Investigator-assessed Objective Response Rate Research Articles

ABCL-454: CheckMate 436: Extended Follow-Up from the Phase 2 Study Investigating Nivolumab Plus Brentuximab Vedotin (BV) for Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma (R/R PMBL)

Context R/R PMBL has limited treatment options. CheckMate 436 (NCT02581631), an open-label phase 1/2 study, assessed combination nivolumab (anti–PD-1) and brentuximab vedotin (anti-CD30) in patients with R/R PMBL; the primary analysis (median follow-up 11.1 months) showed an objective response rate (ORR) of 73% and complete remission (CR) rate of 37%. Objective Report extended follow-up data from CheckMate 436. Patients Cohort of patients with R/R PMBL after autologous hematopoietic cell transplantation (auto-HCT) or ≥2 prior multi-agent chemotherapy regimens if ineligible for auto-HCT. Interventions Nivolumab (240 mg IV) + BV (1.8 mg/kg IV) every 3 weeks until disease progression or unacceptable toxicity. Outcome Measure(s) Primary: investigator-assessed ORR (Lugano 2014) and safety. Secondary: duration of response (DOR), CR rate and duration, progression-free survival (PFS), and overall survival (OS). Results Among 30 patients with a median follow-up of 33.7 months, ORR was 73% (95% CI, 54–88; CR, 37%). Median DOR was 31.6 months (95% CI, 23.3–not estimable [NE]), and median duration of CR was not reached. Estimated median PFS was 26.0 months (95% CI, 2.6–NE). Among patients censored in the PFS analysis, 13/17 received consolidation therapy, including auto-HCT (n=6) or allogeneic HCT (n=6) +/- radiotherapy, and radiotherapy alone (n=1). Four patients remained progression free in follow-up for 5+, 9+, 12+, and 20+ months after discontinuation of nivolumab + BV (maximum clinical benefit, n=3; study drug toxicity, n=1) without subsequent therapy. OS was 79% (95% CI, 59–90) at 12 months and 76% (95% CI, 55–88) at 24 months; median OS was not reached. Treatment-related adverse events (TRAEs) occurred in 83% of patients, most frequently neutropenia (30%; all grade 3/4) and peripheral neuropathy (27%; 10% grade 3/4). Six patients discontinued due to TRAEs. Eight patients died, 5 due to disease progression, and none was considered related to treatment. Conclusions Nivolumab + BV demonstrated durable responses and long-term survival benefits; 4 patients remained progression-free without consolidation after nivolumab + BV. Safety was consistent with prior findings. These results further support nivolumab + BV as a treatment option for patients with R/R PMBL. Funding BMS. Previous Presentation: ICML 2021

An open-label phase II study of dostarlimab (TSR-042), bevacizumab (bev), and niraparib combination in patients (pts) with platinum-resistant ovarian cancer (PROC): cohort A of the OPAL trial

Objectives: Preclinical evidence suggests that PARP inhibition (PARPi), anti-PD-1 therapy, and anti-angiogenic therapies have interactions that may support synergistic antitumor activity in pts with PROC. This phase 2 study evaluated activity of combination therapy with the PARPi niraparib, the PD-1 inhibitor dostarlimab, and bev in pts with PROC. Methods: Eligible pts had high-grade, platinum-resistant (progressed ≤6 mo after completion of ≥4 cycles of platinum-based chemo), recurrent epithelial ovarian, fallopian tube, primary peritoneal cancer, or recurrent carcinosarcoma of the ovary (high-grade mixed histology permitted). Pts had 1–2 prior lines of anticancer therapy for OC, and no prior therapy with an anti-PD-1/-L1 or PARPi. Pts received a regimen of 500 mg dostarlimab Q3W x 4, then 1000 mg Q6W + 15 mg/kg bev Q3W + niraparib 300 mg or 200 mg (for weight <77 kg or platelet count <150,000/µL at screening) QD until discontinuation. The primary endpoint was investigator-assessed objective response rate (ORR) per RECIST v1.1. Secondary objectives were progression-free survival (PFS), safety, and disease control rate (DCR). A posthoc analysis by biomarker (BRCA mutation [BRCAm] status, homologous recombination repair mutation [HRRm], and combined positive score [CPS; a measure of intratumoral and immune infiltrate PD-L1 expression], prior lines of therapy, and prior bev use) was performed. Results: Conclusions: Conclusion: Triplet therapy with niraparib, dostarlimab, and bev is tolerable and demonstrated clinical activity in pts with PROC, most of which were BRCA or HRR wt. AEs were as expected. Clinical trial identification: NCT03574779. Funding: GlaxoSmithKline. Preclinical evidence suggests that PARP inhibition (PARPi), anti-PD-1 therapy, and anti-angiogenic therapies have interactions that may support synergistic antitumor activity in pts with PROC. This phase 2 study evaluated activity of combination therapy with the PARPi niraparib, the PD-1 inhibitor dostarlimab, and bev in pts with PROC. Eligible pts had high-grade, platinum-resistant (progressed ≤6 mo after completion of ≥4 cycles of platinum-based chemo), recurrent epithelial ovarian, fallopian tube, primary peritoneal cancer, or recurrent carcinosarcoma of the ovary (high-grade mixed histology permitted). Pts had 1–2 prior lines of anticancer therapy for OC, and no prior therapy with an anti-PD-1/-L1 or PARPi. Pts received a regimen of 500 mg dostarlimab Q3W x 4, then 1000 mg Q6W + 15 mg/kg bev Q3W + niraparib 300 mg or 200 mg (for weight <77 kg or platelet count <150,000/µL at screening) QD until discontinuation. The primary endpoint was investigator-assessed objective response rate (ORR) per RECIST v1.1. Secondary objectives were progression-free survival (PFS), safety, and disease control rate (DCR). A posthoc analysis by biomarker (BRCA mutation [BRCAm] status, homologous recombination repair mutation [HRRm], and combined positive score [CPS; a measure of intratumoral and immune infiltrate PD-L1 expression], prior lines of therapy, and prior bev use) was performed. Conclusion: Triplet therapy with niraparib, dostarlimab, and bev is tolerable and demonstrated clinical activity in pts with PROC, most of which were BRCA or HRR wt. AEs were as expected.

Mesothelin Expression is Correlated with Chemoresistance in Stage IV Colorectal Cancer.

Mesothelin (MSLN) is a cell-surface glycoprotein present on mesothelial cells; its expression in several epithelial cancers generally portends an unfavorable prognosis. We investigated MSLN as a surrogate chemopredictive biomarker and examined the impact of MSLN expression in stage IV colorectal cancer (CRC). We recruited 254 patients with CRC who received systemic chemotherapy following primary tumor resection between 2000 and 2019. Resected specimens were immunostained for MSLN and stratified by MSLN expression. The associations of tumor MSLN expression with tumor response in metastatic lesions and survival were evaluated. Of the 247 patients with stage IV CRC, 41 (16.1%) and 213 (83.9%) had high and low MSLN expression, respectively. Based on the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, the investigator-assessed objective response rate was 22.0% in the high MSLN expression group and 45.5% in the low MSLN expression group (p=0.0050). The disease control rates in these groups were 65.9% and 85.9%, respectively (p=0.00019). In the patients with high MSLN expression, the conversion rate among those with initially unresectable metastases was 0% versus 14% in the patients with low MSLN expression (p=0.0053). The median overall survival (OS) was 1.5 years (95% confidence interval [CI] 1.1-2.8) in the high MSLN expression group versus 2.6 years (95% CI 2.2-3.0) in the low MSLN expression group. The 3-year OS rates in these groups were 23.5 and 41.5%, respectively (p=0.0120). High MSLN expression is correlated with chemoresistance and poor prognoses in stage IV CRC.

Blood First Assay Screening Trial (BFAST) in Treatment-Naive Advanced or Metastatic NSCLC: Initial Results of the Phase 2 ALK-Positive Cohort

IntroductionThe Blood First Assay Screening Trial is an ongoing open-label, multicohort study, prospectively evaluating the relationship between blood-based next-generation sequencing (NGS) detection of actionable genetic alterations and activity of targeted therapies or immunotherapy in treatment-naive advanced or metastatic NSCLC. We present data from the ALK-positive cohort. MethodsPatients aged more than or equal to 18 years with stage IIIB or IV NSCLC and ALK rearrangements detected by blood-based NGS using hybrid capture technology (FoundationACT) received alectinib 600 mg twice daily. Asymptomatic or treated central nervous system (CNS) metastases were permitted. Primary end point was investigator-assessed objective response rate (ORR; Response Evaluation Criteria in Solid Tumors version 1.1). Secondary end points were independent review facility-assessed ORR, duration of response, progression-free survival (PFS), overall survival, and safety. Exploratory end points were investigator-assessed ORR in patients with baseline CNS metastases and relationship between circulating biomarkers and response. ResultsIn total, 2219 patients were screened and blood-based NGS yielded results in 98.6% of the cases. Of these, 119 patients (5.4%) had ALK-positive disease; 87 were enrolled and received alectinib. Median follow-up was 12.6 months (range: 2.6–18.7). Confirmed ORR was 87.4% (95% confidence interval [CI]: 78.5–93.5) by investigator and 92.0% (95% CI: 84.1–96.7) by independent review facility. Investigator-confirmed 12-month duration of response was 75.9% (95% CI: 63.6–88.2). In 35 patients (40%) with baseline CNS disease, investigator-assessed ORR was 91.4% (95% CI: 76.9–98.2). Median PFS was not reached; 12-month investigator-assessed PFS was 78.4% (95% CI: 69.1–87.7). Safety data were consistent with the known tolerability profile of alectinib. ConclusionsThese results reveal the clinical application of blood-based NGS as a method to inform clinical decision-making in ALK-positive NSCLC.

SO-27 Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: 4-year follow-up from CheckMate 142

In the phase 2 multicohort CheckMate 142 study (NCT02060188), nivolumab plus low-dose (1 mg/kg) ipilimumab provided robust and durable clinical benefit with a manageable safety profile in previously treated patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) at a median follow-up of 13.4 months (Overman M et al. J Clin Oncol 2018;36:773–779). At 25.4 months of follow-up, nivolumab plus low-dose ipilimumab continued to provide robust and durable clinical benefit with deepening of response, and no new safety signals were identified (Overman M et al. J Clin Oncol 2019;37:635). Here, we present results from the 4-year follow-up of these patients. Patients received nivolumab (3 mg/kg) + low-dose (1 mg/kg) ipilimumab Q3W (4 doses) followed by nivolumab (3 mg/kg) Q2W until disease progression. Primary endpoint was investigator-assessed objective response rate (ORR; per RECIST v1.1). Other key endpoints reported here include disease control rate (DCR, per investigator), duration of response (DOR, per investigator), progression-free survival (PFS, per investigator), overall survival (OS), and safety. For the 119 treated patients, median age was 58 years, 59% were male, 76% had ≥ 2 prior lines of therapy, 55% had ECOG performance status (PS) 1, 25% had BRAF mutation, 37% had KRAS mutation, and 26% were BRAF/KRAS wild type. Median follow-up was 50.9 months (range, 46.9–62.7 months). Investigator-assessed ORR (95% CI) increased from 55% (45–64) at 13.4 months to 65% (55–73) at 50.9 months; DCR (95% CI) at 50.9 months was 81% (72–87). Complete response (CR) rate increased with longer follow-up from 3% at 13.4 months to 13% at 50.9 months. Partial responses (PR) were observed in 52% of patients; 21% had stable disease (SD), and 12% had progressive disease (PD) as best response. Median time to response was 2.8 months (range, 1.1–37.1 months) and median DOR was not reached (range, 1.4+ to 58.0+ months). At data cutoff, 37 (48%) patients had ongoing responses. Median PFS was not reached (95% CI, 38.4 to not estimable [NE]) and median OS was not reached (95% CI, NE). The 48-month rates of PFS (95% CI) and OS (95% CI) were 53% (43–62) and 70.5% (61.4–77.9), respectively. ORR benefit was observed across evaluated subgroups by BRAF/KRAS mutation status, ECOG PS, age, and sex, and each was consistent with that in the overall population. Grade 3-4 treatment-related adverse events (TRAEs) were observed in 32% of patients; 10% (grade 3-4) and 13% (any grade) of patients had TRAEs leading to discontinuation. Nivolumab plus low-dose ipilimumab provided durable clinical benefit (ORR, PFS, and OS) over 13.4, 25.4, and 50.9 months of follow-up. Extended follow-up showed increasing ORR and deepening of response. The safety profile was manageable with no new safety signals. These results demonstrate long-term benefit of nivolumab plus low-dose ipilimumab for previously treated patients with MSI-H/dMMR mCRC.

Abstract CT025: Dabrafenib plus trametinib in BRAF V600E-mutant high-grade (HGG) and low-grade glioma (LGG)

Abstract Background: More effective treatments are needed to improve outcomes in HGG and LGG. Activating BRAF mutations occur in ~3% of glioblastomas and 15% of LGGs. BRAF inhibitor dabrafenib + MEK inhibitor trametinib combination is FDA-approved in BRAF V600-positive melanoma, NSCLC, and anaplastic thyroid cancer. Methods: We conducted a nonrandomized, open-label, phase 2 basket study (NCT02034110) of dabrafenib + trametinib in pts with BRAF V600E mutation-positive rare cancers; here we report results for the HGG and LGG cohorts. Adult pts with histologically confirmed recurrent/progressive HGG (Grade III, IV) or LGG (Grade I, II) per WHO 2007 classification received oral dabrafenib, 150 mg twice daily, and oral trametinib, 2 mg once daily, until unacceptable toxicity, disease progression, or death. The primary endpoint was investigator-assessed objective response rate (ORR) using RANO criteria. Secondary endpoints included progression-free survival (PFS), duration of response (DOR), overall survival (OS), and safety; molecular characterization of baseline tumor samples was an exploratory endpoint. Results: As of Sept 14, 2020, 45 pts (23 male) were enrolled in the HGG cohort; 35 discontinued, 6 remained on treatment, 4 were in follow up. The majority had glioblastoma (69%), followed by anaplastic pleomorphic xanthoastrocytoma and anaplastic astrocytoma (each 11%); of pts with known IDH/MGMT status, 3/29 pts had IDH1 mutations and 8/17 had MGMT promoter methylation. Prior therapies included radiotherapy (98%), surgery, and chemotherapy (93% each). Median (range) follow-up was 12.7 (1.1-56.1) months (mo); ORR was 33% (3 CR, 12 PR); median DOR was 36.9 mo (95% CI, 7.4-44.2). Median PFS and OS were 3.8 mo (95% CI, 1.8-9.2) and 17.6 mo (95% CI, 9.5-45.2), respectively. The LGG cohort enrolled 13 pts (4 male); 7 discontinued, 5 remained on treatment, 1 was in follow up. Most common histologies were ganglioglioma (31%), diffuse astrocytoma, and pleomorphic xanthoastrocytoma (each 15%); of pts with known IDH/MGMT status, 1/8 pts had IDH1 mutation and 0/2 had MGMT promoter methylation. Prior therapies included surgery (92%), radiotherapy (62%), and chemotherapy (38%). Median (range) follow-up was 32.2 (0.8-71.8) mo; ORR was 69% (1 CR, 6 PR, 2 MR); median DOR, PFS, and OS were not reached. Overall, 54/58 pts (93%) experienced adverse events (AEs) across cohorts, most commonly (≥30%) fatigue (50%), headache (43%), nausea (34%), and pyrexia (33%); 31 pts (53%) had grade ≥3 AEs, most commonly (≥5%) fatigue, decreased neutrophil count (9% each), headache, and neutropenia (5% each). Next-generation sequencing showed a heterogenous landscape and low tumor mutation burden. Conclusions: Dabrafenib + trametinib demonstrated promising efficacy in pts with BRAF V600E mutation-positive recurrent/refractory HGG and LGG. The safety profile was consistent with the known safety profile for other indications. Citation Format: Vivek Subbiah, Alexander Stein, Martin van den Bent, Antje Wick, Filip Y. de Vos, Nikolas von Bubnoff, Myra E. van Linde, Albert Lai, Gerald W. Prager, Mario Campone, Angelica Fasolo, Jose A. Lopez-Martin, Tae Min Kim, Ralf-Dieter Hofheinz, Jean-Yves Blay, Daniel C. Cho, Anas Gazzah, Damien Pouessel, Jeffrey Yachnin, Aislyn Boran, Paul Burgess, Palanichamy Ilankumaran, Eduard Gasal, Patrick Y. Wen. Dabrafenib plus trametinib in BRAF V600E-mutant high-grade (HGG) and low-grade glioma (LGG) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT025.

Abstract CT013: Safety/tolerability and preliminary antitumor activity of sitravatinib plus tislelizumab in patients with advanced platinum-resistant ovarian cancer (PROC)

Abstract Background: Combining a PD-1 inhibitor and an agent with immune modulatory and antitumor properties may enhance antitumor activity of either agent. Sitravatinib, a spectrum-selective TKI targeting TAM receptors (Tyro3/Axl/MerTK) and VEGFR2, reduces the number of myeloid-derived suppressor cells and regulatory T cells while increasing the ratio of M1/M2-polarized macrophages, which may overcome an immunosuppressive tumor microenvironment and augment antitumor immune responses. Tislelizumab, an anti-PD-1 antibody engineered to minimize binding to FcγR on macrophages and abrogate antibody-dependent phagocytosis, has shown single-agent clinical activity in patients (pts) with advanced solid tumors. This open-label, multicohort, phase 1b study assessed safety/tolerability and preliminary antitumor activity of sitravatinib + tislelizumab in advanced solid tumors (BGB-900-103; NCT03666143). We report results from the PROC cohort. Methods: Anti-PD-(L)1 antibody-naïve pts with histologically confirmed, advanced PROC (disease progression &amp;lt;6 mo after last platinum treatment) were enrolled. While platinum-resistant pts were included, pts with platinum-refractory disease were excluded. Patients received sitravatinib 120 mg PO QD and tislelizumab 200 mg IV Q3W. Primary endpoint was safety/tolerability of sitravatinib + tislelizumab. Key secondary endpoints were investigator-assessed objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS) per RECIST v1.1; overall survival (OS) was also assessed. PD-L1 IHC assay (Ventana SP263) and assessment of plasma VEGF/serum CXCL10 were retrospective. Results: As of Oct 13, 2020, 60 PROC pts were enrolled; 13 (22%) remained on treatment. Median age was 64 yrs (range 26-80); pts received a median of 4 (range 1-11) prior regimens. Median follow-up was 6.0 mo (range 0.2-23.4). Treatment-emergent adverse events (TEAEs) of any grade/grade ≥3 occurred in 97%/68% of pts; TEAEs led to sitravatinib dose reduction in 50% of pts. Nausea (33%), hypertension (18%), and abdominal pain (12%) were the most commonly reported grade ≥3 TEAEs. The 2 fatal AEs (malignant GI obstruction, dyspnea) were deemed unrelated to treatment. Confirmed ORR was 26.4% (95% CI, 15.3-40.3), with 14 pts achieving partial response; DCR was 77.4% (95% CI, 63.8-87.7). Median duration of response was 4.7 mo (95% CI, 2.8-not estimable). There was no clear association between PD-L1 expression and clinical response; plasma VEGF and serum CXCL10 increased after treatment (P&amp;lt;0.0001 for both). Median PFS was 4.1 mo (95% CI, 4.0-5.1); preliminary median OS was 12.9 mo (95% CI, 6.3-17.2). Conclusions: Sitravatinib + tislelizumab was tolerable and showed preliminary antitumor activity in pts with advanced PROC. Further investigation of sitravatinib + tislelizumab in PROC is warranted. Citation Format: Jeffrey Goh, Jermaine Coward, Bo Gao, Ines P. da Silva, Mark Voskoboynik, Daphne Day, Amy L. Body, Hui K. Gan, Cheng Chen, Xiao Xiang, Cong Fei, Liu Yang, Michael Millward. Safety/tolerability and preliminary antitumor activity of sitravatinib plus tislelizumab in patients with advanced platinum-resistant ovarian cancer (PROC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT013.

Abstract CT020: Long-term outcomes of patients with TRK fusion cancer treated with larotrectinib

Abstract Introduction: Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in various tumor types. Larotrectinib is a first-in-class, highly selective, central nervous system (CNS)-active TRK inhibitor approved in over 40 countries, including the US, for the treatment of adult and pediatric patients with TRK fusion cancer. Larotrectinib was approved by the FDA in 2018 based on efficacy and safety outcomes in a primary analysis cohort of 55 patients with TRK fusion cancer from 3 clinical trials (Drilon A et al. NEJM. 2018). Here, we report long-term efficacy follow-up for larotrectinib and molecular data on co-occurring mutations in this primary analysis cohort. Methods: Patients with non-primary CNS TRK fusion cancer treated with larotrectinib were identified from 3 clinical trials (NCT02122913, NCT02576431, NCT02637687). NTRK gene status was determined by local molecular testing. Adult and pediatric patients received larotrectinib 100 mg and 100 mg/m2 twice daily, respectively. The primary endpoint was investigator-assessed objective response rate (ORR) (per RECIST v1.1). Next-generation sequencing was performed on pre-treatment tumor samples from a subset of patients with evaluable tumor material (n=31) using the FoundationOne® CDx assay. The data cut-off was July 15, 2019. Results: A total of 55 patients with 17 different tumor types were included in the primary analysis cohort. Median age was 45 years (range 0.3-76 years). Patients had gene fusions involving NTRK1 (45%), NTRK2 (2%), or NTRK3 (53%). For 31 patients the detailed genomic profile, including co-occurring mutations, will be presented. Forty-four (80%) patients had received prior systemic therapy, with a median of 2 prior therapies (range 0-10). ORR with larotrectinib was 80% (95% confidence interval [CI] 67-90%); 13 (24%) patients had a complete response (CR), 31 (56%) patients had a partial response (PR), 5 (9%) patients had stable disease, and 6 (11%) patients had progressive disease. With longer follow-up, best response for 4 patients improved from PR to CR. Median duration of response and progression-free survival were 35.2 months (95% CI 19.8-not estimable [NE]) and 25.8 months (95% CI 9.9-NE), respectively. Median overall survival (OS) was not reached (95% CI 44.4-NE) over a median follow-up of 32.5 months. The 36-month OS rate was 76% (95% CI 63-89%). In an expanded safety population (n=279), larotrectinib-related adverse events were mainly Grade 1-2. Conclusions: Larotrectinib demonstrated a robust response rate with long durability and extended survival benefits in adult and pediatric patients with TRK fusion cancer. These data highlight the importance of identifying NTRK gene fusions in patients with cancer. Citation Format: Alexander Drilon, Shivaani Kummar, Catherine M. Albert, Ramamoorthy Nagasubramanian, Jaclyn F. Hechtman, John A. Reeves, Georg Beckmann, Marion Rudolph, Justyna A. Wierzbińska, Laura Dima, Nicoletta Brega, Theodore W. Laetsch, David S. Hong. Long-term outcomes of patients with TRK fusion cancer treated with larotrectinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT020.

Abstract LB012: Efficacy of atezolizumab in the treatment of solid tumors with high tumor mutational burden (TMB): A MyPathway study cohort

Abstract Purpose Data suggest that TMB is correlated with response to checkpoint blockade. We present an analysis of atezolizumab treatment of patients (pts) with advanced solid tumors and high TMB from MyPathway (NCT02091141), a multi-basket study assessing activity of FDA-approved therapies in non-indicated tumors with targetable alterations. Methods Eligible pts were ≥18 years old with previously treated advanced solid tumors with TMB ≥10 mut/Mb by any CLIA-certified assay. Pts received atezolizumab 1200 mg IV q3w. The pre-planned primary endpoint was objective response rate (ORR) in pts with TMB ≥16 mut/Mb by FoundationOne CDx (F1CDx), a threshold determined by a retrospective study that showed TMB ≥16 mut/Mb is associated with improved ORR and duration of response (DOR) for various tumor types. Other endpoints in this group included disease control rate (DCR), DOR, progression-free survival (PFS), and overall survival (OS). Separate analyses were performed in pts with TMB ≥10 and &amp;lt;16 mut/Mb by F1CDx, and TMB by any CLIA assay. Results Enrollment closed on 7-9-20. By the 12-11-20 data cutoff, 118 pts with 20 tumor types and TMB ≥10 mut/Mb by any CLIA assay were evaluable for efficacy. In the primary efficacy population of 42 pts with TMB ≥16 mut/Mb by F1CDx, confirmed investigator-assessed ORR was 38.1% vs 2.1% in 48 pts with TMB ≥10 mut/Mb and &amp;lt;16 mut/Mb; median DOR was not reached in either group. DCR was 61.9% vs 22.9%, respectively; median PFS was 5.7 vs 1.8 mos; and median OS was 13.7 vs 11.4 mos. In pts with TMB ≥16 mut/Mb by any CLIA assay, ORR was 28.6% and DCR was 55.4%. Responses were observed in diverse tumor types. In pts with TMB ≥16 mut/Mb tumors by F1CDx, those with high microsatellite instability (MSI) had an ORR of 54.5% vs 30.0% for microsatellite stable/low tumors. Conclusions Atezolizumab had durable activity against diverse solid tumor types with TMB ≥16 mut/Mb, independent of MSI status. Limited activity was observed in tumors with TMB ≥10 and &amp;lt;16 mut/Mb. Clinical outcomesSubgroupORRaDCRbDORPFSOSn (%)n (%)Median mosMedian mosMedian mos95% CI95% CI95% CI95% CI95% CITMB by F1CDx assayc≥16 mut/Mb (n=42)16d (38.1)26 (61.9)Not reachede5.713.723.6-54.445.6-76.42.7-9.911.9-NA≥10 and &amp;lt;16 mut/Mb (n=48)1 (2.1)11 (22.9)Not reached1.811.40.1-11.112.0-37.31.4-2.65.3-15.7TMB by any CLIA assayf≥16 mut/Mb (n=56)16d (28.6)31 (55.4)12.24.813.717.3-42.241.5-68.74.4-NA2.6-5.811.9-NA≥10 and &amp;lt;16 mut/Mb (n=62)2 (3.2)13 (21.0)3.51.410.70.4-11.211.7-33.20.7-3.51.4-2.65.3-14.9TMB by F1CDx + MSI statusgTMB ≥16 mut/Mb + MSI-H (n=11)6h (54.5)8 (72.7)Not reached8.3Not reached23.4-83.339.0-94.06.9-NA1.3-NA10.4-NATMB ≥16 mut/Mb + MSS/Li (n=30)9j (30.0)17 (56.7)8.45.612.614.7-49.437.4-74.52.0-NA1.4-8.511.1-NATMB ≥10 and &amp;lt;16 mut/Mb + MSS/Li (n=45)1 (2.2)10 (22.2)Not reached1.811.40.1-11.811.2-37.11.9-NA1.4-2.65.3-15.7Tumor types represented in the safety population with any TMB CLIA assay (n=119) were colon (n=31), breast (n=29), biliary tract (n=6), uterine (n=6), gastroesophageal (n=5), ovarian (n=5), head and neck (n=5), cervical (n=4), prostate (n=4), sarcoma (n=3), urothelial (n=3), lung (n=3), pancreatic (n=3), small bowel (n=3), carcinoma of unknown primary (n=3), pancreatic endocrine (n=2), adrenocortical (n=1), central nervous system (n=1), liver (n=1), and skin (n=1).aIncludes patients with complete or partial response.bIncludes patients with complete or partial response, or stable disease &amp;gt;4 months.cIncludes local F1CDx (n=68) and central F1CDx (n=39); upon central retesting, 17 patients fell below the TMB threshold of 10 mut/Mb required for inclusion in the efficacy analysis.dIncludes three patients with a complete response.eDOR was &amp;gt;15 months in &amp;gt;50% of responders.fIncludes local F1CDx (n=68) and other local CLIA assays (n=51) from the safety population. One patient had no tumor assessment and was not included in the efficacy analysis population.gMSI status was missing for one patient with TMB ≥16 mut/Mb and two patients with TMB ≥10 and &amp;lt;16 mut/Mb. One additional patient with TMB ≥10 and &amp;lt;16 mut/Mb + MSI-H is not shown.hIncludes one patient with a complete response.iMSS/L includes microsatellite stable, low, or intermediate tumors, which were classified as “not high”.jIncludes two patients with a complete response.CI, confidence interval; CLIA, Clinical Laboratory Improvement Amendments; DCR, disease control rate; DOR, duration of response; F1CDx, FoundationOne CDx; MSI-H, high microsatellite instability; MSS/L, microsatellite stable/low; NA, not available; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; TMB, tumor mutational burden.JH and CL contributed equally to this work. Citation Format: John Hainsworth, Claire F. Friedman, Razelle Kurzrock, David R. Spigel, Howard Burris, Christopher J. Sweeney, Funda Meric-Bernstam, Yong Wang, Jonathan Levy, David Shames, Katja Schulze, Arisha Patel, Charles Swanton. Efficacy of atezolizumab in the treatment of solid tumors with high tumor mutational burden (TMB): A MyPathway study cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB012.

Abstract CT035: Safety/tolerability and preliminary antitumor activity of sitravatinib plus tislelizumab in patients with PD-(L)1 refractory/resistant unresectable or metastatic melanoma from a phase 1b study

Abstract Background: While PD-(L)1 inhibitors have improved outcomes for melanoma, a substantial proportion of patients do not respond or develop resistance. Sitravatinib, a spectrum-selective TKI targeting TAM receptors (Tyro3/Axl/MerTK) and VEGFR2, reduces the number of myeloid-derived suppressor cells and regulatory T cells while increasing the ratio of M1/M2-polarized macrophages, which may overcome an immunosuppressive tumor microenvironment and augment antitumor immune responses. Tislelizumab, an anti-PD-1 antibody engineered to minimize binding to FcγR on macrophages to abrogate antibody-dependent phagocytosis, has shown clinical activity as a single agent and in combination with chemotherapy in patients with advanced solid tumors, including melanoma. Methods: We report results from the melanoma cohort of an ongoing multicohort phase 1b study (BGB-900-103; NCT03666143) assessing safety/tolerability and preliminary antitumor activity of sitravatinib + tislelizumab in advanced solid tumors. Eligible patients had unresectable or metastatic melanoma refractory/resistant to PD-(L)1 inhibitors and had not received other prior immunotherapy (eg, anti-CTLA-4, -OXO40, or -CD137) or anti-BRAF/MEK therapy. Patients received oral sitravatinib 120 mg once daily and tislelizumab 200 mg IV Q3W until a discontinuation criterion was met. The primary endpoint was safety/tolerability; key secondary endpoints included investigator-assessed objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Results: As of Oct 13, 2020, 25 patients were enrolled; 16 patients (64%) remained on treatment. All patients received 1 prior line of PD-(L)1 therapy, median age was 51 years (range: 23-79), and baseline histology included cutaneous (n=12; 48%), acral (n=7; 28%), and mucosal (n=4; 16%) subtypes. Median duration of study follow-up was 5.5 months (range: 1.5-13.3). Adverse events (AEs) were reported in 25 patients (100%); the most commonly reported grade ≥3 AE was hypertension (n=3; 12%). Serious AEs were reported in 4% (n=1/25) of patients. Dose reductions of sitravatinib due to AEs occurred in 13 patients. No AEs led to death. Six patients achieved a confirmed partial response. Confirmed ORR was 24.0% (95% CI: 9.36-45.13); DCR was 88.0% (95% CI: 68.78-97.45). Median PFS was 6.7 months (95% CI: 4.07, not evaluable). Conclusions: Sitravatinib + tislelizumab was generally well tolerated, had a manageable safety/tolerability profile, and demonstrated preliminary antitumor activity in patients with refractory/resistant unresectable or metastatic melanoma. Further investigation of sitravatinib + tislelizumab in these patients is warranted. Citation Format: Chuanliang Cui, Hongming Pan, Matteo Carlino, Jiuwei Cui, Xuan Wang, Cheng Chen, Xiao Xiang, Liu Yang, Jun Guo. Safety/tolerability and preliminary antitumor activity of sitravatinib plus tislelizumab in patients with PD-(L)1 refractory/resistant unresectable or metastatic melanoma from a phase 1b study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT035.

Elotuzumab Plus Lenalidomide/Dexamethasone (ELd) Vs Ld in Patients with Newly Diagnosed Multiple Myeloma: Phase 2, Randomized, Open-Label Study in Japan

Introduction: Elotuzumab, a humanized IgG1 monoclonal antibody that binds to SLAMF7 expressed on myeloma and natural killer (NK) cells, has a dual mode of action; it causes targeted myeloma cell death by directly activating NK cells and enhances NK cell-mediated antibody-dependent cellular cytotoxicity. Elotuzumab combined with lenalidomide and dexamethasone (ELd) has been approved in Japan for the treatment of relapsed/refractory multiple myeloma (RRMM). In a 4-y follow-up of the phase 3 ELOQUENT-2 study (NCT01239797) in patients (pts) with RRMM, ELd demonstrated a sustained 29% reduction in risk of disease progression/death and an overall survival benefit vs Ld (Dimopoulos M et al. Haematologica 2017), consistent with prior reports (Dimopoulos M et al. Br J Haematol 2017). We present the first report on the efficacy/safety of ELd vs Ld in pts with newly diagnosed multiple myeloma (NDMM).Methods: In this phase 2, open-label, multicenter study (NCT02272803) in Japan enrolling pts with NDMM ineligible for high-dose chemotherapy plus hematopoietic cell transplantation, pts were randomized 1:1 to intravenous elotuzumab (10 mg/kg weekly for Cycles 1 and 2; every 2 wk for Cycles 3-18; 20 mg/kg monthly thereafter) plus Ld or Ld alone, in a 28-d cycle until disease progression or unacceptable toxicity. All pts in the ELd arm received premedication prior to elotuzumab to mitigate infusion reactions (IRs). In the absence of IRs, infusion rate was increased from 0.5-2.0 mL/min at dose 1, and up to a maximum of 5 mL/min (per FDA/EMA labels for ELd in RRMM) by dose 3 of Cycle 1. Primary endpoint was investigator-assessed objective response rate (ORR) with ELd, per International Myeloma Working Group criteria (1-sided α=0.15 for a true response rate >71%). Secondary endpoints included difference in ORR between the arms and progression-free survival (PFS). Safety was an exploratory endpoint.Results: In total, 40 and 42 pts received ELd and Ld, respectively. At database lock (March 2017; minimum follow-up of 6 mo), 31 (78%) pts in the ELd arm and 25 (60%) in the Ld arm remained on study. At baseline, median (range) age was 72 y (65-83) in the ELd arm and 73 y (62-89) in the Ld arm. Median duration of therapy was 13.0 cycles with ELd and 11.5 cycles with Ld. The most common reason for discontinuation was: ELd (9 pts)-disease progression (4/40 pts [10%]); Ld (17 pts)-drug toxicity, adverse events (AEs) unrelated to study drug, and pt request (each with 4/42 pts [10%]). The primary endpoint was met: investigator-assessed ORR (Table) was 88% with ELd; lower bound of the 2-sided 70% CI in ORR was 80% (> threshold of 71%). The ORR in the LD arm was 74%. ORR was 13% numerically higher with ELd than Ld. Very good partial response or better was observed for 45% of ELd- and 29% of Ld-treated pts. AEs were reported in 40 (100%) and 41 (98%) pts in the ELd and Ld arms, respectively. The most common (≥20%) AEs for ELd vs Ld included constipation (43% vs 31%), pyrexia (35% vs 7%), rash (28% vs 36%), diarrhea (28% vs 21%), nasopharyngitis (25% vs 26%), dysgeusia (23% vs 19%), malaise (23% vs 2%), peripheral edema (20% vs 14%), neutropenia (20% vs 14%), leukopenia (20% vs 7%), and back pain (18% vs 21%). Grade (G) 3-4 AEs occurred in 31 (78%) and 19 (45%) pts in the ELd and Ld arms, respectively. The most common G3-4 AEs (ELd vs Ld) were neutropenia (18% vs 7%) and leukopenia (15% vs 0%). One IR was reported (ELd): G2 hypersensitivity during the first infusion (2-mL/min infusion rate); elotuzumab infusion was interrupted; the pt did not experience any IRs at subsequent infusions. Thirty-eight pts (95%) received elotuzumab at 5 mL/min (representing 1046/1176 [89%] infusions) and no IRs were reported at this increased infusion rate. Secondary primary malignancies were reported in 1 pt in each arm (of the rectum and lung with ELd and Ld, respectively). ELd had a comparable safety profile when given at 10 mg/kg weekly or every 2 wk up to Cycle 18, or at 20 mg/kg monthly from Cycle 19 onwards. PFS data are not yet mature.Conclusions: In this first report of ELd treatment of pts with NDMM, the primary endpoint of ORR was met. ELd had an acceptable safety profile in this pt population, and an increased infusion rate of 5 mL/min, which reduced infusion time and did not induce additional IRs. These data suggested that ELd with a faster infusion rate of 5 mL/min was effective and well tolerated in Japanese pts with NDMM.Study support: Bristol-Myers Squibb K.K. [Display omitted] DisclosuresOhta:Bristol-Meyer Squibb K.K., Celgene K.K., Jansen Pharmaceutical K.K., Novartis Pharma K.K., Ono Pharmaceutical Co. Ltd, Takeda Pharmaceutical Co. Ltd: Honoraria. Hori:Celgene, Fujifilm RI Pharma, Shire Japan: Other: Post-marketing surveillance study fee. Kinoshita:Bristol-Myers Squibb K.K.: Employment. Shelat:Bristol-Myers Squibb: Employment, Equity Ownership. Miyoshi:Bristol-Myers Squibb K.K.: Employment.

CheckMate 040 cohort 5: A phase I/II study of nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh B cirrhosis

Patients with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B liver function are often excluded from clinical trials. In previous studies, overall survival for these patients treated with sorafenib was ∼3-5 months; thus, new treatments are needed. Nivolumab, alone or in combination with ipilimumab, is conditionally approved in the United States to treat patients with aHCC who previously received sorafenib. We describe nivolumab monotherapy outcomes in patients with Child-Pugh B status. This phase I/II, open-label, non-comparative, multicentre trial (27 centres) included patients with Child-Pugh B (B7-B8) aHCC. Patients received intravenous nivolumab 240mg every 2 weeks until unacceptable toxicity or disease progression. Primary endpoints were objective response rate (ORR) by investigator assessment (using Response Evaluation Criteria in Solid Tumors v1.1) and duration of response. Safety was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. Twenty-five sorafenib-naive and 24 sorafenib-treated patients began treatment between November 2016 and October 2017 (median follow-up, 16.3 months). Investigator-assessed ORR was 12% (95% CI 5-25%) with 6 patients responding; disease control rate was 55% (95% CI 40-69%). Median time to response was 2.7 months (interquartile range, 1.4-4.2), and median duration of response was 9.9 months (95% CI 9.7-9.9). Treatment-related adverse events (TRAEs) were reported in 25 patients (51%) and led to discontinuation in 2 patients (4%). Themost frequent grade 3/4 TRAEs were hypertransaminasemia (n= 2), amylase increase (n= 2), and aspartate aminotransferase increase (n= 2). The safety of nivolumab was comparable to that in patients with Child-Pugh A aHCC. Nivolumab showed clinical activity and favourable safety with manageable toxicities, suggesting it could be suitable for patients with Child-Pugh B aHCC. In patients with advanced hepatocellular carcinoma, almost all systemic therapies require very good liver function, i.e. Child-Pugh A status. The evidence from this study suggests that nivolumab shows clinical activity and an acceptable safety profile in patients with hepatocellular carcinoma with Child-Pugh B status who have mild to moderate impairment of liver function or liver decompensation that might rule out other therapies. Further studies are warranted to assess the safety and efficacy of nivolumab in this patient population. NCT01658878.

A phase I study of binimetinib (MEK 162), a MEK inhibitor, plus carboplatin and pemetrexed chemotherapy in non-squamous non-small cell lung cancer

IntroductionMEK inhibition is a potential therapeutic strategy in non-small cell lung cancer (NSCLC). This phase I study evaluates the MEK inhibitor binimetinib plus carboplatin and pemetrexed in stage IV non-squamous NSCLC patients (NCT02185690). MethodsA standard 3 + 3 dose-escalation design was used. Binimetinib 30 mg BID (dose level 1 [DL1]) or 45 mg BID (dose level 2 [DL2]) was given with standard doses of carboplatin and pemetrexed using an intermittent dosing schedule. The primary outcome was determination of the recommended phase II dose (RP2D) and safety of binimetinib. Secondary outcomes included efficacy, pharmacokinetics, and an exploratory analysis of response based on mutation subtype. ResultsThirteen patients (6 DL1, 7 DL2) were enrolled: 7 KRAS, 5 EGFR, and 1 NRAS mutation. The RP2D was binimetinib 30 mg BID. Eight patients (61.5%) had grade 3/4 adverse events, with dose limiting toxicities in 2 patients at DL2. Twelve patients were evaluated for response, with an investigator-assessed objective response rate (ORR) of 50% (95% CI 21.1%-78.9%; ORR 33.3% by independent-review, IR), and disease control rate 83.3% (95% CI 51.6%-97.9%). Median progression free survival (PFS) was 4.5 months (95% CI 2.6 months–NA), with a 6-month and 12-month PFS rate of 38.5% (95% CI 19.3%-76.5%) and 25.6% (95% CI 8.9%-73.6%), respectively. In an exploratory analysis, KRAS/NRAS-mutated patients had an ORR of 62.5% (ORR 37.5% by IR) vs. 25% in KRAS/NRAS wild-type patients. In MAP2K1–mutated patients, the ORR was 42.8%. ConclusionThe addition of binimetinib to carboplatin and pemetrexed appears to have manageable toxicity with evidence of activity in advanced non-squamous NSCLC.

Efficacy and safety of rucaparib in previously treated, locally advanced or metastatic urothelial carcinoma from a phase 2, open-label trial (ATLAS)

BackgroundATLAS evaluated the efficacy and safety of the PARP inhibitor rucaparib in patients with previously treated locally advanced/unresectable or metastatic urothelial carcinoma (UC).MethodsPatients with UC were enrolled independent of tumor homologous recombination deficiency (HRD) status and received rucaparib 600 mg BID. The primary endpoint was investigator-assessed objective response rate (RECIST v1.1) in the intent-to-treat and HRD-positive (loss of genome-wide heterozygosity ≥10%) populations. Key secondary endpoints were progression-free survival (PFS) and safety. Disease control rate (DCR) was defined post-hoc as the proportion of patients with a confirmed complete or partial response (PR), or stable disease lasting ≥16 weeks.ResultsOf 97 enrolled patients, 20 (20.6%) were HRD-positive, 30 (30.9%) HRD-negative, and 47 (48.5%) HRD-indeterminate. Among 95 evaluable patients, there were no confirmed responses. However, reductions in the sum of target lesions were observed, including 6 (6.3%) patients with unconfirmed PR. DCR was 11.6%; median PFS was 1.8 months (95% CI, 1.6–1.9). No relationship was observed between HRD status and efficacy endpoints. Median treatment duration was 1.8 months (range, 0.1–10.1). Most frequent any-grade treatment-emergent adverse events were asthenia/fatigue (57.7%), nausea (42.3%), and anemia (36.1%). Of 64 patients with data from tumor tissue samples, 10 (15.6%) had a deleterious alteration in a DNA damage repair pathway gene, including four with a deleterious BRCA1 or BRCA2 alteration.ConclusionsRucaparib did not show significant activity in unselected patients with advanced UC regardless of HRD status. The safety profile was consistent with that observed in patients with ovarian or prostate cancer.Trial registrationThis trial was registered in ClinicalTrials.gov (NCT03397394). Date of registration: 12 January 2018. This trial was registered in EudraCT (2017–004166-10).

Efficacy of nivolumab/ipilimumab in patients with initial or late progression with nivolumab: Updated analysis of a tailored approach in advanced renal cell carcinoma (TITAN-RCC).

4576 Background: TITAN-RCC uses a tailored immunotherapy approach in renal cell carcinoma (RCC), starting with nivolumab (nivo) induction followed by nivo + ipilimumab (ipi) as immunotherapeutic “boost” in non-responders. Patients with initial partial or complete response (PR/CR) continued with nivo maintenance but received later “boosts” for progressive disease (PD). Here we report updated results focusing on the efficacy of nivo+ipi in patients with initial PD vs. initial responders with later PD. Methods: Patients with IMDC intermediate and poor risk advanced clear cell RCC were recruited between OCT 2016 and DEC 2018. Patients started with nivo 240 mg Q2W induction. Patients with early significant PD (week 8) or non-responders at week 16 received 2-4 nivo+ipi “boost” cycles. Responders (PR/CR) to nivo monotherapy continued with maintenance but could receive nivo+ipi for later PD. The primary endpoint is confirmed investigator assessed objective response rate (ORR) per RECIST in first line (1L) and second line (2L). Secondary endpoints included activity of nivo monotherapy, remission rate with nivo+ipi “boost”, safety and overall survival (OS). Results: 109 1L and 98 2L (after TKI) patients were analyzed for efficacy. Median age was 65 years (range 20-87). 71 % were intermediate and 25 % poor risk. Confirmed ORR with nivo monotherapy was 28 % for 1L and 17 % for 2L. After a median follow-up of 12.8 months best overall response after nivo induction ± nivo+ipi was 36 % in 1L and 30 % in 2L. Of all patients, 38 received nivo+ipi for stable disease (SD) up to week 16, with 1 (3 %), 4 (11 %) and 26 (68 %) achieving CR, PR and SD, respectively. 28 patients in 1L and 43 in 2L were boosted with nivo+ipi for initial PD. Of these, 3 (11 %) and 8 (29 %) achieved PR and SD, respectively, in 1L, whereas 3 (7.0 %) achieved CR, 6 (14 %) PR and 13 (30 %) SD in 2L. 16 and 10 patients received “boosts” later than week 16 for PD during nivo maintenance in 1L and 2L, respectively. Thereof, 3 (19 %) achieved PR and 5 (31 %) SD in 1L, whereas 2 (20 %) achieved PR and 3 (30 %) SD in 2L. Progression-free survival was 6.3 months (95 % CI 3.7 – 10.1) and 3.7 months (95 % CI 2.0 - 4.5) in 1L and 2L, respectively. OS was 27.2 months (95 % CI 19.9 – not estimable (NE)) in 1L and 20.2 months (95 % CI 15.6 – NE) in 2L. Treatment-related adverse events will be presented. Conclusions: Our tailored approach with nivo+ipi “boosts” results in improved response rates compared to nivo monotherapy. Our updated analysis suggests that almost half of the patients receiving “boosts” for PD improve to either PR/CR (18 %) or SD (30 %), irrespective of initial or later progression with nivo. Clinical trial information: NCT02917772. [Table: see text]

CMP-001-007: Open-label, phase 2 study of intratumoral CMP-001 + pembrolizumab in patients with recurrent or metastatic head and neck squamous cell carcinoma.

TPS6089 Background: PD-1 blockade ± chemotherapy has recently become a primary systemic therapy recommended by NCCN guidelines for patients (pts) with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). However, most pts still do not respond to treatment, indicating a large unmet need for pts with unresectable disease. CMP-001 is a toll-like receptor 9 (TLR9) agonist comprising a CpG-A oligodeoxynucleotide packaged in a virus-like particle that can induce type I interferon secretion from tumor-associated plasmacytoid dendritic cells, promoting a Th1-like chemokine milieu in the tumor microenvironment and inducing an antitumor CD8+ T-cell response. In a phase (ph) 1b study in pts with metastatic melanoma, intratumoral (IT) injection of CMP-001 + intravenous (IV) pembrolizumab (pembro) reversed PD-1 blockade resistance, induced responses in injected and noninjected lesions, and had an acceptable safety profile (Milhem et al, SITC 2020). This combination is therefore being tested in pts with HNSCC. Methods: CMP-001-007 (NCT04633278) is an open-label, multicenter, ph 2 study designed to investigate the efficacy and safety of CMP-001 + IV pembro in adult pts with histologically or cytologically confirmed R/M HNSCC considered incurable by local therapies. Eligible pts have undergone a pretreatment tumor biopsy, received no prior systemic therapy in the R/M setting, and have primary tumor locations of oropharynx, oral cavity, hypopharynx, or larynx. In addition, pts must have PD-L1-positive tumors (combined positive score ≥1), known tumor human papillomavirus (HPV) status (for oropharyngeal cancer), and measurable disease per RECIST v1.1 with ≥1 lesion amenable to IT injection. Pts with primary tumors in the nasopharynx are excluded. Enrolled pts will receive CMP-001 10 mg once weekly for 7 doses and every 3 weeks (Q3W) thereafter. The first dose may be administered subcutaneously or via IT injection, with all subsequent doses administered IT. All pts will also receive pembro 200 mg IV Q3W after the CMP-001 injection. Treatment continues until unacceptable toxicity or disease progression. The primary endpoint is investigator-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints include safety, duration of response (DOR), progression-free survival (PFS), overall survival, and effects of HPV infection and PD-L1 expression on ORR, DOR, and PFS. Exploratory endpoints include analyses of baseline and changes from baseline in tumor or serum biomarkers related to TLR9, immune checkpoints, and potential predictors of response, as well as serum concentrations of CXCL10 and CMP-001. Refer to clinicaltrials.gov/ct2/show/NCT04633278 for the most current information on enrolling sites. Clinical trial information: NCT04633278.

Phase 2 study of retifanlimab (INCMGA00012) in patients (pts) with selected solid tumors (POD1UM-203).

2571 Background: Checkpoint inhibitors (CPIs) are an effective treatment (tx) for many tumor types. Retifanlimab, an investigational humanized anti–PD-1 monoclonal antibody, has shown safety, pharmacology, and clinical activity consistent with the class. POD1UM-203 (NCT03679767) assessed efficacy and safety of retifanlimab in pts with selected solid tumors where CPI monotherapy is highly active. Methods: Eligible pts (≥18 y) had tx-naïve metastatic non-small cell lung cancer (NSCLC) with high PD-L1 expression (tumor proportion score ≥50%), cisplatin ineligible locally-advanced/metastatic urothelial cancer (UC) with PD-L1 expression (combined positive score ≥10%), unresectable/metastatic melanoma, or tx-naïve locally advanced/metastatic clear-cell renal cell carcinoma (RCC). Measurable disease (RECIST v1.1) was required. ECOG PS &gt;1 and prior PD-1/PD-L1 directed tx were exclusions. Retifanlimab was administered as an IV infusion at 500 mg every 4 wks over 30 min. Primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints were duration of response (DOR), disease control rate (DCR), progression-free survival, overall survival, safety, and pharmacokinetics. Results: A total of 121 pts (35 melanoma, 23 NSCLC, 29 UC, 34 RCC) received ≥1 dose of retifanlimab and were included in the analyses. Median duration of tx was 169 d (range, 1–442). The efficacy cut-off for the primary analysis occurred once all pts had been followed for at least 6 mo from the time of initial tx. Confirmed RECIST v1.1 responses were observed in all tumor types (Table) and were consistent with published ORR for other CPIs; median DOR was not reached for any tumor cohort and tx was ongoing at the time of data cutoff for 17, 11, 9, and 15 pts with melanoma, NSCLC, UC, and RCC, respectively. The most common tx-emergent AEs (TEAEs, &gt;10% incidence) were asthenia (17.4%), arthralgia (14.9%), decreased appetite (14.0%), pruritus (12.4%), rash (10.7%), and urinary tract infection (10.7%); majority of TEAEs were low grade (≤ grade 2) and none led to tx discontinuation. Immune-related AEs occurred in 23 pts (19.0%), most common (&gt;1% incidence) were hypothyroidism (7.4%), rash (4.1%), hyperthyroidism (2.5%), and pruritus (1.7%). Immune-related AEs led to dose delay in 5 pts (4.1%), but none led to tx discontinuation and/or dose interruption. Conclusions: Retifanlimab demonstrated antitumor activity and was generally well-tolerated in pts with melanoma, NSCLC, UC, or RCC comparable with approved CPIs for these tumor types. These results support ongoing further development of retifanlimab. Clinical trial information: NCT03679767. [Table: see text]

MyPathway HER2 basket study: Pertuzumab (P) + trastuzumab (H) treatment of a large, tissue-agnostic cohort of patients with HER2-positive advanced solid tumors.

3004 Background: HER2 ( ERBB2) amplification and/or overexpression is observed in 2–3% of solid tumors, and is often associated with more aggressive disease. Thus far, HER2-targeted therapies are FDA-approved only for breast, gastric, and gastroesophageal cancers. MyPathway (NCT02091141) is a non-randomized, phase 2a multi-basket study assessing the activity of FDA-approved targeted therapies in non-indicated advanced solid tumors with relevant molecular alterations. We report results from the MyPathway HER2 basket, comprising a large, tissue-agnostic cohort of patients (pts) with HER2-altered tumors treated with P + H. Methods: Pts in this analysis were aged ≥18 years and had HER2-amplified and/or overexpressed tumors. Pts received P (840-mg IV loading dose, then 420-mg every 3 weeks [q3w]) + H (8-mg/kg IV loading dose, then 6-mg/kg q3w). The primary efficacy endpoint was investigator-assessed objective response rate (ORR). Other endpoints included disease control rate (DCR, defined by objective response or stable disease &gt;4 mos) and duration of response (DOR). Subgroup analyses were completed by tumor type and KRAS status. Results: Pts were fully enrolled from April 14, 2014 to June 15, 2020. By January 22, 2021, 260 pts were efficacy-evaluable. Confirmed ORR (cORR) was 23.1% (60/260, including 5 complete responses; 95% confidence interval [CI] 18.1–28.7), DCR was 44.2% (115/260, 95% CI 38.1–50.5), and median DOR was 7.9 mos (95% CI 6.2–9.3). In 199 pts with wild-type KRAS tumors, cORR was 25.6% (51/199, 95% CI 19.7–32.3), DCR was 48.7% (97/199, 95% CI 41.6–55.9), and median DOR was 8.3 mos (95% CI 6.2–10.8). In comparison, in 26 pts with KRAS-mutated tumors, cORR was 3.8% (1/26, responder had colorectal cancer; 95% CI 0.1–19.6), DCR was 3.8% (1/26, 95% CI 0.1–19.6), and DOR was 2.7 mos. KRAS status was unknown in 35/260 pts (cORR 22.9% [8/35, 95% CI 10.4–40.1]; median DOR 6.7 mos [95% CI 2.5–12.7]). Clinical outcomes by tumor type are shown in the Table. Conclusions: P+H was active in a wide variety of KRAS wild-type HER2-amplified/overexpressed tumor types, but had limited activity in KRAS-mutated tumors. Clinical trial information: NCT02091141. [Table: see text]

Intestinal Akkermansia muciniphila predicts overall survival in advanced non-small cell lung cancer patients treated with anti-PD-1 antibodies: Results a phase II study.

9019 Background: The gut microbiome, most specifically centered on one of the most prevalent anaerobic bacterium Akkermansia muciniphila (Akk), has emerged as a potential hallmark of clinical benefit to ICI. The goal of this study was to validate the prognostic significance of Akk in advanced NSCLC patients amenable to ICI. Methods: The multicentric prospective observational study enrolled patients with advanced NSCLC amenable to single agent ICI in first and second line. Stool sample was collected at study entry. Primary end-point was investigator-assessed objective response rate (ORR). We considered that a meaningful clinical difference would correlate to a 10% ORR increase in the Akk-Pos group compared to the Akk-Neg group. At least 292 patients equally divided each in each group would be required for a power at 80% and a two-sided alpha level of 5%. Results: From Dec 2015 to Nov 2019, a total of 409 patients were screened and 311 patients enrolled across 12 academic centers in France and Canada. Median age was 64yr, 32% were female, 77% had non-squamous NSCLC and PD-L1 was ≥1% in 70% of the 213 assessable samples. Akk was detectable in 158 (51%) and absent in 153 (49%) patients. Baseline characteristics were well balanced between the two groups. When considering Akk-Pos vs Akk-Neg groups the primary endpoint ORR was 27% and 17% respectively ( p = 0.04). Rates of partial response, stable disease and progressive disease (PD) were 62%, 50% and 46% respectively in the Akk-Pos group compared to 38%, 50% and 54% in the Akk-Neg group ( p = 0.04). Moreover, 57% of patients were still alive after 12 months in the Akk-Pos group vs 43% in the Akk-Neg group ( p = 0.04). Microbiome profiling demonstrated that Akk-Pos group was associated with increase bacterial diversity and enrichment of Ruminococcus, Alistipes and Eubacterium. When considering the variations of the relative abundance of Akk within the Akk-Pos group, we obtained a large interval ranging from 0.0022% up to 64.78% with a 75th percentile at 4.42%. The relative abundance of Akk within &gt; 0% to &lt; 4.42% range in stools at diagnosis was associated with increased ORR, overall survival (OS) in multivariate analysis, independent of PD-L1 expression and ECOG. This sub-group was associated with more inflamed tumors with upregulation of CD3e, IfngTH1 and Vcam-1. Conversely, patients with overrepresentation of Akk &gt; 4.42% experienced more PD and shorter OS. Antibiotic use was associated with a shift in favor of Gammaproteobacteria, enrichment of Akk ( &gt; 4.42%) and shorter OS. Conclusions: We validated the prognostic role of Akk in patients with NSCLC. Stratification based on Akk relative abundance represents a more accurate independent predictor than the binary modality. Our study provides the rationale to develop microbiome-based approach to study gut dysbiosis in routine clinical oncology care. Clinical trial information: NCT04567446.

CYCLONE 1: A phase 2 study of abemaciclib in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with a novel hormonal agent and taxane-based chemotherapy.

TPS5086 Background: In cancer cells, the cyclin-dependent kinases 4 and 6 (CDK4 &amp; 6)/retinoblastoma protein (Rb) pathway is commonly altered, resulting in uncontrolled cell cycle entry and proliferation. CDK4 &amp; 6 inhibitors represent a major advance in the management of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (ABC or MBC, respectively). Abemaciclib is an oral selective inhibitor of CDK4 &amp; 6 administered on a continuous dosing schedule, approved in combination with endocrine therapy for HR+, HER2- ABC or MBC. In addition, abemaciclib is also approved by the FDA as monotherapy for HR+, HER2- ABC or MBC following endocrine therapy and prior chemotherapy in the metastatic setting. Similar to the estrogen receptor signaling pathway in breast cancer cells, there is evidence that the androgen receptor axis activates CDK4 &amp; 6 to sustain prostate cancer cell proliferation and survival. Preclinical studies in prostate cancer cell lines and xenograft models showed that abemaciclib exhibits single agent activity by inducing cell cycle arrest and tumor growth inhibition. Clinical activity of abemaciclib in combination with abiraterone and prednisone is investigated in a randomized phase 2 study in the first-line mCRPC setting (CYCLONE 2, NCT03706365). Despite recent advances, management of heavily pretreated mCRPC remains a major clinical challenge. Herein, we hypothesize that mCRPC patients whose disease progressed after novel hormonal agents (NHA) and taxane therapies may derive therapeutic benefit from single agent abemaciclib. Methods: CYCLONE 1 is a phase 2, single-arm, multicenter study to assess the safety and efficacy of abemaciclib monotherapy in 40 patients with mCRPC progressing after ≥1 NHA and 2 taxane regimens. Patients will be enrolled at time of prostate specific antigen (PSA) or radiographic progression per PCWG3 criteria and have at least 1 measurable lesion per RECIST 1.1. Metastatic tumor tissue (fresh biopsy or archival material &lt;12 weeks) is required at baseline for biomarker analysis. Patients will receive abemaciclib 200 mg twice daily until unacceptable adverse events or disease progression. The primary objective is investigator-assessed objective response rate (ORR). Key secondary objectives include safety, radiographic progression-free survival, overall survival, PSA response rate, time to PSA progression, time to symptomatic progression, Ki-67 expression, patient-reported outcomes, and pharmacokinetics. Assuming an ORR of 15%, the study has over 73% power to observe a response rate of at least 12.5%. Accrual began in January 2021. Clinical trial information: NCT04408924.