Citations

11550 Background: RPS often have local recurrence (LR) after surgery. Preoperative radiation (RT) to 50.4 Gy can reduce LR risk but is not uniformly effective, especially after (+) margin resections. Therefore, we conducted a multi-institutional, prospective Phase II study to assess efficacy and tolerability of preop IMPT with selective dose escalation to 63 GyRBE to the posterior RPS margin (clinical target volume [CTV] 2) at high risk for (+) margins to further reduce the risk of LR. This dose was tolerable in a prior phase I study (DeLaney T et al, 2017, PMID:28740917). Methods: Primary RPS patients (pts) >18 years received preop IMPT, 50.4 GyRBE in 28 fractions (fx) of 1.8 GyRBE to CTV1 (tumor plus adjacent tissue at risk of subclinical disease) with SIB to CTV2 to 63.0 GyRBE in 28 fx of 2.25 GyRBE. Pts with high-grade tumors could get chemotherapy(CTX) prior to IMPT. To avoid treatment delay, 11 fx of IMRT x-rays could be substituted for IMPT. Pts had restaging and surgery 4-8 weeks after IMPT. Primary study endpoint was local tumor control. Secondary endpoints included clinical and pathologic response, surgical margin status, and disease-free and overall survival. Results: We accrued 60 pts from January 2016 to February 2021. Histology: 35 liposarcoma(LPS) (19 dediff and 16 well diff), 22 leiomyosarcoma(LMS), and 3 undifferentiated pleomorphic sarcoma. IMPT was delivered per protocol in all pts. 51 pts have had surgery, 5 are awaiting surgery, and 4 had no surgery due to metastases(DM) on preop imaging. 22 pts had (+) margins. 2 pts had > 75% necrosis. With 23-month median (range 1-52 months) follow-up after start of RT, there were two LRs. A dediff LPS pt had a well diff LPS LR 26 months postop, resected, and is disease-free. A renal vein/IVC LMS pt treated with CTX and IMPT had LR and DM 4 months postop and died from disease. Surgical Clavien-Dindo morbidity scores: 0(21), 1(9), 2(8), 3a (4), 3b(4), 4a(2), 4(b)1, 5(2); the periop deaths were from sepsis(pneumonia) and duodenal ulcer. The grade 3-4 periop morbidity included abscess(3), treated by catheter(2) or operative(1) drainage, prolonged hospital stays (2 pts with IVC LMS), small bowel obstruction (1), and late sigmoid colon anastomotic failure (1). Readmissions for lymphopenia(1), pneumoperitoneum (1), and volume overload (1). One late neuropathy was seen in a Type II diabetic pt with transient postop weakness after femoral nerve dissection who later had significant lower extremity weakness 3.75 years postop. Study was amended to reduce IMPT dose in diabetic pts. Conclusions: Preoperative IMPT with selective dose escalation to 63 GyRBE to the high risk posterior RPS margin is feasible. Early local control results with this approach appear promising. Some peri-operative morbidity was noted but appears to be in the expected range for RPS resections. Clinical trial information: NCT01659203.

11014 Background: The well-being of oncology providers (OP) is in jeopardy with increasing workload, limited resources, and personal challenges that result from the COVID-19 pandemic. We aim to evaluate the impact of COVID-19 on work-related (WR) satisfaction and fatigue among OP in Latin America. Methods: We conducted an international cross-sectional online survey of OP practicing in Latin America. The survey was administered in English, Spanish, and Portuguese. Data was analyzed using descriptive statistics and Chi-square tests. Results: In August 2020, 704 OP from 20 Latin American countries completed the survey (77% of 913 who started the survey). Table outlines baseline characteristics. Higher frequency of WR fatigue (67% vs. 58%, p=0.010) and exhaustion (81% vs. 70%, p=0.001) were reported by OP who cared for patients with COVID-19, compared to OP who cared for patients without COVID-19. Providers that observed delays in referrals to radiation (p=0.002) and surgery (p=0.04) reported WR fatigue at higher rates than their counterparts. Higher exhaustion (p=0.016) and dissatisfaction (p=0.046) were reported by OP who lacked access to supportive services, as social work. A significantly higher proportion of women reported WR fatigue (72% vs. 56%, p=0.003) and exhaustion (86% vs. 68%, p=0.001), when compared to men. Women were more likely than men to endorse higher current levels of fatigue when compared to pre-COVID-19 (61% vs. 46%, p=0.0001). To reduce stress, women were more likely than men to cut the time spent watching the news (p=0.002). Both genders declined research collaborations and speaking opportunities. Conclusions: Fatigue and dissatisfaction with work-life were prevalent among OP in Latin America. Higher rates of WR fatigue were seen in women, OP caring for patients with COVID-19, and OP with patients who experienced cancer care delays. Our data imply that OP may be a prime target for psychosocial support, particularly as current challenges will continue for the foreseen future. Baseline characteristics (N=704).[Table: see text]

9566 Background: Cemiplimab-rwlc is the first immunotherapy to receive approval in the US, fully for pts with laBCC and accelerated for metastatic BCC, post hedgehog inhibitors or for whom hedgehog inhibitors are not appropriate. Cemiplimab resulted in clinically meaningful anti-tumor activity in pts with laBCC who progressed on or were intolerant to hedgehog inhibitor therapy (NCT03132636). This analysis evaluated HRQoL in these pts. Methods: Adults with laBCC and ECOG performance status ≤1 (n=84) received IV cemiplimab 350 mg Q3W for up to 9 treatment cycles. At baseline (BL) and day 1 of each cycle (C), pts completed EORTC QLQ-C30 and SKINDEX-16 questionnaires that assess Global Health Status (GHS)/QoL, functioning, and BCC-related symptoms. Mixed-effects repeated measures (MMRM) models were used to estimate least squares (LS) mean (standard error [SE]) change from BL during treatment (i.e., across C2 to C9); changes ≥|10| points were considered clinically meaningful. Responder analyses were conducted in pts with non-missing data from BL to determine the proportions with clinically meaningful improvement or deterioration, or stability on QLQ-C30 and SKINDEX-16 at C2 and C9; a 10-point threshold was considered meaningful for both instruments. Results: BL scores showed moderate to high levels of functioning and low symptom burden. In MMRM models, overall changes from BL on QLQ-C30 indicated stability for GHS/QoL and all scales except for clinically meaningful worsening of fatigue (LS mean [SE] change 12.5 [3.9]; P<.05). In responder analysis, the majority of pts reported clinically meaningful improvement or stability at C2 and C9 on all QLQ-C30 functioning scales and the key symptom of pain but not fatigue (Table). On SKINDEX-16, MMRM models showed clinically meaningful improvement on the emotional subscale (LS mean [SE] change –13.2 [3.9]; P<.05) and stability on the symptom and functional subscales. Responder analysis showed clinically meaningful improvements or stability across the SKINDEX-16 subscales in approximately 80% of pts at C2, and 70–80% of pts at C9. Conclusions: In laBCC pts treated with cemiplimab, the majority reported clinically meaningful improvement or stability in GHS/QoL and functional status while maintaining a low symptom burden except for fatigue. Clinical trial information: NCT03132636. [Table: see text]

9093 Background: Treatment addressing non-small cell lung cancer (NSCLC) harboring EGFR or HER2 exon 20 insertion mutations remains an unmet need. These tumors are associated with a high incidence of CNS metastases and unfavorable survival rates. Poziotinib is a potent, irreversible, tyrosine kinase inhibitor (TKI) with a structure that can overcome the steric hindrance of the exon 20 limited binding pocket. Preclinical data suggest poziotinib CNS penetration, and here we show meaningful poziotinib CNS activity in patients with NSCLC harboring exon 20 insertion mutations in an ongoing multi-cohort, multi-center Phase 2 study (ZENITH20; NCT03318939). Methods: ZENITH20 enrolled previously treated and naïve patients with advanced/metastatic NSCLC and EGFR or HER2 exon 20 insertion mutations in several cohorts: Cohort 1 (C1) EGFR previously treated; Cohort 2 (C2) HER2 previously treated and Cohort 3 (C3) EGFR treatment-naïve. All patients with stable CNS metastases at baseline were included. Poziotinib (16 mg) was administered orally QD, with follow-up for up to 24 months. The primary endpoint was Objective Response Rate (ORR) evaluated centrally using RECIST v1.1 by an independent image review committee. Secondary endpoints included Disease Control Rate (DCR), Duration of Response (DOR), Progression-Free Survival (PFS) and safety. Primary efficacy results have been previously released. Intracranial response was determined based on the modified RECIST criteria. Results: A total of 284 patients across 3 cohorts (C1 n=115; and C2 n=90; and C3 n=79) with a median age of 60.5 years were enrolled. The median follow-up was 7.3, 8.3, and 9.2 months for all patients in C1, C2, and C3, respectively. In NSCLC patients that had baseline CNS lesions (N=36), the analysis showed a patient-based ORR of 22.2% (8/36) and a DCR of 88.9% (32/36). One patient in each cohort had a complete intracranial response and stable disease was 80.6% across 3 cohorts and 92.9% in C2. Two patients each in C1 and C3 had progressive disease (PD) and none had CNS progression in C2 (Table). Conclusions: Poziotinib exhibited clinically meaningful CNS activity in patients with EGFR or HER2 exon 20 mutations in ZENITH20 Cohorts 1-3. The majority of the patients had no CNS progression and 3/36 patients had intracranial complete responses. The preliminary data suggest that poziotinib may provide a meaningful treatment alternative for patients with NSCLC that harbor EGFR or HER2 exon 20 mutations and who present with CNS metastases that have poor prognosis. Clinical trial information: NCT03318939. [Table: see text]

9089 Background: RET fusions are targetable oncogenic drivers in 1–2% of non-small cell lung cancer (NSCLC). ARROW (NCT03037385) supported the US FDA approval of pralsetinib, a highly potent oral selective RET inhibitor for RET-altered NSCLC and thyroid cancer. Here, we present updated results for a larger population of patients with RET fusion–positive NSCLC enrolled in ARROW. Methods: ARROW is a phase 1/2 open-label study conducted at 84 sites in 13 countries. Phase 2 expansion cohorts included patients with RET fusion–positive NSCLC. Initially, all treatment-naïve patients were not candidates for platinum-based therapy, a requirement removed by protocol amendment in July 2019. Primary objectives are overall response rate (ORR; blinded independent central review [BICR] per RECIST v1.1), assessed for patients with baseline measurable disease, and safety. Results: Updated analyses were completed as of Nov 6, 2020 (data cut-off), for patients who initiated pralsetinib 400 mg QD by May 22, 2020 (enrollment cut-off). Efficacy results, including analyses for treatment-naïve patients enrolled after eligibility criteria were revised to allow candidates for platinum-based therapy, are shown in the Table. Conclusions: Pralsetinib showed rapid, potent, and durable clinical activity in patients with RET fusion-positive NSCLC (regardless of prior therapies), including poor prognosis patients not eligible for platinum-based therapy. Overall, pralsetinib was well-tolerated. These data highlight the need for RET testing early in the course of disease to identify candidates who may benefit from treatment with pralsetinib. Clinical trial information: NCT03037385. [Table: see text]

e17025 Background: PT-112 is a novel pyrophosphate-platinum conjugate that induces immunogenic cell death, reaches highest concentrations in bone (osteotropism), and synergizes with immune checkpoint inhibitors (ICIs) in preclinical models. Phase I studies in solid tumors, as monotherapy and in combination with PD-L1 inhibitor avelumab (“PAVE”), as well as in multiple myeloma as monotherapy have demonstrated that PT-112 is well-tolerated and active. We present updated safety and exploratory efficacy findings in a mCRPC sub-population treated with PAVE, including a cohort of patients at a lower-frequency dosing schedule. Methods: A total of 32 mCRPC patients (pts) received 800 mg of avelumab on days 1 and 15 of a 28-day cycle, of whom 18 received PT-112 on days 1, 8 and 15 at 200mg/m2 (n = 17) or 150 mg/m2 (n = 1); a separate cohort of 14 received PT-112 on days 1 and 15 at 300 mg/m2 (n = 13) or 200mg/m2 (n = 1). Results: Median age was 68 (range 47-87) and number of prior lines of therapy (Tx) was 7 (2-12), including prior platinum-containing therapy in 11 (34%) and ICI Tx in 9 pts (28%). Baseline grade 2 anemia was seen in 7 (22%) pts. The most common treatment-related adverse events (TRAEs) were anemia (47%) and thrombocytopenia (41%); 23 pts (72%) had ≥1 grade 3-4 TRAE, with no cases of bleeding, sepsis, or grade 5 TRAEs. Antitumor effects included 8 (25%) pts with a PSA reduction of ≥50% (PSA50); 5 (16%) were maintained through ≥1 follow-up. Of ten pts with RECIST-measurable disease, 3 had tumor volume reductions, one with a confirmed partial response (PR). Twenty-four (75%) pts experienced a reduction in serum alkaline phosphatase (ALP) (median reduction 15%), and improvement in patient-reported pain and quality of life was observed. For the 13 pts given 300 mg/m2 PT-112 bi-weekly, 7 (54%) had prior platinum-containing Tx and 4 (31%) had baseline grade 2 anemia. The most common TRAEs were anemia (69%) and thrombocytopenia (54%), with 11 (85%) pts having ≥1 grade 3-4 TRAE. Four pts (31%) had PSA50 reductions; 3 (23%) were maintained through ≥1 follow-up. Conclusions: PAVE is safe and generally well tolerated in mCRPC patients at the doses and schedules tested, providing meaningful antitumor effects in heavily pre-treated patients, including tumor volume, PSA and ALP reductions. Reductions in ALP may be indicative of anti-cancer activity at bone sites of disease. Although the sample sizes are small, the frequency of confirmed PSA50 responses and of grade 3-4 TRAEs was slightly higher in the group receiving biweekly 300 mg/m2 PT-112, and higher rates of TRAEs may be explained by higher baseline anemia and/or prior platinum Tx. Further clinical investigation of the combination of PT-112 plus ICIs in a less heavily pre-treated mCRPC population is warranted. A phase 2 study of PT-112 monotherapy in mCRPC is ongoing. Clinical trial information: NCT03409458.

4069 Background: CCA is a rare cancer for which there are limited effective therapies. IDH1 mutations occur in ̃20% of intrahepatic CCAs, resulting in production of the oncometabolite D-2-hydroxyglutarate, which promotes oncogenesis. IVO (AG-120) is a first-in-class, oral, small-molecule inhibitor of mutant IDH1 (mIDH1). ClarIDHy aimed to demonstrate the efficacy of IVO vs PBO in pts with unresectable or metastatic m IDH1 CCA. The primary endpoint was met with significant improvement in progression-free survival (PFS) by independent radiology center (IRC) with IVO vs PBO (hazard ratio [HR] = 0.37, p < 0.0001). Objective response rate (ORR) and stable disease for IVO were 2.4% (3 partial responses) and 50.8% (n = 63) vs 0% and 27.9% (n = 17) for PBO. IVO pts experienced significantly less decline in physical and emotional functioning domains of quality of life at cycle 2 day 1 vs PBO pts (nominal p < 0.05). Methods: Pts with m IDH1 CCA were randomized 2:1 to IVO (500 mg PO QD) or matched PBO and stratified by prior systemic therapies (1 or 2). Key eligibility: unresectable or metastatic m IDH1 CCA based on central testing; ECOG PS 0–1; measurable disease (RECIST v1.1). Crossover from PBO to IVO was permitted at radiographic progression. Primary endpoint: PFS by IRC. Secondary endpoints included overall survival (OS; by intent-to-treat), ORR, PFS (by investigator), safety, and quality of life. The planned crossover-adjusted OS was derived using the rank-preserving structural failure time (RPSFT) model. Results: As of 31 May 2020, ̃780 pts were prescreened for an IDH1 mutation and 187 were randomized to IVO (n = 126) or PBO (n = 61); 13 remain on IVO. Median age 62 y; M/F 68/119; 91% intrahepatic CCA; 93% metastatic disease; 47% had 2 prior therapies. 70% of PBO pts crossed over to IVO. OS data were mature, with 79% OS events in IVO arm and 82% in PBO. Median OS (mOS) was 10.3 months for IVO and 7.5 months for PBO (HR = 0.79; 95% CI 0.56–1.12; one-sided p = 0.093). The RPSFT-adjusted mOS was 5.1 months for PBO (HR = 0.49; 95% CI 0.34–0.70; p < 0.0001). Common all-grade treatment emergent adverse events (TEAEs, ≥ 15%) in the IVO arm: nausea 41%, diarrhea 35%, fatigue 31%, cough 25%, abdominal pain 24%, decreased appetite 24%, ascites 23%, vomiting 23%, anemia 18%, and constipation 15%. Grade ≥ 3 TEAEs were reported in 50% of IVO pts vs 37% of PBO pts, with grade ≥ 3 treatment-related AEs in 7% of IVO pts vs 0% in PBO. 7% of IVO pts experienced an AE leading to treatment discontinuation vs 9% of PBO pts. There were no treatment-related deaths. Conclusions: IVO was well tolerated and resulted in a favorable OS trend vs PBO despite a high rate of crossover. These data – coupled with statistical improvement in PFS, supportive quality of life data, and favorable safety profile – demonstrate the clinical benefit of IVO in advanced m IDH1 CCA. Clinical trial information: NCT02989857.

1537 Background: The severe acute respiratory syndrome 2 (SARS-cov-2) virus causing COVID-19 has brought great challenges to global health services affecting cancer care delivery, outcomes, and increasing the burden in oncology providers (OP). Our study aimed to describe the challenges that OP faced while delivering cancer care in Latin America. Methods: We conducted an international cross-sectional study using an anonymous online survey in Spanish, Portuguese, and English. The questionnaire included 43 multiple choice questions. The sample was stratified by OP who have treated patients with COVID-19 versus those who have not treated patients with COVID-19. Data was analyzed with descriptive statistics and Chi-square tests. Results: A total of 704 OP from 20 Latin American countries completed the survey (77% of 913 who started the survey). Oncologists represented 46% of respondents, followed by 25% surgical-oncologists. Of the respondents, 56% treated patients with COVID-19. A significant proportion of OP reported newly adopting telemedicine during COVID-19 (14% vs 72%, p=0.001). More than half (58%) of OP reported making changes to the treatments they offered to patients with cancer. As shown in the table, caring for patients with COVID-19 significantly influenced practice patterns of OP. Access to specialty services and procedures was significantly reduced: 40% noted significantly decreased or no access to imaging, 20% significantly decreased or no access to biopsies, 65% reported delays in surgical oncology referrals, and 49% in radiation oncology referrals. A vast majority (82%) reported oncologic surgeries were delayed or cancelled, which was heightened among those treating patients with COVID-19 (87% vs 77%, p=0.001). Conclusions: The COVID-19 pandemic has significantly affected the way cancer care is delivered in globally. Although changes to healthcare delivery are necessary as a response to this global crisis, our study highlights the significant disruption and possible undertreatment of patients with cancer in Latin America that results from COVID-19.[Table: see text]

7541 Background: FT516 is an investigational, NK cell cancer immunotherapy derived from a clonal master iPSC line. FT516 is engineered with a novel hnCD16 Fc receptor, demonstrated preclinically to maximize antibody-dependent cellular cytotoxicity (Zhu et al. Blood 2020). FT516 can be mass produced and made available off-the-shelf for broad pt access and multi-dose administration. Methods: This is a Phase I trial of FT516 combined with rituximab (R) in pts with R/R BCL. Treatment consists of 2 cycles, each with 3 days lympho-conditioning (fludarabine 30 mg/m 2 and cyclophosphamide 500 mg/m 2 ) and 1 dose of R followed by 3 weekly infusions of FT516 (planned doses 30-900 million/dose) with IL-2 (6 MIU after each FT516 dose). The primary objective is to identify the incidence of dose-limiting toxicity (DLT)/dose cohort and the recommended Phase II dose using a standard 3+3 design. Additional objectives include safety, tolerability, preliminary activity, pharmacokinetics, and immunogenicity. Results: Six pts (5 DLBCL, 1 FL, median age 65.5 y) have completed (5) or discontinued (1) study treatment after the DLT period (data cutoff 9 Dec 2020): 2 received 30 million cells/dose, 3 received 90 million cells/dose, and 1 received 300 million cells/dose. All pts received > 1 prior R-containing regimen, and median number of prior therapies was 3 (range 2-6), including CAR-T in 3 pts. FT516 was primarily administered in the outpatient setting. No FT516-related Grade ≥3 adverse events (AEs) or serious AEs, and no events of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), or graft-versus-host disease (GvHD) of any grade were reported. DLT (Grade 4 neutrophil count decreased, not recovered to baseline by D29) was reported in the first pt at 30 million cells/dose and R dosing of 375 mg/m 2 weekly x 4/cycle, resulting in modification of R dosing to once/cycle; no DLTs were observed with modified R dosing. Most common all grade AEs in ≥3 pts: fatigue (4 pts) and decreased appetite, nausea, neutrophil count decreased, and headache (3 pts each). Grade ≥3 AEs in ≥2 pts: neutrophil count decreased (3 pts) and febrile neutropenia and platelet count decreased (2 pts each); none considered related to FT516. Host anti-product B- or T-cell immunogenicity was not observed. Three of 4 pts treated at ≥90 million cells/dose achieved objective response (2 complete responses [CRs] and 1 partial response). Conclusions: Administration of up to 6 doses of FT516 cells, including up to 300 million cells/dose, appears to be safe and tolerable, without CRS, ICANS, or GvHD. Activity was observed, including CRs, in heavily pretreated pts. Dose escalation is ongoing. Updated clinical and translational data will be presented. Clinical trial information: NCT04023071.

508 Background: I-SPY 2 is a multicenter, phase 2 trial using response-adaptive randomization within molecular subtypes defined by receptor status and MammaPrint (MP) risk to evaluate novel agents as neoadjuvant therapy for women with high-risk breast cancer. SD-101 is an investigational Toll-like receptor 9 (TLR9) agonist CpG-C class oligodeoxynucleotide that stimulates the production of IFN-α and interleukin (IL)-12, functional maturation of plasmacytoid dendritic cells, and production of cytotoxic antibodies. IT SD-101 was combined with systemic anti-PD-1 antibody Pb to investigate the antitumor and immunologic activity of this novel immunotherapeutic strategy. Methods: Women with tumors ≥ 2.5cm were eligible for screening. Only pts (pts) with HER2- disease were eligible for this treatment. Treatment included weekly P x 12 in combination with IT SD-101 2 mg/ml (1 ml for T2 tumors, 2 ml for >T3 tumors) weekly x 4, then q3 weeks x 2, and IV Pb q3 weeks x 4, followed by doxorubicin/cyclophosphamide (AC) q2-3 weeks x 4 (SD-101+Pembro 4). Pts in the control arm received weekly P x 12 followed by AC q2-3 weeks x 4. The I-SPY 2 methods have been previously published. This investigational arm was eligible for graduation (>85% chance of success in a 300-person phase 3 neoadjuvant trial) in 3 of 10 pre-defined signatures: HER2-, hormone receptor (HR)+/HER2- and HR-/HER2-. Results: 75 pts were randomized and evaluable in SD-101+Pembro 4 treatment arm. The control arm included 329 historical controls enrolled since April 2010. The study arm was stopped due to maximal patient accrual. Pt characteristics were balanced; 56% HR+, 44% HR-. The probability that SD-101+Pembro4 was superior to control exceeded 97% for all eligible tumor signatures, but did not reach the threshold for graduation in any of the signatures. However, it is notable that the rate of pCR/Residual Cancer Burden 1 (RCB1) in the HR+/HER2- signature was 51%. Preliminary safety events for SD-101+Pembro 4 include increased rates of fever, neutropenia, febrile neutropenia, transaminitis, and immune-related events, including adrenal insufficiency. Conclusions: The SD-101+Pembro 4 regimen was active but did not meet the pre-specified threshold for graduation in I-SPY 2. pCR/RCB 1 analysis suggests improved response in the HR+/HER-negative signature compared to control. The clinical significance of these findings needs to be weighed against the potential risk of immune-related toxicities. Clinical trial information: NCT01042379. [Table: see text]