Burris, Howard A.

This report presents the American Society of Clinical Oncology’s (ASCO’s) evaluation of the adaptations in care delivery, research operations, and regulatory oversight made in response to the coronavirus pandemic and presents recommendations for moving forward as the pandemic recedes. ASCO organized its recommendations for clinical research around five goals to ensure lessons learned from the COVID-19 experience are used to craft a more equitable, accessible, and efficient clinical research system that protects patient safety, ensures scientific integrity, and maintains data quality. The specific goals are: (1) ensure that clinical research is accessible, affordable, and equitable; (2) design more pragmatic and efficient clinical trials; (3) minimize administrative and regulatory burdens on research sites; (4) recruit, retain, and support a well-trained clinical research workforce; and (5) promote appropriate oversight and review of clinical trial conduct and results. Similarly, ASCO also organized its recommendations regarding cancer care delivery around five goals: (1) promote and protect equitable access to high-quality cancer care; (2) support safe delivery of high-quality cancer care; (3) advance policies to ensure oncology providers have sufficient resources to provide high-quality patient care; (4) recognize and address threats to clinician, provider, and patient well-being; and (5) improve patient access to high-quality cancer care via telemedicine. ASCO will work at all levels to advance the recommendations made in this report.

Abstract Two death receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5), expressed in a wide variety of cancer cell types including lymphoma, enable TRAIL (TNF related apoptosis inducing ligand), a member of the TNF ligand superfamily, to induce apoptosis. HGS-ETR1 (TRM-1, mapatumumab) is a fully human monoclonal antibody agonistic to TRAIL-R1 with preclinical evidence of anti-tumor activity in vitro and in vivo. We conducted a phase 2 multicenter study of HGS-ETR1 in 40 subjects with relapsed or refractory NHL. Patients were included on the study if they had relapsed/refractory NHL of any histologic subtype, irrespective of the number of previous treatment regimens. HGS-ETR1 was administered at 2 dose levels: 3 mg/kg (8 subjects) or 10 mg/kg (32 subjects) every 21 days in the absence of disease progression or prohibitive toxicity for up to 6 cycles. The primary endpoint was tumor response evaluated with the International Working Group Criteria after every third treatment. Responses were confirmed between 4 and 8 weeks after initial documentation of response. Secondary endpoints included safety and tolerability. The median age of subjects was 62 years (range 32–81) (24M:16F) with an ECOG performance status 0–2. Subjects had received up to 12 previous therapeutic regimens (69% received 3 or more prior regimens). Original histologic classification is presently available for 34 subjects (14 follicular, 7 diffuse large B-cell, 6 mantle cell, 1 small lymphocytic, 2 peripheral T-cell, 1 anaplastic large cell, 3 lymphomas not classified). Preliminary response data are available for all 40 subjects. 3 subjects (8%), all with follicular lymphoma, had clinical responses (1CR, 2PR). Additionally, 12/40 subjects (30%) had stable disease, and the remainder had progressive disease at the time of first evaluation. 8 subjects (7 follicular) remain on study without disease progression for >5 to >13 months. One subject with a PR (special permission) has continued to receive HGS-ETR1 (10 cycles to date). Subjects tolerated therapy well with no subjects discontinuing therapy due to toxicity related to drug. There have been 10 reported SAEs, 2 of which were considered possibly/probably related to HGS-ETR1 administration (shingles, fever). In conclusion, HGS-ETR1 can be safely administered to heavily treated NHL patients. Clinical responses were seen in 3/14 follicular lymphoma subjects to date. Final data for all subjects will be reported at the meeting. These data suggest that HGS-ETR1 has activity in heavily pretreated lymphoma patients and further studies in combination with agents active in lymphoma are justified.

Abstract Introduction: Although HER2+ breast cancer (BC) is considered a moderately immunogenic tumor, several studies have shown a role of pre-existing immunity associated with favorable long-term prognosis and better response to treatment. In this study, we performed exploratory analyses to assess whether the efficacy of HER2 targeted treatment in the MARIANNE trial correlated with immune gene expression. Methods: MARIANNE (NCT01120184) is a phase 3 study in patients (pts) with centrally confirmed HER2+ local advanced/metastatic BC naïve to prior treatments in the advanced disease. Pts were randomized (1:1:1) to trastuzumab+taxane (HT), T-DM1, or T-DM1+Petuzumab (P) and the trial showed noninferior PFS of T-DM1 and T-DM1+P vs HT. Gene expression (RNA) analysis was performed on tumor samples by a custom 800-gene codeset on the nCounter platform. PD-L1, CD8 expressions and immune gene signatures (sign) analyses were assessed by multivariate Cox regression models using median (cut-off) as categorical variable and adjusted by prior HT, presence of visceral disease, world region, baseline ECOG, measureable disease at baseline, therapy setting, HER2 mRNA expression, PIK3CA mutation status. Results: MARIANNE randomized 1095 pts (HT, n=365; T-DM1, n=367; T-DM1+P, n=363). Gene expression results were available for 671 pts (61.3% of the intent-to-treat [ITT] population) which was representative of ITT. In ITT, HR below 1 was observed when comparing pts with high (>median) vs low (≤median) immune gene expression by clinical outcome suggesting a potential association of high immune marker expression with improved PFS (Table 1) and to some extent with OS (data not shown). This association was primarily observed in the T-DM1 arm where the HR suggested a risk reduction of disease progression(PD)/death especially in the high Teff, high PD-L1 and high CD8 subgroups, and to some extent in the HT arm (Table 1). When assessing the predictive impact on PFS by comparing T-DM1 vs HT, HR below 1 was observed especially in pts with high Teff signature, high PD-L1 and high CD8 expressions (HR 0.67 (95% CI (0.47-0.95)), HR 0.68 (95% CI (0.48-0.97), and HR 0.64 (95%CI 0.44-0.93), respectively). When comparing T-DM1+P vs. HT, HR below 1 was observed especially in pts with low Teff signature and low PD-L1 expression (HR 0.70 (95% CI (0.50-0.99), and HR 0.68 (95% CI (0.48-0.96) respectively). No clear differences between immune gene expression subgroups was observed when comparing treatment arms in regards to OS (data not shown). Conclusions: In the exploratory analysis from the MARIANNE study, high immune gene expression, especially in the high PD-L1, CD8 and Teff subgroups, showed an association with improved clinical benefit with HRs reflecting for a risk reduction of PD/death for PFS and partially for OS. This association was less obvious in the T-DM1+P arm. When comparing the treatments effect, the data showed a potential impact of high Teff signature, and high CD8 and PD-L1 expressions on T-DM1 and less on HT. The potential opposite association of low Teff signature and low PD-L1 expression with improved benefit in the T-DM1+P arm was unexpected and needs further investigation. Table 1: Prognostic biomarker effect on PFSBiomarker by categories (>Median vs ≤Median)HR (95% CI) ITT n=671HR (95% CI) HT n=220HR (95% CI) T-DM1 n=227HR (95% CI) T-DM1+P n=224Teff sign0.89 (0.73-1.09)0.97 (0.68-1.38)0.64 (0.45-0.91)1.09 (0.75-1.58)Th1 cytokine sign0.91 (0.74-1.11)0.92 (0.64-1.31)0.78 (0.55-1.11)0.96 (0.67-1.36)Checkpoint inhibitor sign0.95 (0.78-1.15)0.91 (0.64-1.29)0.90 (0.64-1.26)1.02 (0.71-1.47)PD-L10.80 (0.66-0.98)0.79 (0.55-1.13)0.62 (0.44-0.87)1.07 (0.74-1.55)CD80.91 (0.75-1.11)1.10 (0.77-1.57)0.66 (0.46-0.93)0.98 (0.68-1.41) Citation Format: Edith A Perez, Sanne Lysbet de Haas, Carlos H Barrios, Wolfgang Eiermann, Masakazu Toi, Young-Hyuck Im, Pier Franco Conte, Miguel Martin, Tadeusz Pienkowski, Xavier B Pivot, Howard A Burris III, Chiara Lambertini, Silke Hoersch, Monika Patre, Paul Anthony Ellis. Association of immune gene expression with outcome in the MARIANNE phase 3 clinical trial in HER2-positive metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD5-11.

299 Background: In 2011, ASCO launched a forum for the oncology research community to facilitate and promote the implementation of quality clinical research. The ASCO Research Community Forum (RCF) was created to provide a solution-oriented venue for research sites to address common challenges with conducting clinical trials. It offers in-person and virtual forums and resources to learn and share best practices with peers on a variety of topics, including site quality assessment and improvement, research site operations, and clinical trial access and accrual. Methods: An assessment was performed to measure the ASCO RCF output and to gather information on its potential impact on the cancer community. Results: The ASCO RCF has provided an in-person venue for physicians and research administrators with a steady increase in attendance, from 52 attendees in 2012 to 159 in 2018. Multi-stakeholder meetings and manuscripts have promoted best practices and solutions to address challenges with implementing quality clinical trials. Tools and resources to facilitate best practices and quality improvement at trial sites have been accessed by a range of types of research sites from across the U.S. and internationally. Its web-based library of resources was accessed over 27,000 times in 2018, alone. An online forum was launched in 2019 to provide a new opportunity to connect and impact the research community. Conclusions: The ASCO RCF is a productive and esteemed resource for the cancer research community. In-person and virtual forums, along with practical tools, promote access and accrual to clinical trials by facilitating networking, developing solutions, and providing education and resources. The ASCO RCF impact has extended from community-based oncology practices to larger research networks and academic centers across the U.S. and internationally. Its efforts to promote and facilitate access to quality clinical trials align with the vision and mission of ASCO to conquer cancer through research, education, and promotion of the highest quality patient care.

Abstract Btz (VELCADE®) is approved for patients (pts) with relapsed MM. This study characterized PK/PD of btz at 2 doses (1.0, 1.3mg/m2) after single- and multiple-dose administration, and evaluated their relationship. 24 pts with relapsed MM and creatinine clearance ≥50mL/min were randomized to btz 1.0 (n=12) or 1.3mg/m2 (n=12) on D 1, 4, 8 and 11 of a 21-D cycle (C). Pts could continue therapy for ≥8 Cs if beneficial. PK/PD samples were drawn at multiple time points on D1 and D11 of C1 and C3 over 48h. Plasma concentrations of btz were similar following administration of 1.0 and 1.3mg/m2; differences in mean plasma Cmax and AUC values were within the degree of intersubject variability (Table). There was a decrease in clearance and an increase in terminal half-life of btz on D11 vs D1 of C1.The volume of distribution of btz suggests extensive peripheral tissue distribution. After single or repeat administration, mean maximum percent inhibition of 20S proteasome activity (vs baseline) in whole blood was 70–84% and 73–83% for the 1.0 and 1.3mg/m2 doses, respectively. The percentage of pts who had >90% inhibition was greater in subsequent doses vs first dose. Reversibility of 20S proteasome inhibition in whole blood was demonstrated. PK/PD modeling revealed an exposure-response relationship, with Emax and EC50 values consistent across study days. These results confirm btz is a potent inhibitor of the 20S proteasome. The efficacy of single-agent btz has been explored and validated in the pivotal phase 2 SUMMIT and phase 3 APEX trials at 1.3mg/m2, and explored in the phase 2 CREST trial at 1.0mg/m2. Complete safety and efficacy data by dose will be presented. Mean±SD PK parameters of btz in plasma 1.0mg/m2 1.3mg/m2 1.0mg/m2 1.3mg/m2 D1/C1 (n=11) D11/C1 (n=12) an=5;bn=11;cn=10;dn=7;en=11;fn=9 Tmax (h) 0.13±0.13 0.11±0.06 0.07±0.03 0.20±0.29 Cmax (ng/mL) 56.7±36.3 112±122 106.2±46.7 88.6±47.6 AUC48h(ng·h/mL) 26.5±12.4 34.6±19.8 82.8±35.9b 82.4±28.6b AUClast (ng·h/mL) 22.6±12.6 31.5±18.6 137±106 122.2±67.4 CL (L/h) 102.1±48.1 111.6±73.6 23.2±17.8 28.0±19.8 Vβ (L) 1976±2498a 2015±2974d 1659±752c 2415±1711 t1/2λz(h) 30.7±44.8a 11.5±12.7d 78.9±50.9c 75.6±49.9 D1/C3 (n=12) D11/C3 (n=12) Tmax (h) 0.12±0.12 0.10±0.05 0.16±0.17 0.10±0.05 Cmax (ng/mL) 66.5±42.6 120.3±70.7 83.9±69.3 114.9±98.3 AUC48h(ng·h/mL) 66.4±24.1 79.4±24.5b 101.6±58.2b 85.2±18.7f AUClast (ng·h/mL) 74.8±35.8 86.0±27.6 227±181 160.7±67.1 CL (L/h) 32.2±19.0 32.1±15.4 15.1±13.9 18.2±9.2 Vβ (L) 1852±951d 2059±1231 3294±2993e 2505±1641 t1/2λz (h) 39.9±14.4d 49.1±34.6 193±169e 108.6±64.8

Background In the phase 3 MARIANNE trial, trastuzumab emtansine (T‐DM1) with or without pertuzumab showed noninferior progression‐free survival and better tolerability than trastuzumab plus a taxane (HT) for the first‐line treatment of human epidermal growth factor receptor 2 (HER2)–positive advanced breast cancer. This article reports the final descriptive overall survival (OS) analysis, updated safety data, and additional patient‐reported outcomes and biomarker analyses. Methods OS was assessed in 1095 patients with HER2‐positive breast cancer and no prior therapy for advanced disease who had been randomized to HT, T‐DM1 plus a placebo (hereafter T‐DM1), or T‐DM1 plus pertuzumab (T‐DM1+pertuzumab). A post hoc exploratory landmark analysis of OS, baseline patient and disease characteristics, and tumor biomarkers in patients with and without an objective tumor response (OR) according to the Response Evaluation Criteria in Solid Tumors within 6.5 months of randomization was conducted. Results The median OS was similar across groups (50.9, 53.7, and 51.8 months for the HT, T‐DM1, and T‐DM1+pertuzumab groups, respectively). Among patients with an OR, the median OS was longer with T‐DM1 (64.4 months) and T‐DM1+pertuzumab (not reached) versus HT (56.3 months). No baseline characteristics or biomarkers were strongly associated with OR. The incidence of grade 3 or higher adverse events was greater with HT (55.8%) than T‐DM1 (47.1%) or T‐DM1+pertuzumab (48.6%). The median time to clinically meaningful deterioration (a 3‐point or greater change) in neurotoxicity symptoms was shorter with HT (2.1 months) and T‐DM1+pertuzumab (4.2 months) than T‐DM1 (6.2 months). Fewer patients reported alopecia and diarrhea and were bothered by treatment side effects in the T‐DM1 arm. Conclusions These results support T‐DM1 as a first‐line treatment for patients with HER2‐positive metastatic breast cancer who are deemed unsuitable for taxane‐based therapy.

1030 Background: Previous studies have shown that 44-71% of trastuzumab (T)-treated pts develop HER2-specific immunity (Clin Cancer Res 2007, 13:5133; Cancer Res 2016, 76:3702; Breast Cancer Res 2018, 20:52). M is an Fc-engineered mAb that shares similar HER2 binding and antiproliferative activity as T. The Fc region of M has been engineered for increased affinity to the activating FcγRIIIA (CD16A) and lower binding to the inhibitory FcγRIIB (CD32B), attributes that may enhance the mAb’s immune function, such as antigen presentation. Methods: HER2+ cancer pts who progressed on prior therapy received M (0.1-6 mg/kg QW for 3 of every 4 weeks [N = 34]; or 10-18 mg/kg Q3W [N = 32]) in phase 1 trial NCT01148849. PBMC and plasma were collected pre-dose and 50 days post-dose for 46 pts and > 4 years for 3 pts on long-term treatment. Response to HER2 or control antigens (Ag) was assessed by IFNγ ELISpot and antibody (Ab) ELISA. In 14 pts, T-cell antigen receptor (TCR) repertoire was assessed by immunosequencing. Results: Following M treatment, mean frequencies of IFNγ-producing T cells specific for intra- or extracellular fragments of HER2 increased by 2.5 to 6-fold (p < 0.0027, paired t test). Most (95%) of subjects responded to ≥2 of 6 (median = 5) HER2 Ag. Mean HER2-specific Ab concentration increased by 19-54% (p < 0.0001), with all subjects responding to ≥2 (median = 5) of the 6 Ag. A small 1.6-fold increase in IFNγ response to control CMV/EBV/Flu (but not tetanus or cyclin D1) peptides was observed; no increase in Ab response to control Ag was noted. Subsets of HER2-specific T-cell and Ab responses persisted during long-term treatment. Median TCR clonality increased by 54% (p = 0.003), with an average of 125 unique clones expanding, while overall TCR diversity remained unchanged (p = 0.19). Conclusions: Treatment of HER2+ cancer with M was associated with enhanced HER2-specific T-cell and Ab responses together with increased TCR clonality, indicative of a more focused T-cell repertoire. The high frequency of HER2-specific immunity in M-treated patients ( > 95%) is consistent with its enhanced Fc region contributing to linkage of innate and adaptive immune responses.