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Background: Standard first line treatment for unresectable malignant pleural mesothelioma (MPM) is platinum-based chemotherapy with pemetrexed. Two recent, single-arm, phase 2 trials (DREAM1 and PrE05052) combining the PD-L1 inhibitor durvalumab and standard first line cisplatin and pemetrexed (CP) exceeded pre-specified criteria for proceeding to phase 3. DREAM3R aims to determine the effectiveness of adding durvalumab to first line CP chemotherapy in advanced MPM. Methods: Treatment-naïve patients with advanced MPM will be randomised (2:1) to EITHER durvalumab 1500 mg every 3 weeks plus doublet chemotherapy (cisplatin 75 mg/m2 and pemetrexed 500 mg/m2) every 3 weeks for 4-6 cycles, followed by durvalumab 1500 mg every 4 weeks until disease progression, unacceptable toxicity or patient withdrawal; OR doublet chemotherapy alone for 4-6 cycles, followed by observation. The target sample size is 480 patients (320 durvalumab, 160 control) recruited over 27 months, with follow up for an additional 24 months. This provides over 85% power if the true hazard ratio for overall survival is 0.70, with 2-sided alpha of 0.05, assuming a median survival of 15 months in the control group. Key inclusion criteria: MPM of any histological subtype; measurable disease as per RECIST 1.1 modified for mesothelioma (mRECIST 1.1) without prior radiotherapy to these sites; ECOG PS 0-1; and, adequate hematologic, renal, and liver function tests. Key exclusion criteria: prior systemic anticancer treatment for MPM; diagnosis based only on cytology or fine needle aspiration biopsy; contraindication to immunotherapy; and conditions requiring immunosuppressives or corticosteroids. Stratification: Age (18-70 years vs. > 70), sex, histology (epithelioid vs. non-epithelioid), and region (USA vs. ANZ). The primary endpoint is overall survival. Secondary endpoints include progression-free survival; objective tumour response (by mRECIST 1.1 and iRECIST); adverse events; health-related qua

Background: 1L NIVO + IPI was shown to provide durable long-term overall survival (OS) benefit vs chemo regardless of tumor programmed death ligand 1 (PD-L1) expression in patients (pts) with advanced NSCLC in CheckMate 227 Part 1 (NCT02477826); 3-year OS rates were 33% vs 22% in pts with PD-L1 ≥ 1% (HR, 0.79 [95% CI, 0.67–0.93]) and 34% vs 15% in pts with PD-L1 < 1% (HR, 0.64 [95% CI, 0.51–0.81]). Here we report updated results from the study with 4 years’ minimum follow-up. Methods: Adults with previously untreated stage IV / recurrent NSCLC, no known EGFR/ALK alterations, and ECOG performance status ≤ 1 were enrolled; pts were stratified by squamous (SQ) and non-squamous (NSQ) histology. Pts with PD-L1 ≥ 1% (n = 1189) were randomized 1:1:1 to receive NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), NIVO alone (240 mg Q2W), or chemo. Pts with PD-L1 < 1% (n = 550) were randomized 1:1:1 to receive NIVO + IPI, NIVO (360 mg Q3W) + chemo, or chemo. OS with NIVO + IPI vs chemo in pts with PD-L1 ≥ 1% was the primary endpoint. Results: With minimum follow-up of 49.4 months (database lock, Feb 18, 2021), pts were at least 2 years beyond the protocol-specified end of immunotherapy treatment. Pts with PD-L1 ≥ 1% continued to show durable benefit with NIVO + IPI vs chemo (HR, 0.76 [95% CI, 0.65–0.90]); 4-year OS rates were 29% (NIVO + IPI), 21% (NIVO), and 18% (chemo). At 4 years, 14% (NIVO + IPI), 10% (NIVO), and 4% (chemo) remained progression free. Among responders, 34%, 30%, and 7% remained in response, respectively. In an exploratory analysis in pts with PD-L1 ≥ 50%, 4-year OS rates were 37% (NIVO + IPI), 26% (NIVO), and 20% (chemo). In pts with PD-L1 < 1%, OS HR for NIVO + IPI vs chemo was 0.64 (95% CI, 0.51–0.81); 4-year OS rates were 24% (NIVO + IPI), 13% (NIVO + chemo) and 10% (chemo). At 4 years, 12% (NIVO + IPI), 7% (NIVO + chemo), and 0% (chemo) remained progression free. Among responders, 31%, 13%, and 0% remained in response, respectively. Among pts who progressed on NIV

Background: Despite increasing evidence of benefit supporting CGP in personalizing cancer therapy, its widespread uptake remains limited. Barriers include low patient understanding, unmet patient expectations related to low utility, clinician concerns over cost-effectiveness, perceived value, and discomfort in management of complex genomic results. Methods: This prospective cross-institutional demonstration study was designed to evaluate implementation of CGP in the care of adult and paediatric advanced cancer pts, incorporating pt reported outcomes (PROMs), discrete choice experiment (DCE), ongoing process optimization and clinician evaluations. DNA sequencing of FFPE tumor and matched blood was completed with CGP (PMCC Comprehensive Cancer Panel; 391 genes) via central laboratory. A tumor board reported results weekly with emphasis on therapeutic relevance. Oncologists performed consent and results delivery. Pts completed pre-and post-test surveys, including validated and study-specific questions, DCE and if eligible, semi-structured interviews. Qualitative interviews were undertaken with study clinicians and laboratory staff to evaluate processes. Results: 86% (315) of 365 enrolled pts had successful CGP; of these 63% (199) had relevant therapeutic, diagnostic or germline results. 50 (16%) had treatment change at 6m, 49 (16%) had germline mutations. 293 (88% of adult pts) completed PROMs. 17 of 19 clinicians/laboratory staff approached consented to an interview. At consent pts cited multifaceted value in testing, showed good understanding of basic concepts, but most (69%) overestimated the likelihood of result-led change. Post-test pts remained consistently satisfied with accessing CGP; valuing research contribution, taking opportunities and information for family. 21% struggled with understanding results but there were low levels of decisional regret following participation (89% had nil/mild regret). Pt-elicited preferences (via DCE) indicated priority for high

Background: Rare cancers (RCs) often lack proven treatments and consequently have poorer outcomes. Identification of molecular biomarkers can facilitate treatment selection and trials access for RC patients (pts) where histology-based trials are not feasible. We assessed the potential for next-generation sequencing (NGS) to impact RC care. Methods: Pts with a rare histology, poor-prognosis solid-tumor and no standard of care therapy underwent NGS genomic profiling of paired FFPE tumor and blood (PMCC comprehensive cancer panel; 391 genes). A virtual molecular tumour board (MTB) reviewed curated results regarding diagnosis, actionability (OncoKB) and treatment recommendations. Results: Between July 2017 and Nov 2019, 121 pt were prospectively enrolled across 4 Australian sites. 109 (91%) pts had a tumour with an incidence of < 1/100,000 person/years with 83 diverse RC histologies represented. 100 (83%) cases were successfully sequenced. The most commonly aberrant genes ( > 10%) were: TP53 (45%), CDKN2A/B, RB1, PTEN and NF1. 51 (51%) had at least one potentially actionable finding, with 27 matched to a clinically validated drug (OncoKB level 3 or better) [Table]. In 6 cases NGS resulted in a revised diagnosis (includes 4 with FDA approved therapy). Actionable germline mutations were detected in 3 individuals of which 2 were previously known. The majority of pts remain in follow-up, however, 8 died prior to or within 28 days of NGS result availability. Drug access remains a limitation with only 12 receiving therapy based on NGS/MTB guidance. Clinical trial information: ACTRN12616001000493. Conclusions: NGS in RCs is feasible with potential impact in half of cases. Earlier testing and improved off-label/trial drug access is necessary to increase the likelihood that RC patients may benefit from molecularly guided therapy.

Background: Tumour tissue-based information is limited. Liquid biopsy can provide valuable real-time information through circulating tumour cells (CTCs). Profiling and expanding CTCs may provide avenues to study transient metastatic disease. Methods: 70 NSCLC patients were recruited. CTCs were enriched using the spiral microfluidic chip and a RosetteSep™ using bloods from NSCLC patients. CTC cultures were carried out using the Clevers media under hypoxic conditions. CTCs were characterized using immunofluorescence and mutation-specific antibodies for samples with known mutation profiles. Exome sequencing was used to characterized CTC cultures. Results: CTCs ( > 2 cells) were detected in 38/70 (54.3%) of patients ranging from 0-385 CTCs per 7.5ml blood. In 4/5 patients where primary tumours harboured an EGFR exon 19 deletion, this EGFR mutation was also captured in CTCs. ALK translocation was confirmed on CTCs from a patient harbouring an ALK-rearrangement in the primary tumour. Short term CTC cultures were successfully generated in 9/70 NSCLC patients. Whole exome sequencing confirmed the presence of somatic mutations in the CTC cultures with mutational signatures consistent with NSCLC. Conclusions: This study demonstrates a workflow for ex vivo culture of CTCs from NSCLC blood samples.

Background: Traditionally, disease control of brain metastases (BM) has dictated the prognosis of those with metastatic lung cancer. Immune check-point inhibitors (ICI) have shown intracranial response but data on the magnitude of such effect in combination with radiation is still evolving. We report the time to progression of intracranial and systemic disease post gamma-knife radiation (GK) and associations with the use of ICI in this cohort. Methods: Patients with metastatic lung cancer with BM treated with GK between 2015 and 2019 were retrospectively analysed in a single institution at the Princess Alexandra Hospital, Queensland. The primary endpoint was time from first GK to death. Results: 104 patients were eligible. Median age was 63 years. BM was seen in 46.7% at diagnosis (versus relapsed in brain). Solitary BM was seen in 37.1% patients. 7.7% had prior whole-brain radiation (WBRT) prior to GK. 45.7% received ICI either at the time of GK or as the next line of treatment immediately post GK. 56.2% received ICI at any time during the study period. Oncogenic driver mutations were seen in 13 cases [EGFR mutant (9.5%), ALK mutation (2.5%)]. 15.2% patients had a high-PDL1 (≥50%) level. Time from GK to death was: 14 (9.7-18.3) months for all patients. Incidence of progressive BM was 46.7%. Time to intracranial PD was 5 months. Systemic PD was seen post GK in 44.8% patients. Survival was improved in those patients with the presence of a driver mutation (p = 0.043) on univariate analysis. Factors which did not impact survival included: the number of BM (solitary vs multiple; p = 0.837), PD-L1 status (PD-L1 < 50% vs ≥50%; p = 0.186), use of ICI (used vs not used; p = 0.307) and previous WBRT (treated vs not treated; p = 0.251). Failure of BM requiring GK on ICI was not associated with a worse outcome (p = 0.707). Conclusions: The presence of driver mutations was associated with prolonged overall survival in select patients undergoing GK for BM. High PDL-1 expressivit

Background: In the phase 3 CheckMate 227 Part 1 (NCT02477826; minimum follow-up, 29.3 mo), 1L NIVO + IPI significantly improved overall survival (OS) vs chemo in treatment-naive patients (pts) with aNSCLC and tumor PD-L1 expression ≥ 1% (primary analysis) or < 1% (pre-specified descriptive analysis). Here we report data with 3-y minimum follow-up. Methods: Pts with stage IV / recurrent NSCLC and PD-L1 ≥ 1% (n = 1189) were randomized 1:1:1 to NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), NIVO (240 mg Q2W) alone, or chemo. Pts with PD-L1 < 1% (n = 550) were randomized to NIVO + IPI, NIVO (360 mg Q3W) + chemo, or chemo. Primary endpoint was OS with NIVO + IPI vs chemo in pts with PD-L1 ≥ 1%. An exploratory analysis of OS in pts by response status (CR/PR, SD, progressive disease [PD]) at 6 mo was conducted. Results: After a median follow-up of 43.1 mo (database lock, 28 Feb 2020), pts with PD-L1 ≥ 1% continued to derive OS benefit from NIVO + IPI vs chemo (HR: 0.79; 95% CI, 0.67–0.93); 3-y OS rates were 33% (NIVO + IPI), 29% (NIVO), and 22% (chemo). At 3 y, 18% of pts with PD-L1 ≥ 1% treated with NIVO + IPI remained progression-free vs 12% with NIVO and 4% with chemo; 38% of confirmed responders remained in response in the NIVO + IPI arm at 3 y vs 32% in the NIVO arm and 4% in the chemo arm. In pts with PD-L1 < 1%, OS HR for NIVO + IPI vs chemo was 0.64 (95% CI, 0.51–0.81); 3-y OS rates were 34% (NIVO + IPI), 20% (NIVO + chemo), and 15% (chemo); 13%, 8%, and 2% of pts remained progression-free; and 34%, 15%, and 0% of confirmed responders remained in response, respectively. Pts with PD-L1 ≥ 1% with either CR/PR at 6 mo had longer subsequent OS with NIVO + IPI vs chemo; pts with SD or PD at 6 mo had generally similar subsequent OS between treatments (Table); results in PD-L1 < 1% pts will be presented. Any-grade / grade 3–4 treatment-related AEs were observed in 77% / 33% of all pts treated with NIVO + IPI, and 82% / 36% with chemo. Conclusions: With 3 y minimum follow-up, NIV

Background: Nivo is approved as 240 mg Q2W in the EU and Japan and 240 mg Q2W or 480 mg Q4W in the US and Canada for second-line treatment (tx) of advanced NSCLC. Pharmacokinetic modeling in various tumors predicts that exposure, efficacy and safety can be maintained with less frequent Q4W dosing, which may provide a more convenient tx option. We present an interim analysis of efficacy and safety from CheckMate 384 (NCT02713867), an international, open-label, randomized phase 3b/4 trial evaluating less frequent nivo dosing (480 mg Q4W vs 240 mg Q2W) in patients (pts) with advanced NSCLC and prior Q2W nivo tx. Methods: Pts (N = 329) with previously treated histologically confirmed stage IIIB/IV or recurrent NSCLC, ECOG performance status 0–2, and prior tx with nivo 3 mg/kg or 240 mg Q2W for ≤12 mo, with ≥2 consecutive assessments of complete / partial response or stable disease, were randomized 1:1 to nivo 480 mg Q4W or 240 mg Q2W over a 30-min infusion. Co-primary endpoints: post-randomization (RND) progression-free survival rates (PFS) at 6 mo and 1 y. Secondary endpoints included safety. Due to tx landscape changes in NSCLC, statistical analyses were amended for a reduced sample size. One-sided 95% CIs were generated to compare PFS rates; presented data analyses are descriptive. Results: Of 166 and 163 pts randomized to 480 mg Q4W and 240 mg Q2W, 164 and 161 pts were treated, respectively. Median follow-up was 9.5 mo (480 mg Q4W) and 10.2 mo (240 mg Q2W). Baseline characteristics were balanced between tx arms. Stratified PFS rates post-RND were comparable between tx arms at 6 mo and 1 y (Table). Safety profiles were similar; any grade tx-related adverse events (TRAEs) and TRAEs leading to discontinuation were reported in 48% vs 61% and 6% vs 9% of pts with 480 mg Q4W vs 240 mg Q2W. No tx-related deaths were reported. Conclusions: Nivo 480 mg Q4W showed similar efficacy and safety to 240 mg Q2W in pts with disease control on nivo, supporting the potential use of 48

PURPOSE CheckMate 568 is an open-label phase II trial that evaluated the efficacy and safety of nivolumab plus low-dose ipilimumab as first-line treatment of advanced/metastatic non-small-cell lung cancer (NSCLC). We assessed the association of efficacy with programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB). PATIENTS AND METHODS Two hundred eighty-eight patients with previously untreated, recurrent stage IIIB/IV NSCLC received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary end point was objective response rate (ORR) in patients with 1% or more and less than 1% tumor PD-L1 expression. Efficacy on the basis of TMB (FoundationOne CDx assay) was a secondary end point. RESULTS Of treated patients with tumor available for testing, 252 patients (88%) of 288 were evaluable for PD-L1 expression and 98 patients (82%) of 120 for TMB. ORR was 30% overall and 41% and 15% in patients with 1% or greater and less than 1% tumor PD-L1 expression, respectively. ORR increased with higher TMB, plateauing at 10 or more mutations/megabase (mut/Mb). Regardless of PD-L1 expression, ORRs were higher in patients with TMB of 10 or more mut/Mb (n = 48: PD-L1, ≥ 1%, 48%; PD-L1, < 1%, 47%) versus TMB of fewer than 10 mut/Mb (n = 50: PD-L1, ≥ 1%, 18%; PD-L1, < 1%, 5%), and progression-free survival was longer in patients with TMB of 10 or more mut/Mb versus TMB of fewer than 10 mut/Mb (median, 7.1 v 2.6 months). Grade 3 to 4 treatment-related adverse events occurred in 29% of patients. CONCLUSION Nivolumab plus low-dose ipilimumab was effective and tolerable as a first-line treatment of advanced/metastatic NSCLC. TMB of 10 or more mut/Mb was associated with improved response and prolonged progression-free survival in both tumor PD-L1 expression 1% or greater and less than 1% subgroups and was thus identified as a potentially relevant cutoff in the assessment of TMB as a biomarker for first-line nivolumab plus ipilimumab.

Background: Immune checkpoint inhibitors are routinely used in Non Small Cell Lung Cancer (NSCLC) patients following progression on first-line therapy. Immune-related Adverse Events (IrAEs) have been associated with the efficacy of PD-1 inhibitors in melanoma. The association between the development of IrAEs and efficacy of nivolumab remains unclear in NSCLC. Methods: We retrospectively collected data from patients who received nivolumab for advanced NSCLC on an Open Access Program across seven oncology institutions in Queensland, Australia, and analyzed whether there was an association between outcomes and the development of immune-related toxicity. Results: One hundred and ninety six patients were enrolled to this ethics committee approved audit – 77 females (39%) and 119 (61%) males; PS 0-1 (62%); PS 2-3 (38%); median age 67 (range 42-84). An objective response was recorded in 24% of patients; partial response (47/196) with one complete response, in addition 28% (55/196) had stable disease. The median overall survival was 9.2 months; 13.4 months in PS 0-1 patients and 4.2 months in PS 2-3 patients. At 1 year, the overall survival rate was 42%; 57% in patients with PS 0-1 and 18% in PS 2-3 patients. The presence of IrAEs of any grade occurred in 36% of patients and was associated with a longer median PFS of 5.9 months versus 2.3 months (P value < 0.01, 95% CI) in patients with no immune toxicity on Kaplan Meier analysis. The median OS of patients experiencing an IrAE was 24.3 months compared with 6.5 months without (P value < 0.01, 95% CI). A durable clinical benefit was observed in 72% of patients who developed at least one IrAE versus 37% in those without any immune mediated toxicity. Analysis of the prognostic relevance of routine histological, hematological and biochemical parameters is ongoing with a multivariate analysis planned. Conclusions: Nivolumab had clinically significant long-term benefits in the treatment of locally advanced and metastatic NSCLC wit

Background: CheckMate 227 (NCT02477826), a phase 3 study of 1L nivo + ipilimumab (ipi), nivo, or nivo + chemo vs chemo in advanced NSCLC, met its co-primary endpoint of prolonged progression-free survival (PFS) with nivo + ipi vs chemo in patients (pts) with tumor mutational burden ≥10 mutations/Mb. Identifying effective tx for pts without known predictive biomarkers remains an unmet need. Prior studies suggest addition of chemo to anti–PD-(L)1 tx can improve outcomes in an unselected pt population, although benefit is most pronounced in pts with higher tumor PD-L1 expression. We report results for nivo + chemo vs chemo in pts with < 1% tumor PD-L1 expression. Methods: Pts (n = 550) with chemo-naive, stage IV/recurrent NSCLC, no known sensitizing EGFR/ALK mutations, and < 1% tumor PD-L1 expression were stratified by tumor histology and randomized 1:1:1 to nivo 3 mg/kg Q2W + ipi 1 mg/kg Q6W, nivo 360 mg Q3W + chemo, or chemo (optional pemetrexed maintenance after chemo for nonsquamous [non-SQ] NSCLC). Pts were treated up to 2 yr. A descriptive analysis was performed for the secondary endpoint of PFS for nivo + chemo vs chemo in pts with < 1% tumor PD-L1 expression. No alpha was allocated for this analysis. Results: Baseline characteristics were balanced between nivo + chemo (n = 177) and chemo (n = 186) arms. PFS was improved with nivo + chemo vs chemo (HR = 0.74 [95% CI: 0.58, 0.94]; minimum follow-up 11.2 mo; descriptive comparison). PFS benefit with nivo + chemo was observed across most subgroups. Among histologic subgroups, benefit was more pronounced in non-SQ (HR = 0.68) relative to SQ NSCLC (HR = 0.92). Rates of any grade tx-related adverse events leading to discontinuation were 13% with nivo + chemo and 14% with chemo. Conclusions: 1L nivo + chemo improved PFS vs chemo in pts with advanced NSCLC and < 1% tumor PD-L1 expression, and was well tolerated. Results are encouraging in this analysis, which includes only pts with < 1% PD-L1. CheckMate 227 Part 2 (ongo

Background: Oleclumab is a human mAb that binds to CD73 and inhibits production of immunosuppressive adenosine. This is a first-in-human study to investigate the safety, efficacy, and pharmacodynamics of oleclumab alone or in combination with durvalumab in patients (pts) with advanced panc or MSS-CRC. Methods: A 3+3 dose-escalation design was followed in which pts received one of 4 escalating doses of oleclumab IV with or without durvalumab 10 mg/kg IV Q2W until disease progression, followed by study expansion with high dose of oleclumab plus durvalumab 10 mg/kg Q2W. AEs and tumor response (RECIST v1.1) were assessed. Free soluble CD73 and cell surface CD73 on lymphocytes were measured by ELISA and flow cytometry, respectively. Tumoral CD73 was centrally assessed by an in situ enzyme assay and IHC. Results: The initial dose-escalation and PD exploration enrolled 42 monotherapy and 24 combination pts with no reported DLTs. The minimum target serum concentration was exceeded at the top 2 doses. Sustained decrease in free soluble CD73 and CD73 on peripheral T cells was demonstrated across all doses and pts. Decreased CD73 enzymatic activity was observed in all evaluable frozen tumor biopsy samples (n = 4) 20 days after treatment with the top 2 doses of oleclumab. Treatment with oleclumab alone decreased tumoral CD73 expression (5/9) while increasing CD8+ TILs in all 5 samples. Subsequently, durva + oleclumab highest dose was selected for expansion in 2-5L CRC (21 pts) and 2-3L panc (20 pts). The most commonly reported TRAEs in combo expansion were diarrhea (8.7%), pyrexia (8.7%), fatigue (6.5%), and increases in ALT (6.5%), AST (6.5%), and ALP (6.5%). PR was observed for 1/21 CRC (5L) and 2/20 panc (2 and 3L) pts; SD was observed in 2/21 CRC and 3/20 panc pts. Duration of treatment for subjects with disease control was 84-322 days (CRC) and 28-232 days (panc). Treatment is ongoing for 1 CRC (322 days) and 2 panc pts (140 and 182 days). Conclusions: Treatment with olecl

Background: Attempts to isolate reliable predictive biomarkers have been unsuccessful for the use of immunotherapy agents targeting PD-1 and PD-L1 immune checkpoint proteins in the treatment of non-small cell lung cancer (NSCLC). This study assessed whether CT texture analysis as a potential correlate for genomic heterogeneity could predict those patients most likely to benefit from Nivolumab. Methods: A single centre retrospective analysis was undertaken of patients with NSCLC previously treated with platinum doublet chemotherapy who underwent nivolumab immunotherapy. Texture analysis was used to quantify heterogeneity within the single largest tumour site identified on contrast enhanced CT of the thorax prior to commencement of immunotherapy. Based on histogram analysis of tumour regions processed to highlight image features of 4mm radius, tumours were classified as hyperdense (positive skewness) or hypodense (negative skewness) and then sub-classified based on their median standard deviation value (SD). Progression-free survival (PFS) was assessed for each group using Kaplan-Meier analysis. Results: A total of 47 patients were included in the study, median age 64 (47-84) years. Squamous (N = 21) and non-squamous (N = 26) histology were included. All patients had progressed on prior platinum doublet chemotherapy except one who developed toxicity. Nivolumab was discontinued (N = 37) due to progression (N = 34) and toxicity (N = 3), with treatment ongoing in the remaining patients (N = 10). With a median follow up of 18 months, hyperdense tumours with low SD (n = 14), findings consistent with tumour heterogeneity, showed significantly longer PFS compared to the hypodense group (median NR versus 1.5 months, Hazard Ratio: 2.05, p = 0.018). At 12 months more patients had not progressed in the hyperdense group (53%) versus the hypodense group (12%). Conclusions: This to date is the first preliminary study of quantitative CT texture assessment for tumour heterogeneity in

Background: CheckMate 227 (NCT02477826) is a large phase 3 study of 1L nivo + ipi, nivo, or nivo + chemo vs chemo in advanced NSCLC. The study met its co-primary endpoint demonstrating significantly prolonged progression-free survival with nivo + ipi vs chemo in patients (pts) with tumor mutational burden ≥10 mutations/Mb. The safety profile of 1L nivo + low-dose ipi was consistent with previous reports. Additional detailed analyses may inform the management of immune-related adverse events. Methods: Pts (N = 1739) with chemo-naive, stage IV/recurrent NSCLC without known sensitizing EGFR/ALK mutations were randomized 1:1:1 to nivo (3 mg/kg Q2W) + ipi (1 mg/kg Q6W), nivo monotherapy (240 mg Q2W), or chemo for pts with ≥1% tumor PD-L1 expression and to nivo + ipi, nivo (360 mg Q3W) + chemo, or chemo for pts with < 1% tumor PD-L1 expression. Tx continued until disease progression or unacceptable toxicity for up to 2 yr. Safety and PROs were exploratory endpoints. Safety analyses included time to onset and resolution of select treatment-related adverse events (select TRAEs; those with a potential immunologic cause) and corticosteroid use. PROs were assessed using the Lung Cancer Symptom Scale and EQ-5D instruments. Results: Minimum follow-up was 11.2 mo. Median duration of therapy was 4.2 mo with nivo + ipi and 2.6 mo with chemo. Rates of any grade and grade 3–4 TRAEs were 75% and 31% with nivo + ipi, and 81% and 36% with chemo, respectively. TRAEs led to discontinuation in 17% of pts receiving nivo + ipi and in 9% of pts receiving chemo. Most frequent grade 3–4 select TRAEs in pts receiving nivo + ipi were hepatic (8%), endocrine (4%), skin (4%), pulmonary (3%), and gastrointestinal (2%). Median time to onset of select TRAEs ranged from 2–15 wk, and the majority resolved with corticosteroid use (median time to resolution was ≤10 wk). PRO results will be reported in the final presentation. Conclusions: In CheckMate 227, nivo + low-dose ipi was well tolerated in NSCLC. T

Background: DREAM is an open-label, single arm, multi-centre, phase II trial with a safety run in designed to determine the activity, safety and tolerability of durvalumab combined with cisplatin and pemetrexed as first line therapy in malignant pleural mesothelioma (MPM). ANZ Clinical trial registry number: ACTRN12616001170415. Methods: Chemotherapy-naïve patients with MPM of all histological subtypes, planned for first-line cisplatin and pemetrexed who had not received prior radiotherapy and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 were eligible. Patients received durvalumab (1125mg), cisplatin (75mg/m2) and pemetrexed (500mg/m2) 3-weekly for a maximum of 6 cycles, followed by durvalumab alone (1125 mg 3-weekly) until progression or to 12 months total therapy. Primary endpoint was progression-free survival at 6 months (PFS6). The design provides >90% power if the true PFS6 rate is 65%, with 5% type I error using an expected PFS6 from standard treatment of 45%. Matching tissue and bloods were collected for translational research. Results: Between Dec 2016 to Sep 2017 54 participants were recruited. The median age was 68 (42-82) with 82% male and 60% ECOG 0. They received a median of 6 cycles of chemotherapy (range 1-6) and 7 of durvalumab (given with and without chemotherapy) (range 1-18). The 6-patient safety run in confirmed the tolerability of chemoimmunotherapy. In the first 31 evaluable patients (pre-specified primary interim analysis), PFS6 based on modified RECIST (mRECIST) for MPM was 71%. The objective response rate (ORR) was 61% using mRECIST and 53% using iRECIST. Thirty-one patients (57%) experienced adverse events (AEs) that were grade ≥3. Nineteen patients (35%) had immune-related (ir) AEs including 2 grade 3 irAEs. Conclusions: In MPM, adding durvalumab to first line treatment with cisplatin and pemetrexed had higher rates of PFS6 and ORR than expected for chemotherapy alone, with acceptable tolerability. The final r