ABSTRACT:Older patients with advanced-stage classical Hodgkin lymphoma (cHL) have inferior outcomes compared with younger patients, potentially due to comorbidities and frailty. This noncomparative phase 2 study enrolled patients aged ≥60 years with cHL unfit for conventional chemotherapy to receive frontline brentuximab vedotin (BV; 1.8 mg/kg) with dacarbazine (DTIC; 375 mg/m2) (part B) or nivolumab (part D; 3 mg/kg). In parts B and D, 50% and 38% of patients, respectively, had ≥3 general comorbidities or ≥1 significant comorbidity. Of the 22 patients treated with BV-DTIC, 95% achieved objective response, and 64% achieved complete response (CR). With a median follow-up of 63.6 months, median duration of response (mDOR) was 46.0 months. Median progression-free survival (mPFS) was 47.2 months; median overall survival (mOS) was not reached. Of 21 patients treated with BV-nivolumab, 86% achieved objective response, and 67% achieved CR. With 51.6 months of median follow-up, mDOR, mPFS, and mOS were not reached. Ten patients (45%) with BV-DTIC and 16 patients (76%) with BV-nivolumab experienced grade ≥3 treatment-emergent adverse events; sensory peripheral neuropathy (PN; 27%) and neutropenia (9%) were most common with BV-DTIC, and increased lipase (24%), motor PN (19%), and sensory PN (19%) were most common with BV-nivolumab. Despite high median age, inclusion of patients aged ≤88 years, and frailty, these results demonstrate safety and promising durable efficacy of BV-DTIC and BV-nivolumab combinations as frontline treatment, suggesting potential alternatives for older patients with cHL unfit for initial conventional chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT01716806.

Supplemental Figure 1. Distribution of EGFR extracellular domain (ECD) mutations in ctDNA samples from patients with CRC. Supplemental Figure 2. Response to crizotinib in a patient with small bowel adenocarcinoma and GOPC-ROS1 fusion. Supplemental Figure 3. Detection of copy number amplification is associated with increased ctDNA fraction. Supplemental Table 1. List of 62 genes sequenced in this study using the FoundationACT ctDNA assay. Supplemental Table 2. Genomic alterations detected in temporally matched ctDNA and tissue samples.

Brentuximab vedotin (BV) is approved for the treatment of adults with treatment-naïve stage III or IV classical Hodgkin lymphoma (cHL) combined with doxorubicin, vinblastine, and dacarbazine (AVD) and targets CD30, a receptor expressed on the Reed Sternberg cells. Treatment with BV plus AVD has demonstrated improved overall survival (OS) (6-year OS estimate of 93.9% vs 89.4%; HR, 0.59; 95% CI, 0.40-0.88; P=0.009) compared with the standard chemotherapy combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (Ansell 2022). For patients (pts) newly diagnosed with cHL, current treatment options have improved pt outcomes in recent years, but survival rates are still very low for those with significant comorbidities. Pts with comorbid conditions can have poor outcomes due to decreased ability to tolerate dose intensity, increased treatment-related toxicity, and cHL relapse. This study is evaluating the efficacy and safety of single-agent BV as frontline therapy in cHL pts who are ineligible for conventional combination chemotherapy because of comorbidities. SGN35-015 Part E (NCT01716806) was a phase 2, open-label study of BV as frontline cHL therapy. Eligible pts (≥18 years) were unfit for initial conventional combination chemotherapy for cHL as documented by a modified Cumulative Illness Rating Scale score ≥10 or because they required or depended on others for instrumental activities of daily living. Pts received BV (1.8 mg/kg) on Day 1 of each 3-week cycle for up to 16 cycles. Granulocyte colony-stimulating factor prophylaxis was not required. The primary endpoint, objective response rate (ORR), was assessed by Blinded Independent Central Review (BICR) according to the Modified Lugano Criteria (Cheson 2014). Key secondary endpoints included safety, duration of response (DOR), complete response (CR) rate using the Lugano Criteria (Cheson 2014), duration of CR, progression-free survival (PFS), and OS. Thirty pts with cHL received BV and the median age was 76 years (range, 54 to 93 years). Most pts were female (53%) and had a disease stage of II (37%) or III (37%), an Eastern Cooperative Oncology Group (ECOG) performance status of ≥2 (50%; 10 pts [33%] and 5 pts [17%] had an ECOG performance status of 2 and 3, respectively). The median treatment duration was 18 weeks (range, 1 to 50 weeks). Per BICR, the ORR was 60% (18/30) (95% CI: 40.6%, 77.3%), including 33% (10/30) with a CR and 27% (8/30) with a partial response. Six pts (20%) did not respond to treatment: 1 (3%) with progressive disease and 5 (17%) with stable disease; one pt (3%) was not evaluable and the remaining 5 pts (17%) did not have postbaseline responses, either because of death before first scheduled response assessment or not yet reaching the first scheduled response assessment. Median DOR was 7.4 months (95% CI: 7.4 months, not estimable) and median PFS was 8.7 months (95% CI: 5.1 months, not estimable). Median duration of CR was not estimable (95% CI: 7.4 months, not estimable). With a median follow-up of 14.6 months (range, 0 to 44 months), the 2-year OS rate was 70% (95% CI: 48%, 84%). A total of 18 pts (60%) experienced grade ≥3 treatment-emergent adverse events (TEAEs). The most common grade ≥3 TEAEs were fatigue (n=3; 10%), acute kidney injury, anemia, atrial fibrillation, back pain, gait disturbance, hypoxia, neutrophil count decreased, pneumonia, sepsis, syncope, and vomiting (n=2 each; 7%). Nine pts (30%) discontinued treatment because of a TEAE; 1 death due to a TEAE (failure to thrive) was considered treatment-related. Thirteen percent (n=4) of pts experienced grade ≥3 peripheral neuropathy. In pts with cHL who are unfit for initial conventional chemotherapy due to comorbidities, BV monotherapy as frontline treatment appears effective, has an acceptable safety profile, and despite the small sample size could be considered as an option for pts with cHL who are unfit for conventional chemotherapy.

Background CD40 agonist mAbs can enhance the efficacy of checkpoint blockade in preclinical models and can functionally revive PD-1hi exhausted T cells. This Phase 1 study examined safety, clinical activity, and pharmacodynamics of CDX-1140 as monotherapy or in combination with other agents (NCT03329950). We now report the completed results from Part 3 of the study, combination with anti-PD-1 mAb pembrolizumab. Methods Patients with advanced solid tumors and documented disease progression on a single prior anti-PD-1/L1 based regimen were enrolled. In dose-escalation (DE) cohorts, CDX-1140 was administered at 0.72 mg/kg and 1.5 mg/kg. Expansion cohorts (EX) in non-small cell lung cancer (NSCLC) and squamous cell carcinoma of head and neck (SCCHN) evaluated CDX-1140 1.5 mg/kg. Treatment was q3w co-administered with pembrolizumab 200 mg in both DE and EX. Results 10 patients were treated in DE (renal cell carcinoma n=2, SSCHN n=2, n=1 for NSCLC, endometrial cancer, MSIhi-CRC, ocular melanoma, esophageal adenocarcinoma, MSIhi-cholangiocarcinoma) and 15 patients treated in EX; NSCLC (n=9) and SCCHN (n=6). The median number of prior regimens was 3. Treatment was generally well tolerated, with most treatment-related AEs (TRAE) being grade 1 or 2. The most frequent TRAE at the CDX-1140 1.5 mg/kg dose level (n=21) were arthralgia (62%), fatigue (62%), nausea (48%), diarrhea (48%), vomiting (43%), myalgia (43%), fever (38%), chills (38%), AST increase (38%), bilirubin increase (24%), ALT increase (19%), and cytokine release syndrome (CRS) (19%). Across Part 3, there was 1 complete response (CR) in a patient with oropharyngeal cancer (HPV+ and PD-L1 status unknown); 9 additional patients had stable disease (SD), including 4 with SCCHN and 4 with NSCLC. The patient achieving CR received 4 prior regimens (including chemotherapy, pembrolizumab, and cetuximab), discontinued study therapy after 2 doses due to arthralgia (grade 3) and CRS (grade 2), and initially demonstrated a partial response that evolved into CR, with the response ongoing at 12+ months without further anti-tumor treatment. Of the 4 SCCHN with SD, 2 had target lesions shrinkage (-15% and -18%) and 2 had no change. One NSCLC patient has SD for 10+ months with a nadir in target lesions of -15%. Part 3 biomarker data will be presented. Conclusions CDX-1140 in combination with pembrolizumab had an acceptable safety profile. Evidence of clinical benefit was most evident in patients with SCCHN, all of whom had progressive disease on prior anti-PD-1/L1 based therapies. Further studies are warranted. Trial Registration NCT03329950 Ethics Approval The study was reviewed and approved by the following institutional review boards: Providence Health & Services Institutional Review Board for Earle A. Chiles Research Institute/Providence Cancer Institute; approval number/ID: PHS IRB #2017000532 WCG-IRB for Gabrail Cancer Center, Georgia Cancer Specialists, HonorHealth Research Institute, and Nebraska Cancer Specialists; approval number/ID: 20172645 Rhode Island Hospital IkRB#1 for Legorreta Cancer Center at Brown University/Rhode Island Hospital/Lifespan Cancer Center; approval number/ID: LS-P-Camp Office of Regulatory Affairs of the University of Pennsylvania for Hospital of the University of Pennsylvania; approval number/ID: UPCC 18917 Memorial Sloan Kettering Cancer Center Institutional Review Board/Privacy Board; approval number/ID: 18-225 Participants gave informed consent before taking part in the study.

CIRT is a potent, selective pan CLK/DYRK inhibitor that modulates alternative splicing. CIRT is being evaluated in two ongoing phase I studies, a first in human (FIH) and combination trial. Preliminary data from these studies are presented. The FIH study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy of CIRT in pts with advanced solid tumors. The FIH trial included dose escalation (10-60mg daily (qd), 80 mg 2 days on/5 days off (2/5), and 80 mg 7 days on/7 days off (7/7)) and dose finding (30mg qd and 40-160mg 5 days on/2 days off (5/2)) cohorts. The phase Ib study combines CIRT with abiraterone acetate, FOLFIRI-panitumumab, or docetaxel in advanced/metastatic CRPC, CRC, and NSCLC, respectively. Sixty-five subjects participated in the FIH trial. Systemic exposures of CIRT were dose-dependent with an effective terminal half-life > 24 hours. Drug accumulation was 1-2 fold using the 5/2 schedule. PK/PD evaluation from whole blood provided evidence of modulation of CLK1 and SRSF5 with the latter showing a greater effect with increasing exposure. The MTD of CIRT was 120mg (5/2 schedule). Safety and DLTs were as follows: the most common adverse events (AEs) were diarrhea (60%), nausea (60%), fatigue (40%), and vomiting (38.4%); Grade 3 or higher AEs included anemia (15.4%) and diarrhea (10.8%); DLTs included elevated LFTs (40mg qd, 1 subject), diarrhea (80mg 7/7 and 120mg 5/2, 2 subjects), and rash (160 mg 5/2, 1 subject). CIRT monotherapy led to tumor shrinkage (> 10% to < 29%) in 5 pts, PSA30 in 3 CRPC pts, and long-term stable disease (on study > 6 cycles) in 10 pts. In addition, 4 pts with CRPC (1 ARV7+) had a decline in circulating tumor cells. In the phase Ib combination study, in CRPC subjects that would be considered hormonal therapy resistant, we observed 2 PSA50s and 2 PSA30s among 5 subjects treated with at least 2 cycles of therapy. Findings from these 2 studies provide evidence of clinical activity with manageable toxicity for CIRT in an advanced cancer patient population and suggest hormonal therapy resistance can be overcome in CRPC subjects when CIRT is combined with abiraterone acetate.

BACKGROUND:The Janus kinase (JAK)/signal transducers and activators of transcription pathway has been implicated in the pathogenesis and progression of various hematologic malignancies. JAK1-regulated cytokines stimulate proliferation and growth of malignant cells and resistance to certain therapies.PATIENTS AND METHODS:This phase 1/2 study evaluated 2 oral, novel JAK1 inhibitors (INCB052793 and itacitinib) in advanced hematologic malignancies. Phase 1a assessed dose escalation and expansion of INCB052793 monotherapy. Phase 1b evaluated INCB052793 plus standard therapy in relapsed/refractory multiple myeloma, acute myeloid leukemia (AML), or myelodysplastic syndrome (MDS). Phase 2 evaluated INCB052793 or itacitinib plus azacitidine in DNA methyltransferase inhibitor (DNMTi)-refractory AML or MDS. Primary endpoints included safety and tolerability for phase 1, and objective response rate for phase 2.RESULTS:Fifty-eight patients were enrolled, all received study treatment and discontinued either treatment or participation in the study. The most common reasons for treatment discontinuation were progressive disease (35.4% and 50.0%) and adverse events (22.9% and 20.0%) for INCB052793 and itacitinib plus azacitidine, respectively. In phase 1, 12 of 39 patients (31%) achieved an objective response; 35 mg once daily was selected as the phase 2 dose. Two patients with DNMTi-refractory disease had an objective response in phase 2. The study was terminated for lack of efficacy.CONCLUSION:Inhibition of JAK1 with INCB052793 (monotherapy or combination therapy) or itacitinib plus azacitidine did not demonstrate clinically meaningful responses in these patients with hematopoietic malignancies.

BackgroundCurrently approved first-line immunotherapy plus chemotherapy combination options for extensive-stage small-cell lung cancer (ES-SCLC) result in modest improvements in PFS and OS. In the KEYNOTE-604 study, pembrolizumab plus etoposide-platinum (EP) chemotherapy significantly improved PFS vs placebo plus EP as first-line therapy for ES-SCLC (HR, 0.75; 95% CI, 0.61–0.91; P = 0.0023); OS was prolonged but not significantly (HR, 0.80; 95% CI, 0.64–0.98; P = 0.0164). Exploration of new treatment options based on pembrolizumab is warranted. KEYNOTE-B99 (NCT04924101) is a randomized, phase 2, rolling-arm, multicenter open-label study evaluating pembrolizumab plus EP chemotherapy combined with either MK-4830 (an anti-ILT4 antibody), MK-5890 (an anti-CD27 antibody), or lenvatinib as first-line therapy for ES-SCLC.Trial DesignEligible patients are ≥18 years old with histologically or cytologically confirmed diagnosis of ES-SCLC (stage IV per AJCC 8th edition), measurable disease per RECIST version 1.1, and ECOG performance status of 0/1. All patients receive 4 cycles of chemotherapy Q3W (etoposide 100 mg/m2 for 3 days plus cisplatin 75 mg/m2 or carboplatin area under the concentration-time curve [AUC] 5 mg/mL/min). In addition, patients are randomly assigned to receive pembrolizumab 200 mg Q3W (35 cycles [∼2 years]) plus either MK-4830 800 mg Q3W (35 cycles), MK-5890 30 mg Q6W (18 cycles), or oral lenvatinib 8 mg (induction)/20 mg (maintenance) QD. Randomization is stratified by ECOG-PS (0 or 1) and lactate dehydrogenase (≤upper limit of normal [ULN] or >ULN) at screening. Treatment continues until completion of therapy, disease progression per RECIST version 1.1, or unacceptable toxicity. Approximately 40 participants will be enrolled in each group. Primary endpoints are objective response (complete or partial response) and 6-month PFS, each evaluated per RECIST version 1.1 by blinded independent central review. Secondary endpoints are DOR, PFS, OS, tumor size change, safety, and change from baseline to week 19 in health-related quality of life. Enrollment began on July 15, 2021 and is ongoing.Clinical trial identificationNCT04924101.Editorial acknowledgementWriting support was provided by Lisa Baker, PhD, of ICON plc (North Wales, PA, USA).Legal entity responsible for the studyMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.FundingMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.DisclosureN. Peled: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, MSD, Novartis, Pfizer, Roche, Takeda; Financial Interests, Personal, Advisory Role: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, MSD, Novartis, Pfizer, Roche; Financial Interests, Personal, Funding: MSD Oncology, Roche/Genentech, AstraZeneca, Takeda, Merck Serono, Novartis; Financial Interests, Personal, Other, travel, accommodations, expenses: Roche/Genentech, MSD Oncology, AstraZeneca, Pfizer. D. Rodriguez-Abreu: Financial Interests, Personal, Other, Personal fees/honoraria for consultancy and lectures: Roche, AstraZeneca, Bristol-Myers Squibb, MSD, Eli Lilly, Pfizer, and Novartis; Financial Interests, Personal, Other, travel expenses: Roche, Bristol-Myers Squibb, MSD and Novartis; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb. R. Bordoni: Financial Interests, Personal, Advisory Role: AstraZeneca, Guardant Health, PhillipsGilmore Oncology; Financial Interests, Personal, Speaker's Bureau: AstraZeneca, Guardant Health, OncLive Clinical Congress Consultants, NeoGenomics. P.M. Ellis: Financial Interests, Personal, Invited Speaker: AstraZeneca, Pfizer, Eli Lilly, and Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Pfizer, Takeda, Eli Lilly, Bristol Myers Squibb, Merck, Jazz Pharmaceuticals, Novartis, and Janssen. M. Hochmair: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, and Roche; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Novartis, and Roche. V. Müller: Financial Interests, Personal, Other, Consultation fees : MSD and Roche. H. Zhou: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. B. Zhao: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc., Kenilworth, NJ, USA. H. Lara-Guerra: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc., Kenilworth, NJ, USA and Aeglea Biotherapeutics. M. Ahn: Financial Interests, Personal, Advisory Board: AstraZeneca, Lilly, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, ONO, Bristol Myers Squibb, Takeda, Amgen, Novartis, and Roche; Financial Interests, Personal, Other, consultant role: Alpha Pharmaceutical Company, AstraZeneca, Lilly, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, ONO, Bristol Myers Squibb, Takeda, Amgen, Novartis, and Roche. All other authors have declared no conflicts of interest. BackgroundCurrently approved first-line immunotherapy plus chemotherapy combination options for extensive-stage small-cell lung cancer (ES-SCLC) result in modest improvements in PFS and OS. In the KEYNOTE-604 study, pembrolizumab plus etoposide-platinum (EP) chemotherapy significantly improved PFS vs placebo plus EP as first-line therapy for ES-SCLC (HR, 0.75; 95% CI, 0.61–0.91; P = 0.0023); OS was prolonged but not significantly (HR, 0.80; 95% CI, 0.64–0.98; P = 0.0164). Exploration of new treatment options based on pembrolizumab is warranted. KEYNOTE-B99 (NCT04924101) is a randomized, phase 2, rolling-arm, multicenter open-label study evaluating pembrolizumab plus EP chemotherapy combined with either MK-4830 (an anti-ILT4 antibody), MK-5890 (an anti-CD27 antibody), or lenvatinib as first-line therapy for ES-SCLC. Currently approved first-line immunotherapy plus chemotherapy combination options for extensive-stage small-cell lung cancer (ES-SCLC) result in modest improvements in PFS and OS. In the KEYNOTE-604 study, pembrolizumab plus etoposide-platinum (EP) chemotherapy significantly improved PFS vs placebo plus EP as first-line therapy for ES-SCLC (HR, 0.75; 95% CI, 0.61–0.91; P = 0.0023); OS was prolonged but not significantly (HR, 0.80; 95% CI, 0.64–0.98; P = 0.0164). Exploration of new treatment options based on pembrolizumab is warranted. KEYNOTE-B99 (NCT04924101) is a randomized, phase 2, rolling-arm, multicenter open-label study evaluating pembrolizumab plus EP chemotherapy combined with either MK-4830 (an anti-ILT4 antibody), MK-5890 (an anti-CD27 antibody), or lenvatinib as first-line therapy for ES-SCLC. Trial DesignEligible patients are ≥18 years old with histologically or cytologically confirmed diagnosis of ES-SCLC (stage IV per AJCC 8th edition), measurable disease per RECIST version 1.1, and ECOG performance status of 0/1. All patients receive 4 cycles of chemotherapy Q3W (etoposide 100 mg/m2 for 3 days plus cisplatin 75 mg/m2 or carboplatin area under the concentration-time curve [AUC] 5 mg/mL/min). In addition, patients are randomly assigned to receive pembrolizumab 200 mg Q3W (35 cycles [∼2 years]) plus either MK-4830 800 mg Q3W (35 cycles), MK-5890 30 mg Q6W (18 cycles), or oral lenvatinib 8 mg (induction)/20 mg (maintenance) QD. Randomization is stratified by ECOG-PS (0 or 1) and lactate dehydrogenase (≤upper limit of normal [ULN] or >ULN) at screening. Treatment continues until completion of therapy, disease progression per RECIST version 1.1, or unacceptable toxicity. Approximately 40 participants will be enrolled in each group. Primary endpoints are objective response (complete or partial response) and 6-month PFS, each evaluated per RECIST version 1.1 by blinded independent central review. Secondary endpoints are DOR, PFS, OS, tumor size change, safety, and change from baseline to week 19 in health-related quality of life. Enrollment began on July 15, 2021 and is ongoing. Eligible patients are ≥18 years old with histologically or cytologically confirmed diagnosis of ES-SCLC (stage IV per AJCC 8th edition), measurable disease per RECIST version 1.1, and ECOG performance status of 0/1. All patients receive 4 cycles of chemotherapy Q3W (etoposide 100 mg/m2 for 3 days plus cisplatin 75 mg/m2 or carboplatin area under the concentration-time curve [AUC] 5 mg/mL/min). In addition, patients are randomly assigned to receive pembrolizumab 200 mg Q3W (35 cycles [∼2 years]) plus either MK-4830 800 mg Q3W (35 cycles), MK-5890 30 mg Q6W (18 cycles), or oral lenvatinib 8 mg (induction)/20 mg (maintenance) QD. Randomization is stratified by ECOG-PS (0 or 1) and lactate dehydrogenase (≤upper limit of normal [ULN] or >ULN) at screening. Treatment continues until completion of therapy, disease progression per RECIST version 1.1, or unacceptable toxicity. Approximately 40 participants will be enrolled in each group. Primary endpoints are objective response (complete or partial response) and 6-month PFS, each evaluated per RECIST version 1.1 by blinded independent central review. Secondary endpoints are DOR, PFS, OS, tumor size change, safety, and change from baseline to week 19 in health-related quality of life. Enrollment began on July 15, 2021 and is ongoing. Clinical trial identificationNCT04924101. NCT04924101. Editorial acknowledgementWriting support was provided by Lisa Baker, PhD, of ICON plc (North Wales, PA, USA). Writing support was provided by Lisa Baker, PhD, of ICON plc (North Wales, PA, USA). Legal entity responsible for the studyMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. FundingMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

INTRODUCTION:We report the final results of the phase 3 IMpower132 study evaluating atezolizumab plus carboplatin or cisplatin plus pemetrexed (APP) in patients with nonsquamous NSCLC. METHODS:Chemotherapy-naive patients with stage IV nonsquamous NSCLC without sensitizing EGFR or ALK genetic alterations were randomized in a one-to-one ratio to receive four or six cycles of carboplatin or cisplatin plus pemetrexed (PP) or APP every 3 weeks, followed by maintenance therapy with atezolizumab plus pemetrexed or pemetrexed alone. Co-primary end points were overall survival (OS) and investigator-assessed progression-free survival (PFS). RESULTS:The intention-to-treat population included 578 patients (APP, n = 292; PP, n = 286). At the primary PFS analysis (May 22, 2018; median follow-up, 14.8 mo), APP exhibited significant PFS improvement versus PP (median = 7.6 versus 5.2 mo, stratified hazard ratio [HR] = 0.60, 95% confidence interval [CI]: 0.49-0.72, p < 0.0001). OS for the APP group was numerically better but not statistically significant at the interim (May 22, 2018; median = 18.1 versus 13.6 mo, stratified HR = 0.81, 95% CI: 0.64-1.03, p = 0.0797) and final analyses (July 18, 2019; median = 17.5 versus 13.6 mo; stratified HR = 0.86, 95% CI: 0.71-1.06, p = 0.1546). The OS and PFS results favored APP versus PP across subgroups. Grade 3 or 4 treatment-related adverse events occurred in 54.6% (APP) and 40.1% (PP) of patients; grade 5 treatment-related events occurred in 3.8% and 2.9%, respectively. CONCLUSIONS:IMpower132 met its co-primary PFS end point but not its co-primary OS end point, with numerical improvement for OS in the APP arm. APP had a manageable safety profile, with no new or unexpected safety signals identified.

The Phase III IMpower132 study, evaluating first line pemetrexed plus carboplatin/cisplatin with or without atezolizumab in Stage IV non-squamous NSCLC without EGFR or ALK driver mutations, has met its PFS endpoint with an HR of 0.60 (95% CI: 0.49, 0.72; P < 0.0001; Papadimitrakopoulou, WCLC 2018). Here we present the final OS and safety results. Patients were randomised 1:1 to 4 or 6 cycles of carboplatin AUC 6 mg/mL/min or cisplatin 75 mg/m2 + pemetrexed 500 mg/m2 Q3W alone (arm PP) or with atezolizumab 1200 mg Q3W (arm APP), followed by pemetrexed (PP) or atezolizumab + pemetrexed (APP) maintenance. Investigator-assessed PFS and OS were co-primary endpoints. Efficacy by PD-L1 status was an exploratory endpoint. At data cutoff (18 July 2019), 292 patients in arm APP and 286 patients in arm PP had a median follow-up of 28.4 mo. Updated median PFS was 7.7 months (APP) vs 5.2 months (PP); HR, 0.56 (95% CI: 0.47, 0.67). Final OS data are in the table. 38.7% (APP) vs 57.3% (PP) of patients received subsequent anti-cancer therapy, including immunotherapy in 5.5% vs 45.8%. Grade ≥ 3 treatment-related adverse events (AEs) occurred in 58.4% (APP) vs 43.1% (PP) of patients, including immune-mediated AEs in 6.9% (APP) vs 4.7% (PP) of patients.Table: 375OAPPPPITTn = 292n = 286mOS (95% CI), mo17.5 (13.2, 19.6)13.6 (11.0, 15.7)HRa (95% CI; P value)0.86 (0.71, 1.06; P = 0.155)12-Month OS59.7%55.0%24-Month OS39.1%34.0%PD-L1–highbn = 25n = 20mOS (95% CI), moNE (22.4, NE)26.9 (4.7, NE)HR (95% CI)0.73 (0.31, 1.73)PD-L1–lowbn = 63n = 73mOS (95% CI), mo12.7 (8.7, 18.2)16.2 (9.6, 22.6)HR (95% CI)1.18 (0.80, 1.76)PD-L1–negativebn = 88n = 75mOS (95% CI), mo15.9 (11.6, 22.6)10.5 (8.1, 13.5)HR (95% CI)0.67 (0.46, 0.96)NE, not estimable. a Stratified. b PD-L1 status available in 60% of pts. PD-L1–high: ≥ 50% TC or ≥ 10% IC; PD-L1–low: ≥ 1% and < 50% TC or ≥ 1% and < 10% IC; PD-L1–negative: < 1% TC and < 1% IC. Open table in a new tab . NE, not estimable. a Stratified. b PD-L1 status available in 60% of pts. PD-L1–high: ≥ 50% TC or ≥ 10% IC; PD-L1–low: ≥ 1% and < 50% TC or ≥ 1% and < 10% IC; PD-L1–negative: < 1% TC and < 1% IC. IMpower132 had met its co-primary PFS endpoint at the primary analysis but did not meet its co-primary OS endpoint in this final analysis. Atezolizumab + carboplatin/cisplatin + pemetrexed was well tolerated, and no new safety signals were identified.

8032 Background: Older patients with classical Hodgkin lymphoma (cHL) have poor outcomes relative to younger patients, often due to comorbidities and toxicities related to standard first-line (1L) chemotherapy (5-yr PFS: 30%–45% vs 75%–80%) (Evens 2008; Proctor 2009). Brentuximab vedotin (BV, ADCETRIS®), a CD30-directed antibody-drug conjugate, has robust activity in patients refractory to several lines of chemotherapy. Methods: This phase 2, open-label study, SGN35-015 (NCT01716806), evaluated efficacy and tolerability of BV alone or combined with single-agents in treatment-naive cHL patients ≥60 yr. The full-analysis set (FAS) includes all patients who received BV (1.8 mg/kg IV). Patients in Part A received BV monotherapy on Day 1 of every 3-week cycle (n = 26); Part B: BV+dacarbazine (DTIC; 375 mg/m2; n = 19); Part C: BV+bendamustine (benda; 70 mg/m2; n = 20); and Part D: BV+nivolumab (nivo; 3 mg/kg; n = 20). The efficacy evaluable (EE) set includes all patients who had at least 1 post-baseline response assessment (n = 25, 19, 17, 19). Results: Demographic characteristics were generally similar: median age 78, 69, 75, and 72 yr in Parts A, B, C, and D, respectively, and 62% of patients (range 45%–70%) reported impaired physical functioning at baseline. Most patients had disease stage III/IV (62%, 68%, 75%, 80%), were ECOG 0/1 (77%, 74%, 80%, 95%), and male (54%, 68%, 50%, 75%). Median time from diagnosis was 1.2 to 1.5 mo (FAS; 10 Jan 2019 data cutoff). ORR were high (92%, 100%, 100%, 95%) at a median follow-up of 59.4, 58.6, 51.3, and 19.4 mo in the EE data set. Median OS in the FAS set was 77.5 mo with monotherapy; 64.0, 46.9, and not reached in the combination parts. Treatment-related AE ≥ Grade 3 occurred in 50%, 37%, 70%, and 60% of patients; peripheral neuropathy (PN) was most common (35%, 26%, 20%, 35%). Treatment-related SAEs occurred in 12%, 11%, 40%, and 5% of patients. Part C enrollment (BV+benda) closed early due to multiple acute toxicities. There were no treatment-related deaths in any part of the study. The median treatment cycles per patient were 8.0, 12.0, 5.0, and 14.5. Treatment discontinuation due to related AEs occurred in 42%, 42%, 40%, and 30% of patients, most commonly due to PN (38%, 37%, 30%, 20%). Conclusions: Older patients with cHL and multiple comorbidities have very high response rates with BV as monotherapy or combined with other single agents and improved tolerability versus combination chemotherapy. Median overall survival exceeded 6 yr with BV monotherapy. BV+nivo or BV+DTIC appeared to be the most reasonable combination treatment options in this study. Clinical trial information: NCT01716806 .

Background CDX-1140 is an agonist anti-CD40 mAb selected to optimize systemic exposure and hence tumor microenvironment (TME) ingress. CDX-1140 activity may be enhanced by combining with CDX-301 (recombinant Flt3L), a dendritic cell growth factor, or with pembrolizumab, an anti-PD-1 mAb. Methods Patients with advanced solid or hematologic (Part 1 only) tumors are enrolled. Part 1 dose-escalation results have been presented (SITC 2019). In Part 2, CDX-1140 dose-escalation (0.09–1.5 mg/kg q4w) is in combination with CDX-301 (75 mcg/kg sc QD x 5 for 2 cycles). In Part 3, CDX-1140 dose-escalation (0.72–1.5 mg/kg q3w) is in combination with pembrolizumab 200 mg q3w. Part 1 and 2 expansion cohorts are dosed at the CDX-1140 MTD, 1.5 mg/kg q4w. Part 3 expansion cohorts are planned. Peripheral blood and tumor biomarkers analysis are ongoing. Results 92 patients have been treated (Part 1 n=57, Part 2 n=31, Part 3 n=4). Part 1 expansion cohorts in SCCHN (n=7) and RCC (n=5) are fully enrolled. Part 2 dose-escalation completed to the highest CDX-1140 dose and a SCCHN expansion cohort is ongoing. Part 3 dose-escalation recently initiated. Safety data is available for 23 and 10 patients at the MTD in Part 1 and 2, respectively. In general, the safety profiles were similar, with arthralgia (52% vs. 50%), pyrexia (44% vs 50%), fatigue (30% vs. 50%), chills (39% vs. 40%), vomiting (30% vs. 20%), nausea (26% vs 40%), myalgia (22% vs. 30%), increased ALT (22% vs. 20%), and increased AST (22% vs. 30%) being the most common drug related AEs at the MTD in Part 1 and 2, respectively. Most AEs were low grade. Across all cohorts, cytokine release syndrome (CRS) (G2 n=4, G3 n=2) occurred in 6 (Part 1 n=2; Part 2 n=4) and pneumonitis (G3) occurred in 5 (Part 1 n=4; Part 2 n=1) patients. Immune activation in the TME consistent with CD40 agonism and increases serum inflammatory cytokines were observed. Evidence of anti-tumor activity/clinical benefit include SD (n=13), tumor cavitation (n=2) and a uPR in solid tumors. A patient with follicular lymphoma has an ongoing durable complete metabolic response. Conclusions The CDX-1140 MTD dose of 1.5 mg/kg, a dose level expected to provide good systemic exposure and TME penetration, is generally well tolerated alone and with CDX-301. Transaminitis and CRS have generally been low grade and infrequent. A cohort combining CDX-1140 with chemotherapy will be initiated in patients with previously untreated metastatic pancreatic adenocarcinoma. Trial Registration NCT03329950 Ethics Approval The study was approved by the following: Providence St. Joseph Health IRB, approval number MOD2020001128; WIRB, approval number 1188814 (Hauke, Gabrail, Bordoni & Gordon); University of Pennsylvania IRB, approval number UPCC 18917; Mount Sinai School of Medicine IRB, approval number 18-00202; Memorial Sloan Kettering Cancer Center IRB, approval number 18-225A; Houston Methodist IRB, approval number MOD00000836

Background Despite the advances in therapy of classical Hodgkin lymphoma (cHL) and CD30-expressing peripheral T-cell lymphoma (PTCL) over the years, the outcomes seen in younger patients with the disease have not been attained in patients ≥60 years of age. Studies cite 5-year progression-free survival (PFS) and freedom from treatment failure rates of 30%-45% in older patients with HL, as compared to rates of 75%-80% expected in younger patients (Evens 2008; Proctor 2009). In a recent retrospective study of patients >60 years of age diagnosed with PTCL between 2008-2014, a multivariate analysis demonstrated that a Charlson Comorbidity Index (CCI) ≥2 and high IPI score (3-5) were independent risk factors for worse overall survival (OS) and PFS (Zhao 2016). Similarly, multivariate analysis of registry data from Sweden shows that a CCI ≥2, when adjusted for age, is independently associated with worse OS and PFS outcomes (Ellin 2018). There is no standard treatment regimen for elderly patients with cHL and PTCL, and co-morbidities including depressed cardiac and renal function limit the ability to use combination chemotherapy, and represent a high unmet need. Brentuximab vedotin (BV, ADCETRIS®) is a CD30-directed antibody-drug conjugate (ADC) consisting of the chimeric IgG1 antibody cAC10, specific for human CD30; the microtubule-disrupting agent monomethyl auristatin E (MMAE); and a protease-cleavable linker that covalently attaches MMAE to cAC10. Following the binding of BV to CD30-expressing cells, the ADC-CD30 complex is internalized, and MMAE released via proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest and apoptosis. Single-agent BV has demonstrated robust activity in patients with HL refractory to several lines of chemotherapy and the ECHELON-1 study (Connors 2017) established its efficacy in combination with chemotherapy for the front line treatment of HL. In a phase 2 study of single-agent BV in 27 patients aged ≥ 60 years with HL, there was an objective response rate of 92%, with 73% achieving complete remission (Forero-Torres, 2015). For CD30-expressing PTCL, single-agent BV is an active and well-tolerated treatment for patients with relapsed or refractory disease (Horwitz 2014) and the ECHELON-2 study showed that the addition of BV to combination chemotherapy in the frontline treatment improves both PFS and OS (Horwitz 2018). In the elderly patient populations who are not candidates for multi-agent chemotherapy, frontline treatment with single-agent BV may have the potential to be an active and well-tolerated treatment. Study Design Two additional cohorts have been added to the SGN35-015 phase 2 open-label study (NCT01716806) to evaluate the efficacy and tolerability of BV as monotherapy in treatment-naive patients with cHL, which excludes nodular lymphocyte-predominant HL (Part E) or treatment-naive patients with CD30-expressing PTCL (Part F). The primary objective of these cohorts is to assess objective response rates of single-agent BV as frontline therapy in patients ≥60 years of age and ineligible for conventional chemotherapy for HL (Part E) or CD30-expressing PTCL (Part F). Eligible patients in Parts E and F must be ≥75 years or ≥60 years of age and have one of the following: confirmed ejection fraction <45% or estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 and <50 mL/min/1.73 m2, as determined by the Modification of Diet in Renal Disease study equation. Approximately 30 evaluable patients will be enrolled in Parts E and F of the study and administered BV 1.8 mg/kg as a single intravenous infusion on Day 1 of each 21-day cycle. Patients achieving a complete remission, partial remission, or stable disease will receive up to 16 cycles of treatment. Treatment response will be assessed by spiral CT scans of the chest, abdomen, and pelvis and PET scans at Cycles 2, 6, and 11. Response assessment will be determined by blinded independent central review. Disclosures Yasenchak: BMS: Consultancy; Seattle Genetics: Consultancy. Bordoni:Phillips & Gilmore: Honoraria; Genentech: Speakers Bureau; Merck: Speakers Bureau; Seattle Genetics, Inc.: Research Funding; Practice Point Communication: Honoraria; Deciphera: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Honoraria; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Yazbeck:Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Research Funding. Patel-Donnelly:Seattle Genetics, Inc.: Research Funding. Larson:Seattle Genetics, Inc.: Research Funding. Newhook:Seattle Genetics, Inc.: Employment. Ho:Seattle Genetics, Inc.: Employment, Equity Ownership. Mei:Seattle Genetics, Inc.: Research Funding.

Background. In patients with Hodgkin lymphoma (HL) aged ≥60 years, comorbidities and treatment-related toxicities often prevent delivery of optimal intensity and/or duration of standard frontline chemotherapy. Brentuximab vedotin (BV) and nivolumab (Nivo) have two distinct mechanisms of action, tolerability of the combination has been observed in relapsed/refractory HL in a phase 1/2 study (85% objective response rate [ORR]; 62% complete remission [CR] rate) (Herrera 2017); thus, our phase 2 study was amended to evaluate this combination in a cohort of newly diagnosed HL patients aged ≥60 years (NCT01716806). Methods. Eligible subjects have treatment-naive classical HL and are ineligible for or declined initial conventional combination chemotherapy (planned N = 20). Subjects received BV 1.8 mg/kg + Nivo 3 mg/kg as well as prophylactic premedication for infusion-related reactions on Day 1 of each 3-week cycle for ≤16 cycles. CT/PET scans were performed at Cycles 2 (CT only), 4, 8, 12, and 16 (assessed per Lugano Classification Revised Staging System [Cheson 2014] and Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) [Cheson 2016]). The primary objective is ORR. Results. Twenty-one subjects received BV + Nivo (median age, 72 years [range, 60-88]). The majority had an ECOG performance status of 0/1 (95%), Stage III/IV disease (77%), and presented with B symptoms at baseline (57%). In this elderly population, 48% had bulky disease and 38% had extranodal disease at the initial diagnosis. Of the 21 subjects treated, 7 remain on treatment, 2 discontinued treatment due to progressive disease, 6 completed treatment, 4 withdrew due to subject decision, 1 withdrew due to pneumocystis jiroveci pneumonia, and 1 had an unrelated Grade 3 serious adverse event of acute renal failure and sepsis, resulting in death. The most common treatment-related adverse events (TRAE) of any grade were fatigue (48%), peripheral sensory neuropathy (38%), diarrhea, infusion-related reactions, and pyrexia (24% each). No infusion-related reactions required steroid intervention. Among TRAE ≥Grade 3, the most common were elevated lipase (19%) and peripheral motor neuropathy (14%). Three subjects had immune-related AEs with a maximum severity of Grade 3. Three of the 21 subjects treated were not evaluable for efficacy, defined in the protocol as subjects who had both a baseline and at least one post-baseline disease assessment or who had documented progression of disease any time after receiving any amount of BV. Non-evaluable subjects included 1 who died from renal failure prior to assessment, 1 who withdrew consent prior to assessment, and 1 who had not been assessed at the time of the data cutoff. Based on the 18 evaluable subjects, the ORR was 100%, with a 72% CR rate and a 28% PR rate. Conclusions. Elderly HL remains an unmet clinical need. These data suggest that BV + Nivo is an active treatment with an encouraging CR rate (72%) and appears well tolerated in these patients. These results also suggest that with further follow-up and validation, treatment with BV + Nivo may improve patient outcomes. Enrollment in this cohort is complete (21 subjects), with 7 subjects continuing to receive treatment. Disclosures Yasenchak: BMS: Consultancy; Seattle Genetics: Consultancy. Bordoni:Seattle Genetics, Inc.: Research Funding; Practice Point Communication: Honoraria; Phillips & Gilmore: Honoraria; Merck: Speakers Bureau; Genentech: Speakers Bureau; Deciphera: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Honoraria; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Yazbeck:Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Patel-Donnelly:Seattle Genetics, Inc.: Research Funding. Anderson:Seattle Genetics, Inc.: Research Funding. Larson:Seattle Genetics, Inc.: Research Funding. Newhook:Seattle Genetics, Inc.: Employment. Mei:Seattle Genetics, Inc.: Research Funding. Ho:Seattle Genetics, Inc.: Employment, Equity Ownership. Friedberg:Bayer: Honoraria, Other: Data & Safety Monitoring Committee; Acerta: Other: Data & Safety Monitoring Committee.

Approximately one third of patients with NSCLC have tumours harbouring actionable EGFR mutations (Zhang et al. Oncotarget 2016). These patients are routinely treated with EGFR-tyrosine kinase inhibitors (TKIs) that are approved based on their efficacy and safety in clinical trials. Clinical trials do not fully reflect patient experiences as felt and perceived by patients, and in the real world, symptoms related to EGFR-TKIs and impact on patients' daily lives are not well documented or understood. EP1C assessed patients' experience with EGFR-TKIs and their impact on patients' daily lives. Patient insights gained from EP1C can help guide symptom management strategies and improve communication with patients, helping to improve outcomes and quality of life. This pilot, non-interventional, US-based, real-world study involved individual interviews with adult patients. Eligible patients were those diagnosed with EGFR-mutated metastatic NSCLC, taking one of three US-approved EGFR-TKIs (erlotinib/afatinib/osimertinib) as first-line treatment. Exclusion criteria included: major surgery or radiation therapy three months before treatment, chemotherapy or other therapy as first-line treatment, a second active cancer, or a cognition or sensory issue. Trained qualitative interviewers used a semi-structured interview guide, and conducted all interviews by telephone. Rating questions were included for the severity and degree of bother caused by their symptoms (0–10 point response scale: 0=not at all severe, 10=extremely severe). All interviews were audio recorded, transcribed and coded (ATLAS.ti software) for analysis of similar themes. A total of 19 patients participated in the interviews. The average age was 54.0 years (range 37–76). The sample was 73.7% female (n=14), and 89.5% (n=17) had an education level of college or above. The most frequently reported symptoms were respiratory and gastrointestinal symptoms (n=18; 94.7% each), skin-related sympoms (n=18; 94.7%), discomfort and pain (n=17; 89.5%), hair and nail-related symptoms (n=17; 89.5% each), fatigue and other energy-related symptoms (n=15; 78.9%). Ratings of severity and bothersomeness trended toward the mid-range of the scale (4.0 to 6.0) for most of the more commonly reported symptoms. The higher ratings were seen for very specific symptoms reported by only one or two patients, including constipation (8.0 severity/8.0 bother), armpit rash (7.0/8.0), tightness in throat (8.0/8.0), mouth soreness (8.0/9.0) and stinging/burning in the genital area (10.0/10.0). All 19 patients reported impacts on their daily performance and emotional health. Sleep difficulties were reported by 12 patients (63.2%), and 9 patients (47.4%) reported limitations with inter-personal relationships and social functioning. The impacts on patients' daily activities (work, chores, daily routine; 7.8) and emotions (anxiety, worry, fear and depression; 7.2) were found to be the most difficult to cope with. Several specific impacts, reported by fewer patients, included decreased independence (n=2; 7.0), economic burden (n=6; 7.7), and childcare difficulties (n=2; 8.5). In EP1C, real-world interviews allowed patients to express a broader range of symptoms and impacts compared with clinical trials, which mostly focus on symptoms. Some of the traditionally less commonly reported symptoms had a greater impact on patients' daily lives. Clinicians should also consider these when assisting patients in managing their symptoms.