Follow-Up Imaging Guidelines for Patients with Stage III Unresectable NSCLC: Recommendations Based on the PACIFIC Trial.

The PACIFIC trial showed a survival benefit with durvalumab through five years in stage III unresectable non-small cell lung cancer (NSCLC). However, optimal use of imaging to detect disease progression remains unclearly defined for this population. An expert working group convened to consider available evidence and clinical experience and develop recommendations for follow-up imaging after concurrent chemotherapy and radiation therapy (CRT). Voting on agreement was conducted anonymously via online survey. Follow-up imaging was recommended for all suitable patients after CRT completion regardless of whether durvalumab is received. Imaging should occur every 3 months in Year 1, at least every 6 months in Year 2, and at least every 12 months in Years 3-5. Contrast computed tomography was preferred; routine brain imaging was not recommended for asymptomatic patients. The medical oncologist should follow-up during Year 1 of durvalumab therapy, with radiation oncologist involvement if pneumonitis is suspected; medical and radiation oncologists can subsequently alternate follow-up. Some patients can transition to the family physician/community primary care team at the end of Year 2. In Years 1-5, patients should receive information regarding smoking cessation, comorbidity management, vaccinations, and general follow-up care. These recommendations provide guidance on follow-up imaging for patients with stage III unresectable NSCLC whether or not they receive durvalumab consolidation therapy.

Final results of a phase 1b/2 study of tivozanib in combination with durvalumab in patients with advanced hepatocellular carcinoma in both previously untreated patients and patients progressing on atezolizumab and bevacizumab

Background: The approval of atezolizumab + bevacizumab for untreated advanced HCC was a significant benefit for patients, but with an increased risk of potentially severe bleeding complications. Tivozanib (a selective VEGFR 1, 2, & 3 tyrosine kinase inhibitor [TKI]) has been combined with durvalumab in the DEDUCTIVE study;preliminary results presented in January 2022 showed that this combination was well tolerated with comparable efficacy to other immune checkpoint and VEGF containing regimens in patients with previously untreated HCC (J Clin Oncol 40, no. 4 suppl 462-462). We now report the final results of this cohort (cohort A) of patients as well as those with previously treated HCC, including safety results for all the patients. Method(s): Major eligibility criteria included age .18 yrs with documented advanced HCC, Child-Pugh Class A, ECOG 0 or 1, and creatinine clearance .40 ml/min. Major exclusion criteria included co-infection with HBV and HCV and significant organ dysfunction. Patients were treated with 0.89 mg tivozanib p.o., 21 days on followed by 7 days off and 1500 mg durvalumab i.v. every 28 days. The primary objective was to determine the safety and tolerability of this combination in patients with advanced HCC;secondary objectives included assessing objective response rate (ORR), progression free survival, and overall survival (OS). The study was amended in 2021 to include a cohort of patients previously treated with atezolizumab and bevacizumab (cohort B). Result(s): 21 patients were enrolled in cohort A and 6 in cohort B;the median age was 67, 88% of patients were male, and 24% were Asian. The median followup time was 13.2 mos and 3.4 mos for cohorts A and B, respectively. Data were available for 25 of the 27 patients enrolled. For cohort A, the ORR was 25% (5/20) and 1-year OS was 76%. For safety analysis, 24 (96%) patients had at least 1 treatment-emergent adverse event (TEAE);92% were attributed possibly to either tivozanib or durvalumab;32% were serious TEAEs and there was 1 TEAE leading to death (unrelated). Of the 8 (32%) serious TEAE, 2 were coronavirus infection. 2 patients had serious (grade 3) treatment-related AEs: 1 pneumonitis and 1 with gastrointestinal hemorrhage and anemia. There were no grade 4 or 5 treatment-related AEs. Conclusion(s): Treatment with the combination of tivozanib and durvalumab in patients with either untreated advanced HCC or those previously treated with atezolizumab and bevacizumab was well tolerated;no severe bleeding events occurred in this study. Efficacy outcomes were comparable to other IO-TKI combinations in HCC. Data for PDL1 status, HBV/HCV status was collected and will be presented along with final safety and efficacy results for both cohorts.

Intravesical administration of durvalumab to patients with high risk non muscle invasive bladder cancer after BCG failure. A phase II trial by the Hellenic GU Cancer Group

Introduction & Objectives: Patients with high risk non muscle invasive bladder cancer (NMIBC) who experience BCG failure have limited bladder preserving treatment options as radical cystectomy currently represents the standard therapeutical approach. Systematic immunotherapy (IO) has changed the landscape in advanced bladder cancer and is currently being investigated in NMIBC. Based on the hypothesis that intravesical administration will not be related with severe adverse events, we evaluated the role of intravesically administered durvalumab in NMIBC patients after BCG failure. Material(s) and Method(s): An open label, single-arm, multi-center, phase II clinical trial was conducted. A run-in phase had the objective to determine the maximum tolerated dose (MTD) of durvalumab and to exclude a detrimental effect on disease relapse by this strategy. Durvalumab was administered for a total of 6 instillations per patient at consecutive levels of 500, 750 and 1000 mg. Phase II has as primary end point the 1-year high-grade-relapse-free (HGRF)-rate. Secondary endpoints included toxicity, and high-grade progression-free rat at 1, 3 and 6 months after treatment. Result(s): Thirty patients were enrolled (run in phase: 9, phase II: 21). One patient withdrew consent prior to receiving study treatment, so 29 patients were included in efficacy and toxicity analyses. Mean age was 66.5 years. MTD of durvalumab was set at 1000 mg as no dose related toxicities (DLTs) occurred at any level studied. Three of 9 patients included in the run-in phase (33.3%) were tumor free one month after the last durvalumab instillation, therefore, the null hypothesis was rejected by the futility analysis. Western blot showed that durvalumab remained stable in urine during instillation. One patient died from Covid-19, 3 months after the last durvalumab administration. All patients concluded at least 1 year follow up. One-year HGRF rate was 34.6%. HGRF rates at 1, 3 and 6 months was 73%, 65.3% and 50% respectively. Five patients (17%) experienced a T2 or above disease relapse. Five out of the six patients who received 500mg or 750mg of durvalumab relapsed within 1 year. When efficacy analyses were restricted to patients receiving 1000mg of durvalumab, 1-year HGRF rate was 35%. Interestingly, 2 out of 2 patients with only CIS disease at baseline experienced a tumor complete response, which was durable and was maintained at least for a year. No severe adverse events were noted. The most common adverse event was Grade 1 hematuria. Conclusion(s): Intravesical IO using durvalumab was proved to be feasible with an excellent safety profile. Oncological results seem to be promising and comparable with other bladder preserving strategies in BCG failure with the advantage of a better safety profile. Further study of intravesical IO in high-risk patients with NMIBC after BCG failure is warranted.Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Trastuzumab deruxtecan (T-DXd) + durvalumab (D) as first-line (1L) treatment for unresectable locally advanced/metastatic hormone receptor-negative (HR-), HER2-low breast cancer: updated results from BEGONIA, a phase 1b/2 study

Background: Patients with HR- advanced/metastatic breast cancer (a/mBC) with a low level of HER2 (immunohistochemistry [IHC] score 1+ or IHC 2+ and negative in situ hybridization [ISH]) have poor prognosis. Combining 1L chemotherapy with immune checkpoint inhibitors can modestly improve outcomes vs chemotherapy alone, but treatment benefit is largely seen in patients with PD-L1+ disease. BEGONIA (NCT03742102) is an ongoing 2-part, open-label platform study, evaluating safety and efficacy of D, an anti-PD-L1 antibody, combined with other novel therapies in 1L triple-negative a/mBC, including HR-, HER2-low disease. T-DXd is a trastuzumab-topoisomerase I inhibitor antibody-drug conjugate that improves survival in patients with previously treated HR-, HER2-low mBC (NCT03734029;Modi NEJM 2022). Here, we report updated results of the T-DXd + D combination from BEGONIA. Method(s): Patients with unresectable HR-, HER2-low (per local testing, IHC 2+/ISH-, IHC 1+/ISH-, or IHC 1+/ISH untested) a/mBC were enrolled in the T-DXd + D arm. Patients eligible for 1L treatment, regardless of PD-L1 status, received intravenous T-DXd 5.4 mg/kg + D 1120 mg every 3 weeks until progression or unacceptable toxicity. PD-L1, assessed using the VENTANA PD-L1 (SP263) Assay, was defined as high if >= 5% of the tumor area was populated by PDL1-expressing tumor or immune cells. Primary endpoints were safety and tolerability. Secondary endpoints included investigator-assessed objective response rate (ORR;RECIST v1.1);progressionfree survival [PFS];and response duration. Patients included in the efficacy analysis had >= 2 ontreatment disease assessments, progressed, died, or withdrew from the study. Result(s): As of April 8, 2022, 56 patients received T-DXd + D (34 ongoing) and 46 were included in the efficacy analysis. Median (range) follow-up was 10.1 (0-22) months. Median age was 53.5 years, 71% had received prior treatment for early stage BC, and 64% had visceral metastases at baseline. Confirmed ORR was 26/46 (57% 95% CI, 41-71) and unconfirmed ORR was 33/54 (61% 95% CI, 47-74);1/46 patients (2%) had complete and 25/46 (54%) had partial responses. Confirmed response occurred irrespective of PD-L1 expression (PD-L1 high ORR, 5/7 [71%];PD-L1 low, 13/21 [62%];PD-L1 missing, 8/18 [44%]). Median duration of response was not reached;however, 64% of patients remained in response at 12 month follow-up and 73% had an ongoing response at data cutoff. Median PFS was 12.6 months (95% CI, 8-not reached). Adverse events (AEs) were consistent with the agents' known safety, with treatment-related AEs occurring in 49 patients (88%), any Grade 3/4 AEs in 18 patients (32%), and any serious AEs in 10 patients (18%). The most common all-Grade AEs were nausea (41 [73%]), fatigue (26 [46%]), and vomiting (17 [30%]). Adjudicated treatment-related interstitial lung disease/pneumonitis occurred for 5 patients (9%), which were mostly Grade 1 or 2 and 1 case of Grade 5 associated with COVID pneumonia. Seven patients (13%) and 21 patients (38%) had T-DXd dose reduction and dose delay, respectively;22 (39%) had D dose delay. Seven patients (13%) discontinued treatment due to AEs. Conclusion(s): For patients with HR-, HER2-low a/mBC, T-DXd in combination with D in the 1L setting shows manageable safety and promising efficacy including durable responses and an encouraging PFS. Although subgroups were small, responses were observed irrespective of PD-L1 expression. Analysis of additional translational data is ongoing. Funding(s): AstraZeneca/Daiichi Sankyo.

Phase Ib study of AVB-S6-500 (axl inhibition) in combination with durvalumab (MEDI4736) in patients with platinum-resistant, recurrent epithelial ovarian cancer (NCT04019288) (320)

Objectives: Immune checkpoint blockade (ICB) has demonstrated efficacy in a small fraction of patients with platinum-resistant ovarian cancer (PROC), some with durable responses. The receptor tyrosine kinase AXL and its sole ligand, GAS6, are possible mediators of T cell exclusion and an attractive target due to the expected synergy between AXL inhibition and immune targeting agents. The recommended phase II dose (RP2D), safety, and efficacy of the combination of AXL inhibition via AVB-S6-500 with durvalumab (MEDI4736) were evaluated in patients with PROC. Methods: In this open-label Phase Ib open-label study, patients with PROC received AVB-S6-500 and durvalumab therapy in escalating dosing regimens guided by a Bayesian optimal interval (BOIN) design: durvalumab (1500 mg Q4W) and AVB-S6-500 (10mg/kg Q2W, 15mg/kg Q2W, 20mg/kg Q2W) with durvalumab infused prior to AVB-S6-500. The response was evaluated using modified RECIST v1.1. Pharmacokinetic/pharmacodynamic (PK/PD) studies were collected, and PD-L1 status and tumor/tumor microenvironment AXL and GAS6 staining pre and on-treatment were assessed. Results: Eleven patients with epithelial ovarian cancer (six clear cells [55%], four high-grade serous [36%], one endometrioid histology [1%]) received treatment per protocol. The median number of prior lines of therapy was 3 (range: 1-5);73% (8/11) of patients had received prior bevacizumab. There were no DLTs noted over the 6-week period and no grade ≥3 adverse events attributed to study drugs. Five patients experienced an immune-related AE, most commonly liver enzyme elevations (36%). Infusion reaction with AVB-S6- 500 was noted in the first two subjects, prompting the institution of a premedication regimen, after which only one of the nine additional patients experienced an infusion reaction. Dose delays greater than one week occurred in six (55%) patients;three patients experienced delays for cancer-related complications (small bowel obstruction, pneumonia, severe fatigue), while three patients experienced delays for non-medical causes (COVID/travel, weather). Patients received therapy for a median of two cycles (range: 1-6), and there were no responses noted across all dosing levels. One patient had stable disease, with a duration of response of three months. Only two patients had strong (2+) AXLstaining on pretreatment biopsy, both with high-grade serous histology. The majority of serum AXL levels were within previously demonstrated ranges (range: 5.6-112ng/mL), though two patients had comparatively high levels (102, 112ng/mL). PK/PD analysis revealed expected AVB-S6-500 levels at initial postdose (C1D1), but low levels at trough (C2D1 predose) when compared to prior AVB-S6-500 data [1]. Conclusions: The combination of AVB-S6-500 and durvalumab was tolerable in this PROC patient population at all dosing levels tested. Exploratory studies to correlate lack of response to AXL-GAS6 pathway alterations, tumor microenvironment, and clinical characteristics, such as prior treatment, dosing delays, burden of disease, and ascites, are ongoing.

Who Benefits More of Durvalumab after Chemoradiotherapy (CRT) in Real-World Patients with Locally Advanced Non-Small-Cell Lung Cancer (NSCLC)?

Introduction: Durvalumab received EMA approval as consolidation therapy (CT) for unresectable stage III NSCLC with PD-L1 ≥1% and who did not have progression after CRT. Our objective was to analyze in real clinical practice the effectiveness of durvalumab and explore the clinical factors that may be associated with the benefit from CT. Methods: Retrospective study was made at Hospital of Leon (Spain), including 37 patients with locally advanced NSCLC treated with durvalumab after CRT treatment between March 2018 and october 2021 (40.5% patients were included in the durvalumab early access program). The neutrophil-to-lymphocyte ratio (NLR) could identified after CRT as a factor that may be benefit from durvalumab. Results: Median age was 67 years (range 46-82 years). 40.5% of patients were ≥70 years old. 78.4% were male and 51.4% smokers. 54% had non-squamous histology. PD-L1 expression was <1% in 5% and not available in 8% patients. 2.7% ROS1 rearrangements, 5.4% KRAS mutations and not available in 43.2% patients. Stage IIIA, IIIB, IIIC disease were 24.3%, 54.1% and 21.6%, respectively. Median time from end of CRT to onset durvalumab was 44 days (range 13-120 days). Overall median CT duration was 214.8 days (range 69-399 days) with a median of 14 infusions (range 6-27 infusions). With a median follow up of 19.7 months (range 1.4-34.9 months);67.6% had stopped CT: 37.8% due to completing treatment, 16.2% disease progression, 10.8% adverse event and 2.7% due to COVID19 infection. Median real-world progression-free survival (rwPFS) was 17 months (95% CI, 11-23). Median real-world overall survival (rwOS) was 29.9 months (95% CI, 23.3-36.6). %rwOS at 6, 18 and 24 months were 100%, 86.9% and 74.5%, respectively. For patients with post-CRT NLR not exceeding the cohort median value of 6, receipt of durvalumab was associated with an improvement in rwOS (median not reached vs 25.7 months;p=0.025). 56.8% patients had any grade of radiation pneumonitis (median time from CRT start: 119 days [range 36-241 days]). Of these, 19% patients developed worsening of radiation pneumonitis with durvalumab. 54,1% developed immune-mediated toxicity, mostly G1-2 (85.1%). Conclusions: Our results demonstrate the effectiveness of durvalumab consolidation in this patients population in a real-life setting. We identified low NLR after CRT as a potentially predictive factor for the benefit of CT in locally advanced NSCLC. Keywords: DURVALUMAB, PACIFIC, REAL WORLD DATA

Durvalumab (D) and PET-directed chemoradiation (CRT) after induction FOLFOX for esophageal adenocarcinoma: Final results

Background: Induction FOLFOX followed by PET-directed CRT prior to surgery demonstrated positive results in the CALGB 80803 study. We investigated the safety and efficacy of adding D, an anti-PD-L1 antibody, to PET-directed CRT. Methods: Patients (pts) with locally advanced esophageal/GEJ adenocarcinoma were enrolled. Pts received 2 cycles of mFOLFOX6 prior to repeat PET/CT. PET responders (≥35% reduction in SUV (PETr)) received 5-FU/capecitabine and oxaliplatin with RT to 50.4Gy, while induction PET non-responders (PETnr) received carboplatin/paclitaxel with RT. All Pts received D 1,500 mg q4W ×2 starting 2 weeks prior to CRT. Esophagectomy was planned 6-8 weeks after CRT. Pts with R0 resections received adjuvant D 1,500mg q4W ×6. The primary endpoint was the pathologic complete response (pCR) rate. Results: 36 pts were enrolled. Clinical ≥T3 disease was seen in 32 pts (88.9%, cT4 = 3) and ≥N1 in 23 (63.9%) pts. PD-L1 CPS was ≥1 in 25 (71.4%) of 35 tested with 14 (40%) ≥5. Microsatellite instability (MSI) was identified in 3 (8.3%) pts. 25 (70%) pts were PETr. Preop treatment was well tolerated with no new safety signals. Three pts had disease progression prior to surgery. pCR was identified in 8 (22.2%) pts and 22 (64.7%) had major pathologic response (MPR;ypTanyN0 + ≥90% response). Those with MSI tumors had ≥90% treatment response (1 pCR, 1: ypT1aN0 99% response, 1: ypT2N0, 90% response). 17 (73.9%) of 23 cN+ pts had ypN0 disease. MPR was associated with PD-L1 ≥1 (p = 0.03) and with a higher tumor mutational burden (TMB;p = 0.016) on MSK-IMPACT testing. Adjuvant D was commenced in 27 pts, with a median number of 6 cycles. Early discontinuation was due to risks of visits due to COVID19 (4, 15%), progressive disease (3, 11%), late surgical complications (2, 7%) and immune toxicity (1, 4%). With a median follow-up of 30 months, OS rates were 92% [95%CI: 83%-100%] and 85 % [95%CI: 74%-98%] at 12 and 24 months post induction. 12 and 24-month PFS rates were 81% [95%CI: 69%-95%] and 71% [95%CI: 58%-88%] respectively. In the 33 operated pts, 12 and 24-month disease free survival was 82% [95%CI: 70%-96%] and 78% [95%CI: 65%-94%], respectively. In addition to SUV on PET, total lesion glycolysis (TLG) was correlated with pathologic response. In cases with borderline change in SUV, TLG could predict response to treatment. One PETnr with 30.8% reduction in SUV had 88.1% reduction in TLG and pCR. Conversely, a PETr (-36.3%) who had an increase in TLG (39.3%) had only 40% treatment response on pathology. Conclusions: The addition of D to induction FOLFOX and PETdirected CRT prior to surgery is safe and appears effective with a high rate of pathologic response, as well as encouraging survival data. PD-L1 CPS≥1 and higher TMB may be associated with MPR. TLG is a novel PET variable that should be studied prospectively. Additional correlatives and comparison to a cohort treated with standard PET-directed CRT will be presented.

Concurrent chemoradiotherapy (cCRT) at the Northern Centre for Cancer Care (NCCC): preliminary results from a stage III cCRT database

Introduction: Due to COVID-19, NCCC established a Stage III cCRT review clinic. From April 2020 a prospective audit of patients treated was established. Methods: All lung radiotherapy referrals were scrutinised from January-December 2020. Electronic data was obtained from radiotherapy software. Patients treated with cCRT were analysed for: 1) Toxicity data. 2) Hospital admissions. 3) PDL1 status. 4) Adjuvant durvalumab treatment. Patients who received either unimodality radiotherapy or sequential chemoradiotherapy were reviewed for justification for not treating with cCRT . Results: Of 670 patients treated. 295 received palliative and 375 radical radiotherapy. 141 patients received radical radiotherapy (55Gy in 20#). 55 were Stage III NSCLC, 18 received sequential chemoradiotherapy. 49 patients received cCRT, 41 were stage III NSCLC. 55 stage III patients did not receive cCRT. 8 reason codes were identified: 1) Comorbidity (N=16). 2) Size (N=18). 3) No histopathology (N=3). 4) Consented for cCRT, but disease progression/too big at time of radiotherapy planning (N=6). 5) Relapse (N=3). 6) Reason not annotated (N=5). 7) Patient declined (N=2). 8) Adjuvant RT after surgery (N=2). Of the 41 cCRT NSCLC patients. All patients experienced some toxicity. There were no grade 4 toxicity. 2 patients reported Grade 3 toxicity (nausea and fatigue);dyspnoea, cough, fatigue, oesophagitis and nausea being the most common. 4 out of 41 patients were admitted. Reasons were dehydration, chest infection, oesophagitis, hyponatraemia, neutropenia. 1 patient did not proceed to durvalumab, due to deterioration of performance status. 30 out of 41 patients were PDL1 +, of which 26 were consented for durvalumab. Reasons for no durvalumab were: rheumatoid arthritis, inflammatory bowel disease, interstitial lung disease and deterioration after cCRT. Conclusion: cCRT is an effective delivery as an outpatient. However, ongoing audit is imperative to ensure optimal patient treatment. The data as highlights multidisciplinary input is essential, as most cCRT patients experience toxicity. Disclosure: No significant relationships.

Optimisation of the treatment pathway for stage III non-small cell cancer (NSCLC) patients receiving concurrent chemo-radiation (cCRT)

Introduction: Patients undergoing concurrent chemo-radiation (CCRT) for stage III NSCLC can be clinically and technically challenging to manage due to extensive treatment volumes including lymph nodes, oesophageal and lung radiotherapy tolerances. Patients experience toxicities including: oesophagitis, dehydration, pneumonitis and weight loss. During treatment lung changes can affect tumour position. As a result of Covid-19, our centre optimised the CCRT pathway in April 2020, to formalise a specific cCRT radiographer review clinic, to deliver an outpatient service. Former practice involved delivering inpatient chemoradiotherapy. Aim: To formalise and optimise the cCRT pathway to ensure a resilient streamlined pathway by: 1) Avoid patient admissions by early intervention and management of toxicities. 2) Problem solving of technical imaging challenges while supporting on-treatment radiographers. 3) Supporting clinical consultant oncologists by coordination post cCRT investigations and eligibility for adjuvant immunotherapy. Methods: Treatment consultation included;analysis of daily imaging, dosimetric data, blood results, electronic recording of assessment and management of patients, reviewing medications, arranging fluids, transfusions;timely intervention for chemotherapy. Patient consent for Durvalumab was instigated on the final week of review and any anatomical lung changes from the daily treatment imaging was initiated. Results: Optimisation by combining clinical and technical skills has demonstrated a positive patient and organisational impact. A formalised clinic has ensured the ability to continue to provide a cCRT service, with increasing patient numbers despite Covid-19 . Conclusion: Optimising the pathway has proven cCRT can be delivered as an outpatient service. However, future optimisation is required from the multidisciplinary team to provide prehabilitation and rehabilitation. As the service increases, capacity and resource impact needs consideration. Thus, continual audit of the service is imperative to ensure provision can be maintained. Disclosure: No significant relationships.

Pulmonary toxicities after chemoradiation followed by durvalumab for stage III NSCLC: a real setting

Purpose or Objective Evaluation of the incidence of pulmonary toxicities, especially pneumonitis, for patients treated in a real setting with concurrent chemoradiation (CRT) followed by adjuvant durvalumab for unresectable stage III non-small-cell lung cancer (NSCLC). Materials and Methods This study included retrospectively 84 patients with unresectable stage III NSCLC treated by CRT followed by durvalumab in 5 french centers from May 2017 to May 2021. Pneumonitis incidence was analysed with a distinction between immune pneumonitis, lung infection and radiation pneumonitis. A multivariate analysis was realized for radiation pneumonitis to find predictive factors. Overall survival (OS) and Progression Free Survival (PFS) were also evaluated. Results With a median follow-up of 23 months, grade 3-4 pneumonitis were as follows: 3.4% of radiation pneumonitis, 5.9% of immune pneumonitis and 13.4% of lung infections. . In multivariate analysis, age ≥ 68 years-old, cardiovascular history and use of docetaxel came out as predictive factors for radiation pneumonitis.Considering the entire population, median PFS was 28.9 months and the 2-year OS was 70.8%. Besides, among our population study, 31% of patients presented at least one or more exclusion or non-inclusion criteria according to initial PACIFIC protocol. But there was no difference between the patients who meet the PACIFIC criteria and the others, whether for toxicity or survivals. The beginning of the durvalumab consolidation within 14 days after ending CRT seemed to improve the PFS according to PACIFIC’s findings. Conclusion In our real-word study, incidence of grade 3-4 radiation pneumonitis and immune pneumonitis are similar to those in the PACIFIC trial. Incidence of lung infections was higher, probably because of the context of SARS-CoV-2 pandemic. Age ≥ 68 years-old, cardiovascular history and use of docetaxel were found to be predictive factors for radiation pneumonitis. Moreover, PFS and OS were excellent

CASE REPORT OF LOCALLY ADVANCED NON-SMALL-CELL LUNGCANCER

Lung cancer is among the most commonly diagnosed cancers in Croatia in both genders, as well as the most common cause of cancer-related deaths. There are two major histological subtypes of lung cancer, non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). In the last decade great achievements have been made in the treatment of NSCLC in metastatic setting, with the discovery and identification of druggable oncogenes and compatible targeted therapies, as well as with the utilization of immunotherapy. Until recently, the standard treatment for patients with unresectable locally advanced NSCLC was definitive concurrent chemotherapy and radiation with curative intent, but it was often followed by a rapid progression of the disease. That being said, there was a need for new treatment options that could improve outcomes. The Pacific trial, which evaluated durvalumab consolidation therapy after concurrent chemotherapy and radiotherapy in unresectable NSCLC, demonstrated a statistically significant and clinically meaningful improvement in the terms of progression-free survival and overall survival. We report a case of locally advanced NSCLC diagnosed in 67-year old male. Computed tomography of the thorax and upper abdomen described the tumor of the upper left lobe with pathologically enlarged mediastinal lymph nodes. To obtain the diagnose he underwent bronchoscopy and transthoracic needle biopsies. Histopathological examination confirmed the diagnose of adenocarcinoma with no targetable mutations found on further testing, but PD-L1 expression was 50%. As there was no evidence of metastatic disease on fluorodeoxyglucose positron emission tomography/computed tomography scan, he was staged as having T2bN2M0 (Stage IIIA) disease. We recommended radical intent radiation therapy with concurrent chemotherapy and consolidation therapy with durvalumab up to twelve months. Concurrent radiotherapy and chemotherapy was interrupted by the sars-cov-2 virus infection. Follow-up CT scans of the thorax and upper abdomen were made approximately every 3 months. In the end of the treatment, a complete radiological response was achieved.

Durvalumab with cetuximab and radiotherapy for locally advanced squamous cell carcinoma of the head and neck: A phase 1/2 trial.

BACKGROUND AND PURPOSE: To report on the anti-tumor activity of a novel combination in high-risk locally advanced head and neck squamous cell carcinoma. MATERIALS AND METHODS: At a fixed dose of 1500 mg every 28 days, anti PD-L1 Durvalumab was given concomitantly to Radiotherapy and Cetuximab starting from the first week of combined treatment, followed by adjuvant Durvalumab to a maximum of 6 months after completion of radiation. The primary endpoint of the study was 2-year progression-free survival (PFS). A safety run-in was planned. Due to regulatory issues which prevented from opening multiple centers, COVID-19 pandemic and withdrawal of Durvalumab from supporting company, the study was prematurely terminated in April 2021. RESULTS: Between July 2019 and August 2020, 9 patients were enrolled in the study. All tumors had a PD-L1 Combined Positive Score > 1. Optimal drug exposure was observed, with mean relative dose intensity of 85.5% and 87.5% for Cetuximab and Durvalumab, respectively. No radiation breaks were necessary. A grade 4 mucositis lasting for 14 days corresponded to the only dose limiting toxicity we reported. At a median follow-up of 11.5 months (IQR 7.7-16.7) all surviving patients (6 out of 9) are disease-free, with 1 and 2-year PFS rates of 77.7% and 58.3%, respectively. A selective sparing of node levels in the elective volume was performed in all cases, yielding a cumulative mean dose of 37.6 Gy (SD 8.4). CONCLUSION: Albeit limited by the small sample size, our preliminary observation of anti-tumor activity and tolerability of Durvalumab in addition to Cetuximab and radiation may warrant further investigations.

Durvalumab in frail and older patients with stage iv non-small cell lung cancer: The randomized phase ii duration trial

Introduction: Checkpoint inhibitors have recently been established as first-line treatment for metastatic NSCLC. Notably, a phenomenon known as immunosenescence, i.e. the progressive remodeling of the immune system with aging, as well as the inflammatory status, may interfere with the activity of PD-1/PD-L1 inhibitors. Although frail and older patients represent a major fraction of non-small cell lung cancer (NSCLC) patients in routine clinical practice, this population is still underrepresented in most clinical trials. Thus, clinical evidence about tolerability and efficacy of these novel agents in the elder and frail population is urgently required. Methods/Design: DURATION (NCT03345810) is a prospective, open label, treatment stratified, randomized, multicenter phase II study. The protocol foresaw the enrollment of 200 patients diagnosed with stage IV NSCLC ≥70 years old and/or with Charlson-Comorbidity Index > 1 and/ or with a performance status ECOG > 1. Patients were stratified according to Cancer and Age Research Group (CARG) score in 'fit' and 'less fit'. Patients were then randomized 1:1 to receive either CT or two cycles of CT followed by two cycles of durvalumab and durvalumab maintenance. Details are shown in figure 1. The primary endpoint is the rate of treatment-related grade III/IV adverse events. Secondary endpoints are progression-free survival, response rate and overall survival and quality of life assessment. The trial is accompanied by a biomaterial repository to explore potential biomarkers. Results: The last patient was enrolled in January 2021. Forty-nine, 48, 51, and 52 patients were allocated to arm A, arm B, arm C, and arm D, respectively. Currently, 145 patients have completed the study, 13 patients are under treatment (12 in total in durvalumab-maintenance arms and 1 in the CT arm), while 42 are in follow-up. Conclusions: Inspite of the COVID-19 pandemic, the DURATION trial successfully completed the planned enrollment of 200 patients, underlying the urgent need for evidence of efficacy and tolerability of immunotherapy in the challenging population of frail and elderly patients.

RAMPART: A phase III multi-arm multi-stage trial of adjuvant checkpoint inhibitors in patients with resected primary renal cell carcinoma (RCC) at high or intermediate risk of relapse.

BACKGROUND: 20-60% of patients with initially locally advanced Renal Cell Carcinoma (RCC) develop metastatic disease despite optimal surgical excision. Adjuvant strategies have been tested in RCC including cytokines, radiotherapy, hormones and oral tyrosine-kinase inhibitors (TKIs), with limited success. The predominant global standard-of-care after nephrectomy remains active monitoring. Immune checkpoint inhibitors (ICIs) are effective in the treatment of metastatic RCC; RAMPART will investigate these agents in the adjuvant setting. METHODS/DESIGN: RAMPART is an international, UK-led trial investigating the addition of ICIs after nephrectomy in patients with resected locally advanced RCC. RAMPART is a multi-arm multi-stage (MAMS) platform trial, upon which additional research questions may be addressed over time. The target population is patients with histologically proven resected locally advanced RCC (clear cell and non-clear cell histological subtypes), with no residual macroscopic disease, who are at high or intermediate risk of relapse (Leibovich score 3-11). Patients with fully resected synchronous ipsilateral adrenal metastases are included. Participants are randomly assigned (3,2:2) to Arm A - active monitoring (no placebo) for one year, Arm B - durvalumab (PD-L1 inhibitor) 4-weekly for one year; or Arm C - combination therapy with durvalumab 4-weekly for one year plus two doses of tremelimumab (CTLA-4 inhibitor) at day 1 of the first two 4-weekly cycles. The co-primary outcomes are disease-free-survival (DFS) and overall survival (OS). Secondary outcomes include safety, metastasis-free survival, RCC specific survival, quality of life, and patient and clinician preferences. Tumour tissue, plasma and urine are collected for molecular analysis (TransRAMPART). TRIAL REGISTRATION: ISRCTN #: ISRCTN53348826, NCT #: NCT03288532, EUDRACT #: 2017-002329-39, CTA #: 20363/0380/001-0001, MREC #: 17/LO/1875, ClinicalTrials.gov Identifier: NCT03288532, RAMPART grant number: MC_UU_12023/25, TransRAMPART grant number: A28690 Cancer Research UK, RAMPART Protocol version 5.0.

Safety monitoring of two and four-weekly adjuvant durvalumab for patients with stage III NSCLC: implications for the COVID-19 pandemic and beyond.

Durvalumab is the first approved adjuvant immunotherapy agent for patients with stage III NSCLC treated with concurrent chemoradiotherapy and is associated with improved overall survival. In order to minimise the number of hospital visits for patients receiving durvalumab during the COVID-19 pandemic we implemented 4-weekly (20 mg/kg) durvalumab in place of 2-weekly infusions at The Royal Marsden Hospital. We assessed the potential impact of the safety of a 4-weekly schedule in patients receiving adjuvant durvalumab. We carried out a retrospective study of 40 patients treated with 2-weekly and 4-weekly infusions of durvalumab prior to and during the COVID-19 pandemic. Clinical documentation was analysed from 216 consultations across 40 patients receiving 2-weekly durvalumab and 66 consultations of 14 patients who switched from 2-weekly to 4-weekly durvalumab during the COVID-19 pandemic. In patients receiving 2-weekly durvalumab, the rate of grade 3 and 4 toxicities was 15 % compared to 7% in patients receiving 4-weekly durvalumab. Pre-existing autoimmune disease was considered a risk factor for the development of grade 3 or 4 toxicities. We did not observe any difference in the rate of grade 1 and 2 toxicities between the two groups. Our findings support the use of 4-weekly durvalumab during the COVID-19 pandemic and beyond, obviating the need for 2-weekly face-to-face consultations and blood tests, relevant given the current pandemic and the need to re-structure cancer services to minimise patient hospital visits and exposure to SARS-CoV-2.

Extended-Interval Dosing Strategy of Immune Checkpoint Inhibitors in Lung Cancer: Will it Outlast the COVID-19 Pandemic?

Patients with lung cancer are particularly vulnerable to complications from coronavirus disease-2019 (COVID-19). Recurrent hospital visits and hospital admission are potential risk factors for acquiring infection with its causative pathogen, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). As immune checkpoint inhibitors (ICIs) constitute the therapeutic backbone for the vast majority of patients with advanced lung cancer in the absence of actionable driver oncogenes, there have been intense discussions within the oncology community regarding risk-benefit of delaying these treatments or use of alternative extended-interval treatment strategies to minimize the risk of viral transmission secondary to unintended nosocomial exposures. In the midst of the COVID-19 pandemic, the U.S. Food and Drug Administration (FDA) granted accelerated approval for extended-interval strategy of pembrolizumab at a dose of 400 mg every 6 weeks for all already approved oncologic indications. Herein, we summarize the evidence from the in silico pharmacokinetic modeling/simulation studies supporting extended-interval dosing strategies for the ICIs used in lung cancer. We further review the evolving clinical evidence behind these approaches and predict that they will continue to be used in routine practice even long after the pandemic, particularly for patients with durable disease control.