tesirine (Lonca) in relapsed or refractory diffuse large B-cell lymphoma

      Kahl, B. S.; Hamadani, M.; Caimi, P. F.; Carlo-Stella, C.; Ai, W. Y.; Alderuccio, J. P.; Ardeshna, K. M.; Hess, B.; Radford, John A; Solh, M.; et al. (2021)
      Context: Patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) who are ineligible for, or relapse after, salvage chemotherapy/stem cell transplant (SCT) have a poor prognosis. Lonca comprises a humanized anti-CD19 antibody conjugated to a potent pyrrolobenzodiazepine dimer toxin. Objective:To assess updated effi cacy and safety fi ndings from a Phase 2 study evaluating Lonca in patients with R/R DLBCL (LOTIS-2; NCT03589469). Design: Multicenter, open-label, single-arm Phase 2 study in adult patients (≥18 years) with pathologically defined R/R DLBCL and ≥2 prior systemic treatments. Intervention: Lonca (150 µg/kg every 3 weeks [Q3W] for 2 cycles; 75 µg/kg Q3W thereafter). Main Outcomes Measures: Primary effi cacy endpoint: Overall response rate (ORR), assessed by central review. Secondary effi cacy endpoints: Duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Safety analyses: Treatment-emergent adverse events (TEAEs). Follow-up period: Q12W for up to 3 years after end of treatment. Results: 145 patients with R/R DLBCL received ≥1 Lonca dose. Median age was 66 years (range 23–94). Patients received a median of 3 prior therapies (range 2–7). At data cut-off (October 26, 2020, 12 months since first dose), 2 patients continued treatment. Patients received a mean of 4.6 Lonca cycles (std 4.1; range 1–22). ORR was 48.3% (complete response [CR]: 24.8%; partial response [PR]: 23.4%). Median DoR was 12.6 months for patients with CR or PR (n=70); not reached for patients with CR. Median PFS and OS were 4.9 and 9.5 months, respectively. Post-Lonca treatment, 15 patients received CD19-directed chimeric antigen receptor T-cell therapy with an investigator-assessed ORR of 46.7%, and 11 patients proceeded to SCT as consolidation after Lonca response. Most common (≥25.0%) all-grade TEAEs were increased gamma-glutamyltransferase (41.4%), neutropenia (40.0%), thrombocytopenia (33.1%), fatigue (27.6%), and anemia (26.2%). Grade 3 TEAEs occurred in 107 (73.8%) patients. Treatment-related TEAEs leading to treatment discontinuation and dose delays occurred in 26 (17.9%) and 62 (42.8%) patients, respectively. Conclusions: After longer follow-up of patients in LOTIS-2, durable responses to Lonca continue to be observed in heavily pre-treated patients with R/R DLBCL. No new safety concerns occurred. Research funding: ADC Therapeutics SA. Keywords: non-Hodgkin lymphoma, diffuse large B-cell lymphoma, antibody-drug conjugate, loncastuximab tesirine, Phase 2
    • Brentuximab vedotin with chemotherapy for patients with previously untreated Stage III/IV classical hodgkin lymphoma: 5-Year update of the ECHELON-1 study

      Ramchandren, R.; Dlugosz-Danecka, M.; Connors, J. M.; Radford, John A; Illes, A.; Picardi, M.; Lech-Maranda, E.; Feldman, T.; Smolewski, P.; Savage, K. J.; et al. (2021)
      Objective: Historically, nearly all relapses in classical Hodgkin lymphoma (cHL) occur within the fi rst 5 years of treatment (Radford et al., BMJ 1997;314:346). In ECHELON-1, brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) signifi cantly improved modifi ed progression-free survival (PFS) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients with stage III/IV cHL (Connors et al., NEJM 2018;378:331). We report updated effi cacy and safety results; median follow-up was 60.9 months. Design: This phase 3, open-label study (NCT01712490) randomized patients with previously untreated stage III/IV cHL to receive 6 cycles of A+AVD or ABVD. Patients underwent an interim positron emission tomography scan after cycle 2 (PET2). An exploratory analysis of PFS per investigator was conducted. Results: There were 664 and 670 patients randomized to receive A+AVD and ABVD, respectively. 64%, 62%, and 58% of patients had stage IV disease, extranodal involvement at diagnosis, and B symptoms, respectively. Five-year PFS was 82.2% (95% confi dence interval [CI]: 79.0–85.0) with A+AVD and 75.3% (95% CI: 71.7–78.5) with ABVD. Overall, PFS favored A+AVD (hazard ratio [HR]: 0.681; 95% CI: 0.534–0.867; P=0.002). PFS benefi ts were observed regardless of PET2 status and International Prognostic Score. Estimated 5-year PFS with A+AVD versus ABVD was 84.9% versus 78.9% in PET2-negative patients (HR: 0.663; 95% CI: 0.502–0.876; P=0.004), and 60.6% versus 45.9% in PET2-positive patients (HR: 0.702; 95% CI: 0.393–1.255; P=0.229). Treatment-emergent peripheral neuropathy (PN) resolved or improved in 85% (n=375/443) and 86% (n=245/286) of the patients with PN on A+AVD and ABVD, respectively. Secondary malignancies occurred in 19 and 29 patients with A+AVD and ABVD, respectively. A total of 131 female patients or partners of male patients reported a pregnancy; both arms showed similar proportions of ongoing pregnancies or live births. Conclusions: At 5 years, A+AVD still demonstrates clinically meaningful improvement in PFS versus ABVD, independent of PET2 status, with a manageable safety profi le, including resolution or improvement of PN. The PFS benefi t observed with A+AVD at this important milestone suggests that A+AVD is an attractive treatment option for all patients with previously untreated stage III/IV cHL
    • Incidence, onset, and management of myelosuppression in patients treated with loncastuximab tesirine for R/R DLBCL in a pooled safety analysis

      Solh, M.; Alderuccio, J. P.; Hess, B.; Radford, John A; Lunning, M.; Ungar, D.; Burke, M.; Wang, L. Q.; Ardeshna, K.; Blood and Marrow Transplant Program, Northside Hospital, Atlanta, GA, USA (2021)
      Context: Loncastuximab tesirine (lonca) is a novel antibody-drug conjugate comprising an anti-CD19 antibody conjugated to a potent pyrrolobenzodiazepine dimer cytotoxin, indicated for treatment of relapsed/refractory DLBCL after ≥2 systemic treatments . Objective: Characterize the occurrence and management of neutropenia, thrombocytopenia, and anemia in patients with relapsed/refractory DLBCL treated with lonca monotherapy. Methods: Patients with relapsed/refractory DLBCL in the completed phase 1 LOTIS-1 trial (NCT02669017) and the ongoing pivotal phase 2 LOTIS-2 (NCT03589469; data cutoff 06 August 2020) trial received lonca IV every 3 weeks. The LOTIS-1 study used doses ranging from 0.015 to 0.2 mg/kg, while the LOTIS-2 study used the labeled dose of 0.15 mg/kg for 2 doses followed by 0.075 mg/kg for subsequent doses. Growth factor was allowed, according to ASCO guidelines. Incidence of hematologic abnormalities was based on laboratory reporting, while therapy modifi cation was based on adverse event reporting. A pooled safety population of patients treated with an initial dose of 0.15 mg/kg was analyzed. Results: Grade 3/4 neutropenia occurred in 32.1% (n=69), thrombocytopenia in 20.0% (n=43), and anemia in 12.6% (n=27, all grade 3) of patients. Most patients with grade 3/4 anemia and thrombocytopenia had onset within the fi rst 2 months, by treatment cycle 4. Most patients with grade 3/4 neutropenia had onset within the fi rst 4 months, by treatment cycle 7. Dose delay occurred due to grade 3/4 neutropenia in 10.2% (n=22), grade 3/4 thrombocytopenia in 8.4% (n=18), and in 10.2% (n=22), grade 3/4 thrombocytopenia in 8.4% (n=18), and grade 3 anemia in 1.4% (n=3) of patients. Dose reduction occurred due to grade 3/4 thrombocytopenia in 0.5% (n=1) of patients and due to grade 3/4 neutropenia in 0.5% (n=1) of patients. No dose reductions occurred due to anemia. Treatment discontinuation occurred due to grade 3/4 thrombocytopenia in 2.3% (n=5) of patients and due to grade 3/4 neutropenia in 0.5% (n=1) of patients. No treatment discontinuations occurred due to anemia. Febrile neutropenia occurred in 3.3% (n=7) of patients. Conclusions: The incidence of grade ≥3 myelosuppression with lonca was moderate. Most myelosuppression events were manageable with dose delays and did not result in dose reduction or treatment discontinuation.
    • Letter to the editor: does multiple intrahepatic cholangiocarcinoma worsen prognosis as 'M1' stage? Reply

      Lamarca, Angela; Santos-Laso, A.; Utpatel, K.; La Casta, A.; Stock, S.; Forner, A.; Adeva, J.; Folseraas, T.; Fabris, L.; Macias, R. I. R.; et al. (2021)
    • Adjuvant and concurrent temozolomide for 1p/19q non-co-deleted anaplastic glioma (CATNON; EORTC study 26053-22054): second interim analysis of a randomised, open-label, phase 3 study

      van den Bent, M. J.; Tesileanu, C. M. S.; Wick, W.; Sanson, M.; Brandes, A. A.; Clement, P. M.; Erridge, S.; Vogelbaum, M. A.; Nowak, A. K.; Baurain, J. F.; et al. (2021)
      Background: The CATNON trial investigated the addition of concurrent, adjuvant, and both current and adjuvant temozolomide to radiotherapy in adults with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas. The benefit of concurrent temozolomide chemotherapy and relevance of mutations in the IDH1 and IDH2 genes remain unclear. Methods: This randomised, open-label, phase 3 study done in 137 institutions across Australia, Europe, and North America included patients aged 18 years or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas and a WHO performance status of 0-2. Patients were randomly assigned (1:1:1:1) centrally using a minimisation technique to radiotherapy alone (59·4 Gy in 33 fractions; three-dimensional conformal radiotherapy or intensity-modulated radiotherapy), radiotherapy with concurrent oral temozolomide (75 mg/m2 per day), radiotherapy with adjuvant oral temozolomide (12 4-week cycles of 150-200 mg/m2 temozolomide given on days 1-5), or radiotherapy with both concurrent and adjuvant temozolomide. Patients were stratified by institution, WHO performance status score, age, 1p loss of heterozygosity, the presence of oligodendroglial elements on microscopy, and MGMT promoter methylation status. The primary endpoint was overall survival adjusted by stratification factors at randomisation in the intention-to-treat population. A second interim analysis requested by the independent data monitoring committee was planned when two-thirds of total required events were observed to test superiority or futility of concurrent temozolomide. This study is registered with ClinicalTrials.gov, NCT00626990. Findings: Between Dec 4, 2007, and Sept 11, 2015, 751 patients were randomly assigned (189 to radiotherapy alone, 188 to radiotherapy with concurrent temozolomide, 186 to radiotherapy and adjuvant temozolomide, and 188 to radiotherapy with concurrent and adjuvant temozolomide). Median follow-up was 55·7 months (IQR 41·0-77·3). The second interim analysis declared futility of concurrent temozolomide (median overall survival was 66·9 months [95% CI 45·7-82·3] with concurrent temozolomide vs 60·4 months [45·7-71·5] without concurrent temozolomide; hazard ratio [HR] 0·97 [99·1% CI 0·73-1·28], p=0·76). By contrast, adjuvant temozolomide improved overall survival compared with no adjuvant temozolomide (median overall survival 82·3 months [95% CI 67·2-116·6] vs 46·9 months [37·9-56·9]; HR 0·64 [95% CI 0·52-0·79], p<0·0001). The most frequent grade 3 and 4 toxicities were haematological, occurring in no patients in the radiotherapy only group, 16 (9%) of 185 patients in the concurrent temozolomide group, and 55 (15%) of 368 patients in both groups with adjuvant temozolomide. No treatment-related deaths were reported. Interpretation: Adjuvant temozolomide chemotherapy, but not concurrent temozolomide chemotherapy, was associated with a survival benefit in patients with 1p/19q non-co-deleted anaplastic glioma. Clinical benefit was dependent on IDH1 and IDH2 mutational status.
    • Nivolumab and ipilimumab +/-UV1 vaccine as 1st line treatment in patients with malignant melanoma (INITIUM-trial)

      O'Day, S.; Bechter, O.; Lorigan, Paul C; Nyakas, M.; John Wayne Cancer, Santa Monica, CA; (2021)
      Nivolumab and ipilimumab +/- UV1 vaccine as 1st line treatment in patients with malignant melanoma (INITIUM-trial)Malignant melanomas (MM) are tumors originating from the melanocytes in the skin or mucosal surfaces. Even if the prognosis has improved considerably with the introduction of checkpoint inhibitors (CPIs) and BRAF/MEK inhibitors, half of the patients with metastatic MM dies within 5 years. Patients indicated for CPI as first line treatment will either receive a PD-1 antibody as monotherapy or a combination of CTLA-4 and PD-1 targeting antibodies. Patients are selected for monotherapy or combination therapy based on tumor staging, clinical- and biochemical status. The combination treatment has shown improved overall survival as compared to monotherapy, but also increased toxicity. The UV1 vaccine comprises 3 long peptides covering the active site of the tumor-associated antigen telomerase. Through UV1 vaccinations, patients induce telomerase-specific T cells with the potential of providing the necessary inflammatory tumor microenvironment for optimal immune-mediated tumor control. The UV1 vaccine is shown to induce immune responses in HLA-unselected patients across 3 completed phase I trials, covering MM, NSCLC, and prostate cancer. Accumulating evidence suggests that CPI efficacy is reliant on spontaneous anti-tumor immune responses. UV1 vaccination thus serves to increase CPI efficacy by providing the necessary anti-tumor immune responses, while the CPIs may reciprocally provide increased expansion and effector capacity of vaccine-induced T cells by blocking CTLA-4 and PD-l, respectively. The combination proposed in this trial may therefore lead to synergistic immunological activity translating to improved clinical outcome for MM patients.The INITIUM study (EudraCT no: 2019‐002026‐75) is an ongoing Ultimovacs sponsored, randomized, open-label, multi-center study comparing the efficacy and safety of nivolumab and ipilimumab with or without UV1 vaccination in 1st line metastatic MM patients.A total of 154 patients are randomized 1:1 to either arm A: 4 cycles of nivolumab (1 mg/kg q3w) + 4 cycles of ipilimumab (3 mg/kg q3w) + 8 injections with 300 μg UV1 and 75 μg GM-CSF as adjuvant (UV1 vaccination) during the first 13 weeks, or arm B: 4 cycles of nivolumab (1 mg/kg q3w) + 4 cycles of ipilimumab (3 mg/kg q3w). Patients randomized to treatment arm A will receive three UV1 vaccinations in week 1 and one in week 2, followed by 4 UV1 vaccinations throughout the following 11weeks, totaling to 8 UV1 vaccinations.Patients will continue with nivolumab maintenance treatment (480 mg q4w) according to the label. The primary endpoint is progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumours (RECIST 1.1) as determined by blinded independent central review (BICR).Samples of blood, feces, and tumor tissue are collected in a subset of patients for translational research purposes.Legal entity Ultimovacs ASA, Oslo, NorwayFundingUltimovacs ASA, Oslo, Norway
    • Tumor growth rate to predict the outcome of patients with neuroendocrine tumors: performance and sources of variability

      Dromain, C.; Sundin, A.; Najran, Pavan; Trueba, H. V.; Burgio, M. D.; Crona, J.; Opalinska, M.; Carvalho, L.; Franca, R.; Borg, Philip; et al. (2021)
      Introduction: Tumor growth rate (TGR), percentage of change in tumor volume/month, has been previously identified as an early radiological biomarker for treatment monitoring in neuroendocrine tumor (NET) patients. We assessed the performance and reproducibility of TGR at 3 months (TGR3m) as a predictor factor of progression-free survival (PFS), including the impact of imaging method and reader variability. Methods: Baseline and 3-month (±1 month) CT/MRI images from patients with advanced, grade 1-2 NETs were retrospectively reviewed by 2 readers. Influence of number of targets, tumor burden, and location of lesion on the performance of TGR3m to predict PFS was assessed by uni/multivariable Cox regression analysis. Agreement between readers was assessed by Lin's concordance coefficient (LCC) and kappa coefficient (KC). Results: A total of 790 lesions were measured in 222 patients. Median PFS was 22.9 months. On univariable analysis, number of lesions (</≥4), tumor burden, and presence of liver metastases were significantly correlated with PFS. On multivariate analysis, ≥4 lesions (HR: 1.89 [95% CI: 1.01-3.57]), TGR3m ≥0.8%/month (HR: 4.01 [95% CI: 2.31-6.97]), and watch and wait correlated with shorter PFS. No correlation was found between TGR3m and number of lesions (rho: -0.2; p value: 0.1930). No difference in mean TGR3m across organs was shown (p value: 0.6). Concordance between readers was acceptable (LCC: 0.52 [95% CI: 0.38-0.65]; KC: 0.57, agreement: 81.55%). TGR3m remained a significant prognostic factor when data from the second reader were employed (HR: 4.35 [95% CI: 2.44-7.79]; p value <0.001) regardless his expertise (HR: 1.21 [95% CI: 0.70-2.09]; p value: 0.493). Discussion/conclusion: TGR3m is a robust and early radiological biomarker able to predict PFS. It may be used to identify patients with advanced NETs who require closer radiological follow-up.
    • ORZORA: Maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer: outcomes by somatic and germline BRCA and other homologous recombination repair gene mutation status

      Pignata, S.; Oza, A.; Hall, G.; Pardo, B.; Madry, R.; Cibula, D.; Klat, J.; Montes, A.; Glasspool, R.; Colombo, N.; et al. (2021)
      Objectives: The Phase III SOLO2 trial (NCT01874353) showed the significant benefit of maintenance olaparib for patients (pts) with platinum-sensitive relapsed ovarian cancer (PSROC) and a BRCA mutation (BRCAm), compared with placebo (median progression-free survival [PFS] 19.1 vs 5.5 months [m], respectively); however, no pts had a confirmed somatic (s) BRCAm and data prospectively evaluating efficacy of olaparib in this pt group were limited. ORZORA (NCT02476968), an open-label, single-arm, multicenter trial, was conducted to assess efficacy and safety of maintenance olaparib in PSROC pts with a BRCAm (s or germline [g]) who were in response to their most recent platinum-based chemotherapy after ≥2 lines of treatment. Methods: Pts underwent prospective central screening for tumor BRCAm status (myChoice CDx, Myriad Genetic Laboratories, Inc.), then s or g BRCAm status was determined by central g testing (BRACAnalysis CDx, Myriad Genetic Laboratories, Inc.). Pts received maintenance olaparib (400 mg bid; capsules) until disease progression. Co-primary endpoints were investigator-assessed PFS (RECIST v1.1) in BRCAm and s cohorts, conducted at 60% maturity. Secondary endpoints included time to second progression or death (PFS2), health-related quality of life (HRQoL; FACT-O trial outcome index) and tolerability. An additional exploratory cohort comprised pts with predefined homologous recombination repair gene mutations (HRRm) excluding BRCAm (Foundatio CDx, Foundation Medicine, Inc.). Conclusions: PFS in pts with PSROC who received maintenance olaparib was similar irrespective of s or g BRCAm status. Activity of maintenance olaparib was also shown in pts with a non-BRCA HRRm. PFS, HRQoL and tolerability were consistent with previous olaparib studies in this population. Results highlight that PSROC pts beyond those with a gBRCAm can benefit from maintenance olaparib.
    • Oxaliplatin/capecitabine or carboplatin/paclitaxel-based preoperative chemoradiation for resectable oesophageal adenocarcinoma (NeoSCOPE): Long-term results of a randomised controlled trial

      Mukherjee, S.; Hurt, C.; Radhakrishna, Ganesh; Gwynne, S.; Bateman, A.; Gollins, S.; Hawkins, M. A.; Canham, J.; Grabsch, H. I.; Falk, S.; et al. (2021)
      Aim: This is the first randomised study to evaluate toxicity and survival outcomes of two neoadjuvant chemoradiotherapy (CRT) regimens for patients with localised oesophageal adenocarcinoma (OAC) or gastro-oesophageal junction (GOJ) adenocarcinoma. The initial results showed comparable toxicity between regimens and pathological complete response (pCR) rate favouring CarPacRT. Herein, we report survival, progression patterns, and long-term toxicity after a median follow-up of 40.7 months. Methods: NeoSCOPE was an open-label, UK multicentre, randomised, phase II trial. Eighty-five patients with resectable OAC or GOJ adenocarcinoma, ≥cT3 and/or ≥cN1 (TNM v7), suitable for neoadjuvant CRT, were recruited between October 2013 and February 2015. Patients were randomised to OxCapRT (oxaliplatin 85 mg/m2 on Days 1, 15, and 29; capecitabine 625 mg/m2 orally twice daily on days of radiotherapy [RT]) or CarPacRT (carboplatin AUC2; paclitaxel 50 mg/m2 on Days 1, 8, 15, 22, and 29). RT dose was 45 Gy/25 fractions/5 weeks. Both arms received induction chemotherapy (two cycles oxaliplatin 130 mg/m2 on Day 1, capecitabine 625 mg/m2 orally twice daily on Days 1-21) before CRT. Surgery was performed 6-8 weeks after CRT. The primary end-point was pCR. Secondary end-points were toxicity, progression-free survival (PFS), overall survival (OS), and patterns of progression. Results: Eighty-five patients were recruited from 17 UK centres. The median OS was 41.7 months (95% confidence interval [CI] 19.6 to not reached) in the OxCapRT arm and was not reached in the CarPacRT arm (multivariable hazard ratio [HR] = 0.48, 95% CIs: 0.24-0.95, P = 0.035). The median PFS was 32.6 months (95% CIs: 17.1 to not reached) in the OxCapRT arm and was not reached in the CarPacRT arm (multivariable HR = 0.54, 95% CIs: 0.29-1.01, P = 0.053). In both arms, the distant progression was twice as common as locoregional progression. Conclusions: OS and PFS favoured neoadjuvant CarPacRT over OxCapRT. Distant was more common than locoregional progression; therefore, priority should be given to optimising the systemic treatment component.
    • Primary results of phase 2 FOENIX-CCA2: The irreversible FGFR1-4 inhibitor futibatinib in intrahepatic cholangiocarcinoma (iCCA) with FGFR2 fusions/rearrangements

      Goyal, L.; Meric-Bernstam, F.; Hollebecque, A.; Morizane, C.; Valle, Juan W; Karasic, T. B.; Abrams, T. A.; Kelley, R. K.; Cassier, P.; Furuse, J.; et al. (2021)
      Background FGFR2 fusions occur in ~15% of patients (pts) with iCCA, a rare cancer with a poor prognosis. Futibatinib, a highly selective, irreversible FGFR1-4 inhibitor, has shown activity across tumor types, including iCCA, in a phase 1 study. The pivotal phase 2 FOENIX-CCA2 trial (NCT02052778) is evaluating futibatinib in iCCA harboring FGFR2 fusions/rearrangements. Here, we report the first efficacy, safety, and quality of life (QoL) data for the complete FOENIX-CCA2 population. Methods Eligible pts had unresectable/metastatic iCCA with an FGFR2 fusion/rearrangement and progressive disease (PD) after ≥1 prior treatment (tx; excluding FGFR inhibitors). Pts received futibatinib 20 mg QD until PD/intolerability. The primary endpoint was objective response rate (ORR) per RECIST v1.1 by independent central review (target ORR: 20%). Secondary endpoints included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and patient-reported outcomes (PROs). Subgroup analyses were performed by pt characteristic and molecular alteration. Results Among 103 pts (56% female), 53% had received ≥2 prior tx. FGFR2 fusions were present in 78% (23% had FGFR2-BICC1 fusions) and FGFR2 rearrangements in 22%. At data cutoff (Oct 1, 2020), 72 pts (70%) had discontinued tx. The study met its primary objective with a confirmed ORR of 41.7% (43/103). Responses were durable, with a median (m) DOR of 9.7 mo and 72% of responses ≥6 mo. DCR was 82.5%. mPFS was 9.0 mo; mOS was 21.7 mo, with a 12-mo OS rate of 72%. ORR was consistent across pt demographic subgroups (≥65 y: 65.2%; 2 prior tx: 38.7%). Common tx-related AEs (TRAEs) were hyperphosphatemia (85%), alopecia (33%), and dry mouth (30%). The most frequent grade 3 TRAE, hyperphosphatemia (30%), resolved with adequate management (median 7 d). Retinal disorders (all grade 1-2) were reported in 8% of pts. TRAEs were managed with dosing interruptions (50%)/reductions (54%); 2 pts discontinued tx due to TRAEs. No tx-related deaths occurred. ORRs were consistent in pts with dosing interruptions (40.2%) or reductions (46.8%). PROs were stable through 11.0 mo of tx. In exploratory biomarker analyses, ORR was consistent in pts with FGFR2 fusions (43.8%) and other FGFR2 rearrangements (34.8%) and in pts with BICC1 (41.7%) and non-BICC1 (44.6%) fusion partners. Notably, no obvious differences in ORR were observed in pts with co-occurring genetic alterations, including TP53 comutations (ORR, 38.5% [5/13]). Additional biomarker data will be presented. Conclusions Futibatinib resulted in frequent, durable objective responses in pts with iCCA harboring FGFR2 fusion/rearrangements, regardless of pt baseline characteristic, molecular alteration, or comutation. AEs were manageable with dosing modifications that did not impact response. QoL was maintained.
    • Clinical feasibility and treatment outcomes with unselected autologous tumor infiltrating lymphocyte therapy in patients with advanced cutaneous melanoma

      Hawkins, R. E.; Jiang, Y. Z.; Lorigan, Paul C; Thistlethwaite, Fiona C; Pillai, Manon; Thomas, M.; Kirilova, N.; Bridgeman, J. S.; Kueberuwa, G.; Guest, R. S.; et al. (2021)
      Introduction: A minority of patients (pts) with advanced melanoma achieve long-term survival with immunotherapy and those who relapse following immune checkpoint inhibition (ICI) or BRAFi have limited treatment options. The intrinsic anti-tumor activity and broad neoantigen-specific TCR repertoire of unselected autologous TIL may provide advantages over other treatments in solid tumors, including ICI-refractory melanoma. Methods: This is a retrospective analysis of a single-center experience of TIL for treatment of advanced cutaneous melanoma. Unselected autologous young TIL derived from digested tumor tissue were manufactured under a MHRA Manufacturing Specials license. Pts with advanced cutaneous melanoma and no other treatment options received non-myeloablative lymphodepleting chemotherapy (cyclophosphamide 60 mg/kg/d x 2d, fludarabine 25 mg/m2/d x 5 d [Cy/Flu]), followed by TIL infusion and post-TIL high-dose (HD) IL-2 (600,000-720,000 IU/Kg) on a compassionate use basis. Efficacy for 15 imaging-evaluable pts was reported by investigator assessment of CT/MRI per RECIST 1.1; 6 additional pts were followed using non-RECIST 1.1 imaging (PET) and clinical monitoring. Clinically significant adverse events (AEs) with onset post-TIL infusion were reported for all treated pts. Data cutoff date: 31-DEC-2019. Results: Between OCT-2011 and AUG-2019, 21 pts with advanced cutaneous melanoma were treated with Cy/Flu, TIL (median 31.9 x109 cells infused), and HD IL-2 (median 8 doses). All had high-risk metastatic disease (median 4 sites, stage IV M1d [38%]), an average of 3 prior therapies (any ICI [91%], PD-1 [57%], BRAFi [52%], and MEKi [24%]). With a median follow up of 52.2 mos, the response rate in imaging-evaluable pts (n=15) was 53% with a CR rate of 13%; DCR was 73% including 3 (20%) pts with stable disease. Additional durable responses were observed in the 6 pts followed by PET and clinical monitoring. Responses were generally consistent across subgroups including age, number of disease sites, tumor burden, brain metastases, number of prior lines of therapies, prior PD-1 blockade, prior BRAFi, and prior MEKi. For all treated pts, the median survival was 21.3 mos. Toxicity was generally self-limited and consistent with Cy/Flu and HD IL-2. Common AEs (≥20%, any grade) were thrombocytopenia (62%), pyrexia (57%), rigors (43%), neutropenia (29%), tachycardia (29%), pulmonary edema (24%), and vascular leak (24%); no treatment-related deaths were observed. Conclusion: The high response rate observed in this series exceeds the 41% ORR estimated for TIL in advanced cutaneous melanoma (meta-analysis by Dafni et al. Ann Oncol., 2019) and highlights the successful bench-to-bedside application of unselected autologous TIL to address unmet medical need in advanced melanoma. Use of tumor digests as starting material for manufacturing of TIL demonstrates feasibility of this approach. A multicenter Phase 2 trial of this therapy in advanced melanoma is planned for 2021.
    • Randomized placebo-controlled Phase 1 trial in healthy volunteers investigating safety, PK and PD of exoIL-12-a novel engineered exosome therapeutic candidate

      Mitchell, J.; Scarisbrick, J.; De Francesco, I.; Cowan, Richard A; McKay, P.; Osborne, W.; Sathyanarayanan, S.; Ascolillo, L.; Gow, I.; Hill, W.; et al. (2021)
      Background: Interleukin-12 is an active cytokine for cancer treatment, however the full potential has yet to be realized despite extensive exploration of dose, schedule, and route and method of administration. These approaches have been limited by systemic exposure, resulting in serious adverse events (SAEs) and/or unpredictable pharmacology. exoIL-12™ is a novel, engineered-exosome that displays functional IL-12 on the surface and is designed for local intra-tumoral administration and retention. Objectives of the study: A Phase 1 study in two parts is being conducted. Part A was a randomized placebo-controlled, single ascending dose trial in healthy volunteers to investigate safety, tolerability and both local and systemic pharmacokinetics (PK) and pharmacodynamics (PD). Methodology: A total of 25 male subjects across 5 cohorts were enrolled and randomized 3:2 to exoIL-12 vs placebo. Study drug was administered subcutaneously to each of the 5 cohorts at dose levels of exoIL-12 of 0.3, 1.0, 3.0, 6.0 and 12.0 µg, respectively. Study subjects were admitted to a Phase 1 unit on day -1 and discharged on day 2 and followed for safety and tolerability until day 29. PK and PD assessments included IL-12, IFNγ and IP-10 levels in plasma and IL-12 and IP-10 in serial skin punch biopsies surrounding the injection site. Results: No SAEs were observed. Only mild AEs were recorded. of the AEs were considered related to the study drug. exoIL-12 demonstrated no systemic IL-12 exposure. All blood samples showed IL-12 levels below the limit of quantification (8 pg/mL) at all dose levels. Confirmation of local retention of IL-12 will be assessed by measurement of IL-12 levels in skin punch biopsies pre-treatment and at 24 hrs, day 8 and day 15 post treatment. Systemic and local pharmacodynamic effects will be assessed by quantifying IP-10 levels in serial blood samples and skin punch biopsies. Conclusions: Studies of recombinant IL-12 conducted by others in healthy volunteers at comparable dose levels to the present study resulted in dose dependent systemic IL-12 exposure as well as IFNγ and IP-10 production and common adverse events such as fever, chills, myalgia, headache, and muscle pain. In contrast, exoIL-12 demonstrated a favorable safety and tolerability profile with no treatment-related adverse events and no systemic IL-12 exposure. Local IL-12 levels in the skin as well as pharmacodynamic data from blood and skin samples will be presented. The study is advancing into Part B, an open label study of exoIL-12 in patients with cutaneous T-cell lymphoma.
    • A phase I trial of the combination of the dual RAF-MEK inhibitor VS-6766 and the FAK inhibitor defactinib: Evaluation of efficacy in KRAS mutated NSCLC

      Krebs, Matthew G; Shinde, R.; Rahman, Rozana A; Grochot, R.; Little, Martin; King, J.; Kitchin, J.; Parmar, M.; Turner, A.; Mahmud, M.; et al. (2021)
      Background KRAS is a known oncogenic driver in non-small cell lung cancer (NSCLC), with KRAS G12C and G12V mutations occurring in ~13% and ~7% of the of NSCLC ( adenocarcinoma subtype). The dual RAF-MEK inhibitor VS-6766 has shown single agent activity against G12V KRAS mutated NSCLC (Guo C et al Lancet Oncology 2020, 21:1478-88). Based on pre-clinical data, we hypothesised that augmented focal adhesion kinase (FAK) signalling is a mechanism of resistance to MEK inhibition and devised the current clinical trial. We have previously reported the safety of an intermittent schedule of the combination of VS-6766 and the FAK inhibitor defactinib and its efficacy in low grade serous ovarian cancer (Shinde et al., AACR 2020). We now report the activity of the combination in KRAS mutated NSCLC. Methods Patients were treated with an intermittent dose of drugs VS-6766 at 3.2 - 4 mg twice a week and defactinib 200 mg twice daily in the dose escalation and expansion cohorts of the study. Both drugs were administered three weeks on/one week off in 28-day cycles. We aim to recruit 20 patients with KRAS mutated NSCLC in an expansion cohort. Results To date, 19 patients with KRAS mutated NSCLC have been treated in the dose escalation and expansion cohorts. All patients had been previously treatment with a PD-1 or PDL-1 targeting immune checkpoint inhibitor. The median age was 64 years (22 - 73), M/F ratio was 7/12, and the median prior lines of treatment was 3. Currently, 17 of 19 patients have had at least one re-staging assessment, 2/17 (12%) patients had a partial response and 10/17 (59%) had stable disease as their best response. Of note, 11/17 (65%) patients had a degree of reduction in size of their tumours and 5/17 (29%) have been treated for 6 months or more with 3 patients still on treatment. Interestingly, 2/2 (100%) of the KRAS G12V NSCLC patients showed a partial response. Conclusions Developing new treatments for non-G12C KRAS mutated NSCLC is an area of unmet need. The combination of VS-6766 and defactinib treatment in cohorts of patients with NSCLC pre-treated with chemotherapy and immunotherapy has shown anti-tumour activity in subsets of patients with KRAS mutated NSCLC, in particular those with tumours harbouring KRAS G12V mutations. A registration-directed study evaluating VS-6766 ± defactinib for treatment of recurrent NSCLC with KRAS G12V mutation (NCT04620330) has been initiated
    • A novel reconstruction method for 3D cone beam CT images in proton therapy using RTK

      Lindsay, J.; Bryce-atkinson, A.; Taylor, Michael J; Meara, Simon; Aznar, Marianne Camille; van Herk, Marcel; The University of Manchester, Manchester (2021)
      Purpose: CBCT reconstruction research requires access to different algorithms. Offline reconstruction for the Varian ProBeam CBCT system has not been reported. We aim to: 1) develop a novel offline reconstruction method for ProBeam CBCT and 2) simulate ultra-low-dose CBCT images. Methods: Straightforward reconstruction of ProBeam projection images with RTK results in significant artefacts. Our reconstruction pipeline includes processing on projection images as well as the reconstructed CBCT. 10 air calibration images are used to correct for bowtie filter, source, and detector shifts during gantry rotation (flood field flex). Beam hardening by the bowtie filter is corrected using an empirically-derived attenuation space map. RTK version 1.4 is used for filtered backprojection and slice averaging is then applied. The pipeline was validated by comparison to clinically-reconstructed CBCT images.To test the simulation of ultra-low-dose images, a Catphan 503 phantom was scanned at 9 mAs exposures (35-811 mAs/projection, 100 kV, SDD 370 cm). The signal-noise relationship was measured from phantom projection data to inform the amount of non-uniform Gaussian noise to be added to simulate low dose scans. Ultra-low-dose CBCTs at 30% and 10% exposure were simulated using datasets from paediatric patients treated on ProBeam. Results: The exposure and hardening corrections completely eliminate artefacts. The processed reconstructed images show excellent visual agreement with clinically reconstructed CBCT images. SNR measured in simulated phantom projection data shows good agreement with that in acquired images. Simulated low-exposure scans of paediatric patients are noisier but maintain good visibility of bone and some soft tissue, even at 10% exposure. Conclusion: We successfully implemented offline reconstruction for Varian Probeam CBCT images. Correcting for flood field image flex is essential in large-geometry imaging systems. Our methods allow optimisation of CBCT acquisition and reconstruction, especially relevant for paediatric treatments, and can be easily applied to other scan types e.g. 4DCBCT.
    • Features Of TOPAS-NBio - Release 1.0

      Schuemann, J.; McNamara, A.; Ramos-Mendez, J.; Dominguez-Kondo, N.; Perl, J.; Yoo, D.; Henthorn, Nicholas; Warmenhoven, John; Ingram, Samuel; Merchant, Michael J; et al. (2021)
      Purpose: The goal of the TOPAS-nBio project is to provide intuitive nanometer scale Monte Carlo (MC) simulations for radiobiology experiments that do not require programming expertise. Here we present new functionalities of the TOPAS-nBio system available in the first full release (v1.0). Methods: Since the open-source beta-release of TOPAS-nBio in 2019, the framework offers to connect energy deposition within irradiated cells (physics) via molecular reactions (chemistry) to cell kill/repair (biology) at the level of sub-cellular targets such as DNA. To facilitate the setup of simulations we further developed a Graphical User (GUI) Interface. TOPAS-nBio is an extension to TOPAS and layered on top of the Geant4/Geant4-DNA MC toolkit. The new release was built for TOPAS release 3.6 (based on Geant4.10.6.p3) and will be compatible with all future releases of TOPAS. Results: New geometries that were developed include two new methods to fill the cell nucleus: a whole nucleus DNA model using chromatin fibers and a fractal walk filling pattern, as well as a filling of the nucleus using spheres to represent topologically associated domains (TADs) of DNA based on the Hi-C technique. New scoring options offer direct scoring of single and double strand breaks (SSB and DSB) as well as output the DNA damage in the SDD (Standard for DNA Damage) scoring format. Chemistry was improved to provide better agreement with experimental data of G-values, both for step-by-step chemistry and a newly included independent reaction time method, which offers faster chemistry simulations. Biological outcome can now be simulated directly within TOPAS-nBio using the DaMaRiS biological effect model, or via the SDD which offers a convenient interface to other models such as MEDRAS. Conclusion: The new features of TOPAS-nBio v1.0, offer improved modeling from initial DNA damage to cell outcome, or from energy depositions to G-value propagation over time is possible
    • Radioembolization with chemotherapy for colorectal liver metastases: a randomized, open-label, international, multicenter, phase III trial

      Mulcahy, M. F.; Mahvash, A.; Pracht, M.; Montazeri, A. H.; Bandula, S.; Martin, R. C. G., 2nd; Herrmann, K.; Brown, E.; Zuckerman, D.; Wilson, Gregory; et al. (2021)
      Purpose: To study the impact of transarterial Yttrium-90 radioembolization (TARE) in combination with second-line systemic chemotherapy for colorectal liver metastases (CLM). Methods: In this international, multicenter, open-label phase III trial, patients with CLM who progressed on oxaliplatin- or irinotecan-based first-line therapy were randomly assigned 1:1 to receive second-line chemotherapy with or without TARE. The two primary end points were progression-free survival (PFS) and hepatic PFS (hPFS), assessed by blinded independent central review. Random assignment was performed using a web- or voice-based system stratified by unilobar or bilobar disease, oxaliplatin- or irinotecan-based first-line chemotherapy, and KRAS mutation status. Results: Four hundred twenty-eight patients from 95 centers in North America, Europe, and Asia were randomly assigned to chemotherapy with or without TARE; this represents the intention-to-treat population and included 215 patients in the TARE plus chemotherapy group and 213 patients in the chemotherapy alone group. The hazard ratio (HR) for PFS was 0.69 (95% CI, 0.54 to 0.88; 1-sided P = .0013), with a median PFS of 8.0 (95% CI, 7.2 to 9.2) and 7.2 (95% CI, 5.7 to 7.6) months, respectively. The HR for hPFS was 0.59 (95% CI, 0.46 to 0.77; 1-sided P < .0001), with a median hPFS of 9.1 (95% CI, 7.8 to 9.7) and 7.2 (95% CI, 5.7 to 7.6) months, respectively. Objective response rates were 34.0% (95% CI, 28.0 to 40.5) and 21.1% (95% CI, 16.2 to 27.1; 1-sided P = .0019) for the TARE and chemotherapy groups, respectively. Median overall survival was 14.0 (95% CI, 11.8 to 15.5) and 14.4 months (95% CI, 12.8 to 16.4; 1-sided P = .7229) with a HR of 1.07 (95% CI, 0.86 to 1.32) for TARE and chemotherapy groups, respectively. Grade 3 adverse events were reported more frequently with TARE (68.4% v 49.3%). Both groups received full chemotherapy dose intensity. Conclusion: The addition of TARE to systemic therapy for second-line CLM led to longer PFS and hPFS. Further subset analyses are needed to better define the ideal patient population that would benefit from TARE.
    • Trifluridine/tipiracil in combination with oxaliplatin and either bevacizumab or nivolumab in metastatic colorectal cancer: a dose-expansion, phase I study

      Bordonaro, R.; Calvo, A.; Auriemma, A.; Hollebecque, A.; Rubovszky, G.; Saunders, Mark P; Pápai, Z.; Prager, G.; Stein, A.; André, T.; et al. (2021)
      Background: In preclinical studies trifluridine/tipiracil (FTD/TPI) plus oxaliplatin (Industriestrasse, Holzkirchen, Germany) sensitised microsatellite stable (MSS) metastatic colorectal cancer (mCRC) to anti-programmed cell death protein-1; the addition of oxaliplatin or bevacizumab (F Hoffmann- la ROCHE AG, Kaiseraugst, Switzerland) enhanced the antitumour effects of FTD/TPI. This study aimed to investigate the safety and efficacy of FTD/TPI plus oxaliplatin and either bevacizumab or nivolumab (Uxbridge business Park, Uxbridge, United Kingdom) in patients with mCRC who had progressed after at least one prior line of treatment. Patients and methods: In 14-day cycles, patients received FTD/TPI 35 mg/m2 (twice daily, days 1-5) plus oxaliplatin 85 mg/m2 (day 1), and, on day 1, either bevacizumab 5 mg/kg (cohort A) or nivolumab 3 mg/kg (cohort B). Patients in Cohort B had confirmed MSS status. Results: In total, 54 patients were enrolled: 37 in cohort A and 17 in cohort B. Recruitment in cohort B was stopped early due to the low response rate (RR) observed at interim analyses of efficacy. The most common adverse events (AEs) in cohort A were neutropenia/decreased neutrophils (75.7%), nausea (59.5%), vomiting (40.5%), diarrhoea (37.8%), peripheral sensory neuropathy (37.8%), fatigue (35.1%) and decreased appetite (35.1%). In cohort B, the most common AEs were neutropenia/decreased neutrophils (70.6%), diarrhoea (58.8%), nausea (47.1%), vomiting (47.1%), fatigue (47.1%), asthenia (41.2%), paraesthesia (41.2%), thrombocytopenia/decreased platelets (35.3%) and decreased appetite (35.3%). Confirmed objective RR was 17.1% in cohort A and 7.1% in cohort B; the corresponding values for median progression-free survival in the two cohorts were 6.3 and 6.0 months. Conclusion: FTD/TPI plus oxaliplatin and bevacizumab or nivolumab had an acceptable safety profile and demonstrated antitumour activity in previously treated patients with mCRC.
    • Role of postoperative radiotherapy in the management for resected NSCLC - decision criteria in clinical routine pre- and post-lungART

      Süveg, K.; Le Pechoux, C.; Faivre-Finn, Corinne; Putora, P. M.; De Ruysscher, D; Widder, J.; Van Houtte, P.; Troost, E. G. C.; Slotman, B. J.; Ramella, S.; et al. (2021)
      Background: The role of postoperative radiation therapy (PORT) in stage III N2 NSCLC is controversial. We analyzed decision-making for PORT among European radiation oncology experts in lung cancer. Methods: Twenty-two experts were asked before and after presentation of the results of the LungART trial to describe their decision criteria for PORT in the management of pN+ NSCLC patients. Treatment strategies were subsequently converted into decision trees and analyzed. Results: Following decision criteria were identified: extracapsular nodal extension, incomplete lymph node resection, multistation lymph nodes, high nodal tumor load, poor response to induction chemotherapy, ineligibility to receive adjuvant chemotherapy, performance status, resection margin, lung function and cardiopulmonary comorbidities. The LungART results had impact on decision-making and reduced the number of recommendations for PORT. The only clear indication for PORT was a R1/2 resection. Six experts out of ten who initially recommended PORT for all R0 resected pN2 patients no longer used PORT routinely for these patients, while four still recommended PORT for all patients with pN2. Fourteen experts used PORT only for patients with risk factors, compared to eleven before the presentation of the LungART trial. Four experts stated that PORT was never recommended in R0 resected pN2 patients regardless of risk factors. Conclusion: After presentation of the LungART trial results at ESMO 2020, 82% of our experts still used PORT for stage III pN2 NSCLC patients with risk factors. The recommendation for PORT decreased, especially for patients without risk factors. Cardiopulmonary comorbidities became more relevant in the decision-making for PORT.