Not Estimable Research Articles

P947: COMPARATIVE EFFECTIVENESS OF ORAL IXAZOMIB-LENALIDOMIDE-DEXAMETHASONE (IRD) AFTER INITIAL BORTEZOMIB (V)-BASED INDUCTION VS PARENTERAL V-BASED THERAPY IN NEWLY DIAGNOSED MULTIPLE MYELOMA (NDMM)

Background: Long-term proteasome inhibitor (PI)-based treatment can improve outcomes for patients (pts) with multiple myeloma (MM). However, prolonged parenteral PI therapy (e.g. with V) can be challenging to achieve in routine clinical practice, and outcomes for pts are often poorer in this setting compared with clinical trials. The phase IV, community-based, single-arm US MM-6 study (NCT03173092) is assessing in-class transition (iCT) from V-based induction to all-oral IRd in transplant ineligible NDMM pts treated in routine clinical practice, with the objective of increasing the duration of PI-based treatment while maintaining quality of life. INSIGHT MM is the largest global, prospective, observational study of MM pts (>4,200), and provided a subset of patients as the comparator cohort. This enabled assessment of iCT vs V-based therapy in NDMM pts in routine clinical practice in the US. Aims: To examine the comparative effectiveness of IRd following initial V-based induction (3 cycles; US MM-6 pts; ‘IRd’ cohort) vs continued V-based therapy (INSIGHT MM pts; ‘V-based’ cohort) in NDMM pts. Methods: A secondary analysis of non-transplant eligible US NDMM pts with ≥stable disease after 3 cycles of V-based induction and baseline Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, 1 or 2 from the US MM-6 (Manda CLML 2020) and INSIGHT MM (Costello Future Onc 2019) studies was performed. Study outcomes included first-line duration of treatment (DOT), overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and reasons for treatment discontinuation. All analyses were weighted using the inverse probability of treatment weighting (IPTW) approach to reduce the imbalance of potential confounding factors between the two cohorts (adjusted analyses). Kaplan–Meier methods were used to examine DOT, PFS, OS, and associated 95% confidence intervals (CIs); the log-rank test was used to compare distribution of time to events. The Clopper-Pearson method was applied to estimate 95% CIs for ORR. Statistical significance was evaluated at alpha=0.05. Results: 100 pts from the IRd cohort (MM-6) and 111 pts from the V-based cohort (INSIGHT) were included. After IPTW, in the IRd vs V-based cohorts: median age was 75.0 vs 74.8 yrs; 56.7 vs 51.3% of pts were male; 37.4 vs 29.1% had an ECOG PS of ≥2; 48.8 vs 41.4% had International Staging System stage III at initial diagnosis, and 79.5/17.7/2.8 vs 77.3/19.5/3.1% pts had received VRd/ V-cyclophosphamide-d (VCd)/ VRCd as initial induction therapy. Adjusted ORRs in the IRd vs V-based cohorts were 74.1 (95% CI 66.0–82.2) vs 57.5% (95% CI 47.9–67.1; p<0.0001). After a median follow-up of 20.3 and 15.8 months in the IRd and V-based cohorts, respectively, DOT was 10.8 (95% CI 6.5–24.4) vs 5.3 months (95% CI 4.3–7.0; p<0.0001) (see Figure). Median PFS was not estimable (NE) in either cohort; 24-month PFS rates were 85.7 (95% CI 68.1–94.0; IRd cohort) vs 76.5% (95% CI 62.6–85.8; V-based cohort). Median OS was NE in either cohort; 24-month OS rates were 94.0 (95% CI 77.7–98.5; IRd cohort) vs 84.9% (95% CI 70.6–92.6; V-based cohort). In the IRd and V-based cohorts, 16.8 and 16.9% of pts discontinued IRd and V, respectively, due to an adverse event. Image:Summary/Conclusion: US MM-6 NDMM pts who transitioned to IRd after 3 initial cycles of V-based induction had a significantly higher ORR and longer DOT compared with pts who received continued V-based therapy in INSIGHT MM. The results suggest that iCT from continued V-based therapy to all-oral IRd may improve outcomes in pts treated at community oncology clinics.

Comparison of survival outcomes between dostarlimab and comparator treatments (tx) in patients (pts) with advanced/recurrent (A/R) endometrial cancer (EC) in England: Matching-adjusted indirect comparisons (MAICs).

e17534 Background: Limited tx options exist for pts with A/R EC who progress on/after platinum-based chemotherapy (PBCT). This study compared survival outcomes of pts with A/R mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) EC receiving dostarlimab in Cohort A1 of the single-arm, Phase I GARNET trial, with an equivalent real-world (RW) cohort receiving current tx in England. The primary objective compared second-line (2L) overall survival (OS) between cohorts; a secondary objective was time to tx discontinuation (TTD; proxy for progression-free survival). Methods: An overall-2L-tx RW cohort was established using National Cancer Registration and Analysis Service data. Five tx-specific RW cohorts were identified (tx received at 2L in &gt; 5% of pts) (Table). Clinical outcomes between GARNET and RW cohorts were compared using MAICs. Relevant prognostic variables were used to create 3 matching scenarios (SC): SC1: grade, histology, PBCT number; SC2: histology, PBCT number; SC3: race/ethnicity, stage at diagnosis, histology, prior surgery (MMR/MSI status not considered). OS was time from first dostarlimab dose (GARNET) or 2L RW tx (RW cohorts) to any-cause death; MAIC-adjusted hazard ratios (HR, 95% confidence interval [CI]) were estimated by weighted Cox proportional-hazards models. TTD after MAIC was summarized descriptively. Results: Effective sample size (ESS) assessed matching capacity; lower ESS in SC1 reduced its robustness (Table). Following matching, distributions of baseline characteristics were similar between cohorts. Across most matching scenarios, there was a lower risk of death in pts treated with dostarlimab compared to the overall RW cohort and for tx-specific RW cohorts (Table). Median TTD (months, 95% CI) was longer for pts treated with dostarlimab across all matching scenarios (SC1: 7.8 [4.1, not estimable (NE)]; SC2: 9.7 [5.5, NE]; SC3: 14.0 [6.4, 17.9]) than the overall RW cohort (3.4 [3.2, 3.4]). Conclusions: Results suggest that pts in GARNET with dMMR/MSI-H A/R EC receiving dostarlimab had better OS and longer TTD compared with pts receiving current 2L tx in England. Funding: GSK (217216; scott.r.goulden@gsk.com).[Table: see text]

Phase 1b results of a multicenter, randomized phase 1b/2 study of gemcitabine and cisplatin +/- CPI-613 as first-line therapy for patients with advanced biliary tract cancer (BilT-04).

4094 Background: Patients (pts) with advanced biliary tract cancers (BTC) have a poor prognosis despite systemic chemotherapy. Gemcitabine (G) and cisplatin (C) is a standard first-line systemic therapy with a reported overall response rate (ORR) of 26% and median overall survival (OS) of 11.7 months (mo). CPI-613/Devimistat (D) is a stable intermediate of a lipoate analog that inhibits pyruvate dehydrogenase and a-ketoglutarate dehydrogenase enzymes of the tricarboxylic (TCA) cycle, preferentially within the mitochondria of cancer cells augmenting chemotherapeutic cytotoxicity. Methods: An investigator-initiated, multi-institutional phase 1b/2 trial is underway across 10 sites in the US investigating the combination of G 1000 mg/m2, C 25 mg/m2 and D (dose levels: (-1) 500, (1) 1000, (2) 1500 and (3) 2000 mg/m2) (GCD) on days 1 and 8 every 21 days in pts with previously untreated advanced BTC. The primary objective of the phase 1b portion (n = 20 pts; TiTE-CRM methodology) was to determine the recommended phase 2 dose (RP2D). The primary objective of the ongoing phase 2 portion (n = 48-58 pts; 2:1 randomization with Bayesian control arm) is to determine the best ORR with an alternative hypothesis of 43% (null of 25%); with 80% power and one-sided alpha of 0.05. Secondary objectives include evaluation of progression-free survival (PFS), OS, and safety. Exploratory objectives include targeted exome/ transcriptomic analysis using tissue, and metabolomic analysis using plasma (pre-, on- and post-treatment). Results: 20 pts were enrolled on phase 1b; median age 65 years (range 43-75), ECOG PS 0/1 (9/11), male/female (11/9), Caucasian (85%), intrahepatic/hilar/distal cholangiocarcinoma and gallbladder (9/5/3/3), and metastatic/locally advanced stage (15/5). CPI-613 dose level assignments were 1 pt each for (-1) and (1), 2 pts on (2), and 16 pts on (3). Median follow-up was 9.4 mos and median number of cycles was 9. Only 1 pt had dose-limiting toxicity (grade 2 creatinine elevation). RP2D for CPI-613 was 2000 mg/m2. In phase 1b, ORR was 40% (7 PR, 1 CR). Median PFS not estimable (NE) but probability of PFS at 9 months was 68.1% [95% CI, 38.1%-85.8%]. Median OS is 16.3 months [95% CI, 9.1-NE]. One locally advanced pt was resected with pathologic CR. Conclusions: The combination of GCD was well tolerated and demonstrates encouraging efficacy with ORR, PFS and OS in phase 1b. The randomized phase 2 portion of the trial is open and accruing patients. Clinical trial information: NCT04203160.

Real-World Treatment Patterns and Clinical Effectiveness of Palbociclib Plus an Aromatase Inhibitor as First-Line Therapy in Advanced/Metastatic Breast Cancer: Analysis from the US Syapse Learning Health Network.

This retrospective single-arm study assessed real-world treatment patterns and clinical outcomes in patients with hormone receptor—positive/human epidermal growth factor receptor 2—negative (HR+/HER2−) advanced/metastatic breast cancer (A/MBC) who received palbociclib plus an aromatase inhibitor as first-line therapy in US community health systems. Using electronic health records from the Syapse Learning Health Network, 242 patients were identified as having received first-line palbociclib plus an aromatase inhibitor between 3 February 2015, and 31 July 2019 (data cutoff 1 February 2020) resulting in a minimum potential 6-month follow-up period. In total, 56.6% of patients had de novo A/MBC at initial breast cancer diagnosis, 50.8% had bone-only disease, and 32.2% had visceral disease. Median follow-up was 22.4 months. Disease progression (26.4%) and intolerance/toxicity (14.9%) were the main reasons for treatment discontinuation. The median (95% CI) real-world progression-free survival was 31.7 (27.9—not estimable (NE)) months and 2-year estimated overall survival (OS) rate was 78.0%. In total, 25.6% of patients died; however, OS data are limited by the small population size and insufficient follow-up time. These real-world effectiveness outcomes complement findings from other real-world studies and randomized controlled trials and support palbociclib plus an aromatase inhibitor as first-line therapy for HR+/HER2− A/MBC.

FDA Approval Summary: Idecabtagene Vicleucel for Relapsed or Refractory Multiple Myeloma.

In March 2021, the FDA approved idecabtagene vicleucel, a chimeric antigen receptor T-cell therapy targeting the B-cell maturation antigen (BCMA), for adult patients with relapsed/refractory multiple myeloma (RRMM) after ≥4 lines of therapy including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 mAb. Approval was based on overall response rate (ORR), complete response (CR) rate, and duration of response (DOR) in 100 adult patients with RRMM treated with idecabtagene vicleucel in a single-arm trial. Patients received a single infusion of idecabtagene vicleucel, preceded by lymphodepleting chemotherapy with cyclophosphamide and fludarabine. Of the 100 patients in the efficacy evaluable population, ORR was 72% [95% confidence interval (CI), 62-81] with stringent CR rate of 28% (95% CI, 19-38). After median follow-up of 10.7 months, median DOR was 11 months (95% CI, 10.3-11.4) in responders (partial response or better) and 19 months [95% CI, 11.4 months, not estimable (NE)] in patients who achieved stringent CR. Serious adverse reactions occurred in 67% of 127 patients evaluated for safety. Grade 3 or higher cytokine release syndrome and neurologic toxicities occurred in 9% and 4%, respectively, leading to a Risk Evaluation and Mitigation Strategy. Hemophagocytic lymphohistiocytosis/macrophage activation syndrome occurred in 4%, with two fatalities. Prolonged cytopenia requiring hematopoietic rescue occurred in 2% (3/127), with two fatalities.

Tepotinib in Patients with Advanced NSCLC with MET Amplification (METamp)

<h3>Purpose/Objective(s)</h3> <i>MET</i>amp, an oncogenic driver occurring in 1–5% of NSCLC cases, confers a poor prognosis and lacks approved targeted therapies. Tepotinib, a highly selective MET inhibitor, provided durable response in advanced NSCLC with <i>MET</i> exon 14 (<i>MET</i>ex14) skipping in VISION Cohort A. VISION Cohort B evaluated tepotinib in patients with advanced NSCLC and <i>MET</i>amp, as detected by a convenient and minimally invasive liquid biopsy (LBx) assay. <h3>Materials/Methods</h3> Patients with advanced NSCLC, ECOG PS 0–1, 0–2 prior therapy lines, <i>EGFR</i>/<i>ALK</i> wild-type status, no <i>MET</i>ex14 skipping, and <i>MET</i>amp by LBx (<i>MET</i> gene copy number ≥2.5) received oral tepotinib 500 mg QD (450 mg active moiety). Primary endpoint was objective response rate (ORR) (RECIST v1.1) by independent review committee (IRC). Duration of response (DOR), progression-free survival (PFS), and safety were secondary endpoints. The data cut-off was July 1, 2020. <h3>Results</h3> Of 24 enrolled patients, the median age was 63.4 years (range 38–73), 21 patients were male (88%), 21 had ECOG PS 1, and 21 were smokers. Seven patients (29%) received tepotinib in first line (1L), 10 (42%) in second line (2L), and seven patients in third line (3L). As of November 2020, treatment was ongoing for >1 year in five patients (1L, n=2; 2L, n=2; 3L, n=1). The ORR was 42% (10/24 patients) overall, 71% (5/7) in 1L, 30% (3/10) in 2L and 29% (2/7) in 3L (Table). The median DOR was not estimable (NE). Five patients (20.8%) discontinued due to adverse events (AEs) considered unrelated to tepotinib. 16 patients reported treatment-related AEs (67%; Grade 3/4 in seven patients [29%]), including peripheral edema (nine patients [38%]; Grade 3/4 in two [8%]), generalized edema (four patients [17%]; Grade 3/4 in two [8%]), and constipation (four patients [17%]; none with Grade 3/4). <h3>Conclusion</h3> In the first study of a MET inhibitor in advanced NSCLC with <i>MET</i>amp prospectively detected by LBx, tepotinib had high and clinically meaningful activity, especially in 1L, and was generally well tolerated. Tepotinib warrants further evaluation in advanced NSCLC with <i>MET</i>amp.

Impact of Blinatumomab Treatment on Bone Marrow Function in Patients with Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia.

Simple SummaryMyelosuppression is a side effect of chemotherapy, in which the production of red and white blood cells and platelets is reduced, increasing risk of infections. Blinatumomab, a bispecific T-cell engager (BiTE®) molecule, is a novel anticancer drug that kills acute lymphoblastic leukemia (ALL) cells while sparing majority of the normal bone marrow cells. Results from our study, which compared the effects of blinatumomab treatment with chemotherapy on bone marrow function in a large number of patients with ALL, indicated that the decrease in blood cell counts was more severe and lasted longer after chemotherapy compared with blinatumomab treatment, in which the effects were transient. Survival in patients treated with blinatumomab achieving complete remission was more similar between those with incomplete recovery of blood cell counts versus those with complete blood cell counts than the corresponding survival outcomes seen with chemotherapy. In conclusion, blinatumomab treatment caused transient myelosuppression when compared with chemotherapy.Association of blinatumomab treatment with myelosuppression was examined in this study. Peripheral blood counts were assessed prior to, during, and after blinatumomab treatment in patients with relapsed/refractory Philadelphia chromosome-negative (Ph−) B-cell precursor (BCP) acute lymphoblastic leukemia (ALL; n = 267) and Ph+ BCP-ALL (n = 45) from the TOWER and ALCANTARA studies, respectively, or chemotherapy in patients with Ph− BCP-ALL (n = 109) from the TOWER study; all the patients with relapsed/refractory BCP-ALL and responders achieving complete remission (CR) or CR with partial/incomplete hematological recovery (CRh/CRi) were evaluated. Event-free survival (EFS) and overall survival (OS) were assessed in patients achieving CR and CRh/CRi. Median leukocyte, neutrophil, and platelet counts increased during two blinatumomab cycles but remained low longer after chemotherapy. Among the responders, there was a trend that a greater proportion of patients achieved CR with blinatumomab (Ph−, 76.5%; Ph+, 77.8%) versus with chemotherapy (Ph−, 63.6%). In the TOWER study, the survival prognosis for patients achieving CRh/CRi versus CR with blinatumomab was more similar (median OS, 11.9 (95% CI, 3.9–not estimable (NE)) vs. 15.0 (95% CI, 10.4–NE) months, p = 0.062) than with chemotherapy (5.2 (95% CI, 1.6–NE) vs. 18.9 (95% CI, 9.3–NE) months, p = 0.013). Blinatumomab treatment, with only temporary and transient myelosuppression, resulted in a greater survival benefit than chemotherapy.

Clinical Characteristics and Contemporary Outcomes of Acute Myeloid Leukemia Evolving from Chronic Myelomonocytic Leukemia

Clinical Characteristics and Contemporary Outcomes of Acute Myeloid Leukemia Evolving from Chronic Myelomonocytic Leukemia

Higher Skeletal Muscle Index Is Associated with Improved Overall Survival in Older Patients with Sarcopenia Undergoing Allogeneic Stem Cell Transplant

Introduction: Allogeneic stem cell transplantation (allo-SCT) can be curative for patients with hematologic malignancies. Despite optimization of supportive measures, the risk of non-relapse mortality is a particularly important consideration in older individuals. Sarcopenia, defined as low skeletal muscle mass, has been shown to be associated with decreased overall survival in cancer patients and may identify individuals at higher risk of treatment-related complications.Methods: Using Mayo Clinic Arizona's hematopoietic stem cell transplantation database, patients aged 60 years or older who underwent allo-SCT between 2008 and 2018 were identified. Patients who underwent abdominal computed tomography (CT) at our institution within 90 days prior to their transplant date were included in the study. The skeletal muscle area (SMA) was obtained using a fully automated algorithm for segmenting abdominal CT images to quantify body composition based on a deep learning approach (Weston et al., Radiology, 2019). The skeletal muscle index (SMI) was then calculated using the SMA and the subject's height at the time the CT was obtained. Sarcopenia was defined based on previously described consensus (Cruz-Jentoft et al., Age Ageing, 2010; Magudia et al., Radiology, 2021). T-tests and Fisher's exact tests compared patient characteristics between groups, where appropriate. Kaplan-Meier methods were used to construct survival times. Log-rank tests compared survival distributions and Cox proportional hazards models estimated hazard ratios.Results: A total of 79 patients met inclusion criteria (Table 1). Of these, 50 (63%, n=50/79) had sarcopenia, and 29 (37%, n=29/79) had normal skeletal muscle mass. Among the sarcopenia group, 43 (86%, n=43/50) had SMI measurements. No differences were seen between groups in age at transplant, sex, Karnofsky performance scale, disease risk index, or conditioning regimen intent.There was no statistically significant difference in overall survival between those with sarcopenia and those with normal skeletal muscle mass (log-rank p=0.18). Median survival was 3.3 years (95% CI: 0.8, not estimable (NE)) for those with sarcopenia and 3.6 years (95% CI: 1.3, NE) for those with normal skeletal muscle mass. Given the infrequency of events, the upper bounds of the median survival confidence intervals were not estimable. The unadjusted hazard ratio (HR) for sarcopenia versus normal skeletal muscle mass was 1.65 (95% CI: 0.79, 3.47; p=0.18).Males had a higher mean SMI than females, as expected (50.4 versus 37.5, p<0.001; mean difference 13.0, 95% CI: 8.9, 17.1). Without considering sex, higher or lower SMI was not associated with survival time in a Cox model in those with sarcopenia (HR: 0.97, 95% CI: 0.92, 1.03; p=0.32). Sex alone was also not associated with any survival benefit among these 43 patients. After adjusting for the difference seen in SMI between sexes, on average, those with higher SMI were associated with a survival benefit (HR: 0.92, 95% CI: 0.84, 0.99; p=0.039). This amounts to roughly an 8% reduction in hazard rate as SMI increased.Conclusions: The presence of sarcopenia alone was not associated with overall survival in patients 60 years and older undergoing allo-SCT for hematologic malignancy. Rating sarcopenia severity using SMI may assist in identifying high risk individuals with sarcopenia as lower sarcopenia severity was associated with improved overall survival. Further studies are warranted to explore the possible impacts of interventions directed at improving skeletal muscle mass on transplant-related outcomes. [Display omitted] DisclosuresGaulin: DeciBio: Honoraria; Olson Research Group: Honoraria. Jain: CareDx: Other: for advisory board participation; CTI Biopharma: Research Funding; Syneos Health: Research Funding; Bristol Myers Squibb: Other: for advisory board participation; Targeted Healthcare Communications: Consultancy. Palmer: PharmaEssentia: Research Funding; Incyte: Research Funding; Sierra Oncology: Consultancy, Research Funding; CTI BioPharma: Consultancy, Research Funding; Protagonist: Consultancy, Research Funding.

PD55-01 AVELUMAB FIRST-LINE MAINTENANCE FOR ADVANCED UROTHELIAL CARCINOMA IN THE JAVELIN BLADDER 100 TRIAL: SUBGROUP ANALYSIS BY DURATION OF TREATMENT-FREE INTERVAL FROM END OF CHEMOTHERAPY TO START OF MAINTENANCE

PD55-01 AVELUMAB FIRST-LINE MAINTENANCE FOR ADVANCED UROTHELIAL CARCINOMA IN THE JAVELIN BLADDER 100 TRIAL: SUBGROUP ANALYSIS BY DURATION OF TREATMENT-FREE INTERVAL FROM END OF CHEMOTHERAPY TO START OF MAINTENANCE

Median time to pain improvement and the impact of baseline pain severity on pain response in patients with psoriatic arthritis treated with tofacitinib

BackgroundPain is a core domain of psoriatic arthritis (PsA). This post hoc analysis evaluated time to pain improvement and the impact of baseline pain severity on pain response in patients...

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]

NCI protocol 10250: A phase II study of temozolomide and olaparib for the treatment of advanced uterine leiomyosarcoma.

11506 Background: Uterine leiomyosarcoma (uLMS) is an aggressive sarcoma subtype with frequent metastatic relapse. After failure of front-line chemotherapy, remaining options provide limited benefit (trabectedin: ORR 11%, mPFS 4.0 mos; pazopanib: ORR 11%, median PFS 2.9 mos; dacarbazine: ORR 9%, mPFS 1.5 mos). Recent molecular studies suggest uLMS harbors characteristic defects in the homologous recombination (HR) DNA repair pathway, including somatic biallelic BRCA2 deletion in 10%, implicating potential sensitivity to PARP-inhibitor based treatment approaches. In preclinical uLMS models in which temozolomide (T, an oral equivalent to dacarbazine) or the PARP inhibitor olaparib (O) showed limited single agent activity, the combination of T + O was highly effective in inhibiting uLMS tumor growth and promoting apoptosis. Methods: NCI protocol #10250 is a single-arm, open-label, multi-center phase II study evaluating T + O in advanced uLMS. Pts had progression on ≥ 1 prior line and ECOG PS ≤ 2. Pts received T 75 mg/m2 PO daily + O 200 mg PO BID days 1-7 in 21-day cycles. Primary endpoint was ORR. A one-stage binomial design was used. If ≥ 5/22 responded, the treatment was considered promising (95% power; α = 0.06). All pts underwent paired tumor biopsies. Correlative assays to evaluate for HR deficiency (whole exome sequencing/RNAseq, RAD51 foci formation) and for intrinsic PARP inhibitor resistance (SLFN11 expression) will be correlated with response. Results: 22 patients were evaluable (median age 55, median prior treatment lines 3). Median follow-up was 10.8 mos. Primary endpoint, ORR within 6 mos of initiating treatment, was 23% (5/22). Overall ORR was 27% (6/22). Median PFS was 6.9 mos (95% CI: 5.4 mos – not estimable (NE)). Median duration of response (DOR) was 12.0 mos (95% CI: 9.5 mos – NE). Hematologic toxicity was common (grade 3/4 neutropenia, 77%; thrombocytopenia 32%) but manageable with dose modification. Correlative assays are ongoing with plans to present at the meeting. An immunohistochemical assay for RAD51 foci has been adapted for uLMS samples and clearly distinguishes BRCA2- deleted and wild-type tumors. Conclusions: NCI 10250 met the prespecified primary efficacy endpoint of ORR in a population of patients with heavily pre-treated uLMS. Responses are durable (median DOR 12 mos). Correlative assays are being completed to evaluate whether uLMS tumors with HR deficiency or with preserved SLFN11 expression are most sensitive to T + O and may underlie durable responses. A randomized study of the combination is planned. Clinical trial information: NCT03880019.

Real-world comparative effectiveness of triplets containing bortezomib (B), carfilzomib (C), daratumumab (D), or ixazomib (I) in relapsed/refractory multiple myeloma (RRMM) in the US

Multiple available combinations of proteasome inhibitors, immunomodulators (IMIDs), and monoclonal antibodies are shifting the relapsed/refractory multiple myeloma (RRMM) treatment landscape. Lack of head-to-head trials of triplet regimens highlights the need for real-world (RW) evidence. We conducted an RW comparative effectiveness analysis of bortezomib (V), carfilzomib (K), ixazomib (I), and daratumumab (D) combined with either lenalidomide or pomalidomide plus dexamethasone (Rd or Pd) in RRMM. A retrospective cohort of patients initiating triplet regimens in line of therapy (LOT) ≥ 2 on/after 1/1/2014 was followed between 1/2007 and 3/2018 in Optum’s deidentified US electronic health records database. Time to next treatment (TTNT) was estimated using Kaplan-Meier methods; regimens were compared using covariate-adjusted Cox proportional hazard models. Seven hundred forty-one patients (820 patient LOTs) with an Rd backbone (VRd, n = 349; KRd, n = 218; DRd, n = 99; IRd, n = 154) and 348 patients (392 patient LOTs) with a Pd backbone (VPd, n = 52; KPd, n = 146; DPd, n = 149; IPd, n = 45) in LOTs ≥2 were identified. More patients ≥75 years received IRd (39.6%), IPd (37.8%), and VRd (36.7%) than other triplets. More patients receiving VRd/VPd were in LOT2 vs other triplets. Unadjusted median TTNT in LOT ≥ 2: VRd, 13.9; KRd, 8.7; IRd, 11.4; DRd, not estimable (NE); and VPd, 12.0; KPd, 6.7; IPd, 9.5 months; DPd, NE. In covariate-adjusted analysis, only KRd vs DRd was associated with a significantly higher risk of next LOT initiation/death (HR 1.72; P = 0.0142); no Pd triplet was significantly different vs DPd in LOT ≥ 2. Our data highlight important efficacy/effectiveness gaps between results observed in phase 3 clinical trials and those realized in the RW.

Abstract PS14-07: Ribociclib + letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) advanced breast cancer (ABC) and central nervous system metastases: Subgroup analysis of the phase IIIb CompLEEment-1 trial

Abstract Background: Approximately 10-30% of patients (pts) with metastatic breast cancer (BC) are diagnosed with central nervous system (CNS) metastases, which are a major cause of morbidity and mortality, and are associated with a poor prognosis. Due to improving diagnostics and treatments in BC, and therefore longer pt survival, more CNS metastases in breast cancer pts are readily detected. However, pts with CNS metastases are often excluded from clinical trials. Ribociclib (RIB), an oral, selective cyclin-dependent kinase 4/6 inhibitor, is approved for use in combination with endocrine therapy (ET) in women with HR+, HER2- ABC. Here, we present a subgroup analysis of pts with CNS metastases at baseline from the Core Phase of CompLEEment-1 (NCT02941926), a Phase IIIb trial of RIB in combination with letrozole (LET) in pts with HR+, HER2- ABC. The eligibility criteria for this study allowed a broader and more diverse pt population than those of previous Phase III trials of RIB + LET, to reflect a typical real-world clinical setting. Methods: CompLEEment-1 included women of any menopausal status and men with HR+, HER2- ABC treated with ≤1 line of prior chemotherapy and no prior hormonal therapy for advanced disease. Pts received RIB (600 mg QD, 3 weeks on/1 week off) in combination with LET (2.5 mg QD, continuous). Men and premenopausal women received a luteinizing hormone-releasing hormone agonist (3.6 mg goserelin or 7.5 mg leuprolide, Q28D). This subgroup analysis assessed the primary outcomes (safety and tolerability) and secondary outcomes of time to progression (TTP), overall response rate (ORR), and clinical benefit rate (CBR) in pts with CNS metastases. Results: At the data cutoff date (November 8, 2019), 51 pts with CNS metastases (1.57%; total pt population N = 3,246) had been evaluated: median age was 56.0 years, 30 (58.8%) pts were postmenopausal, and ECOG PS &amp;lt;2 was observed in 49 (96.1%) pts. Median duration of exposure to RIB was 16.8 months. Adverse events (AEs) were reported in 49 (96.1%) pts; with all but one experiencing a treatment-related AE. Grade ≥ 3 AEs were reported in 38 (74.5%) pts; serious AEs were reported in 8 pts. There was 1 treatment-related fatal AE (sepsis). The most common all-grade AEs were neutropenia (66.7%), nausea (39.2%), and vomiting (29.4%). The most common grade ≥ 3 AEs were neutropenia (51.0%), leukopenia (13.7%), and increased alanine aminotransferase (5.9%), aspartate aminotransferase (5.9%), and gamma-glutamyltransferase (5.9%). Overall, 19 pts (37.3%) had ≥ 1 dose reduction of RIB, 12 (23.5%) due to AEs, and 32 pts (62.7%) permanently discontinued treatment, 6 (11.8%) due to AEs. Median TTP was not estimable (NE) (95% CI, 15.5-NE) in this subgroup analysis; with an event-free probability of 56.1% (95% CI, 39.3-69.8) at 30 months. For the 35 pts with measurable disease and CNS metastases at baseline, ORR was 42.9% (95% CI, 26.3-60.6%) and CBR was 62.9% (95% CI, 44.9-78.5). Conclusions: This subgroup analysis from CompLEEment-1 supports the use of RIB + LET in pts with CNS metastases, who typically have poor outcomes and are frequently excluded from clinical trials. Efficacy results support the use of RIB + LET in HR+, HER2- ABC in a close to real-world setting. The safety profile associated with RIB + LET was manageable, with few pts discontinuing treatment due to AEs, consistent with previous Phase III trials of RIB + LET. Citation Format: Paul Cottu, Michelino De Laurentiis, Paolo Marchetti, Luigi Coltelli, Nadia Califaretti, Marc Debled, Shekar Patil, Ella Evron, Francois Duhoux, Lakshmi Menon-Singh, Jiwen Wu, Katie Zhou, Javier Salvador Bofill. Ribociclib + letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) advanced breast cancer (ABC) and central nervous system metastases: Subgroup analysis of the phase IIIb CompLEEment-1 trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS14-07.

KRASG12C/TP53 co-mutations identify long-term responders to first line palliative treatment with pembrolizumab monotherapy in PD-L1 high (≥50%) lung adenocarcinoma.

BackgroundPembrolizumab is a standard of care as first line palliative therapy in PD-L1 overexpressing (≥50%) non-small cell lung cancer (NSCLC). This study aimed at the identification of KRAS and TP53-defined mutational subgroups in the PD-L1 high population to distinguish long-term responders from those with limited benefit.MethodsIn this retrospective, observational study, patients from 4 certified lung cancer centers in Berlin, Germany, having received pembrolizumab monotherapy as first line palliative treatment for lung adenocarcinoma (LuAD) from 2017 to 2018, with PD-L1 expression status and targeted NGS data available, were evaluated.ResultsA total of 119 patients were included. Rates for KRAS, TP53 and combined mutations were 52.1%, 47.1% and 21.9%, respectively, with no association given between KRAS and TP53 mutations (P=0.24). By trend, PD-L1 expression was higher in KRAS-positive patients (75% vs. 65%, P=0.13). Objective response rate (ORR), median progression-free survival (PFS) and overall survival (OS) in the KRASG12C group (n=32, 51.6%) were 63.3%, 19.8 months (mo.) and not estimable (NE), respectively. Results in KRASother and wild type patients were similar and by far lower (42.7%, P=0.06; 6.2 mo., P<0.001; 23.4 mo., P=0.08). TP53 mutations alone had no impact on response and survival. However, KRASG12C/TP53 co-mutations (n=12) defined a subset of long-term responders (ORR 100.0%, PFS 33.3 mo., OS NE). In contrast, patients with KRASother/TP53 mutations showed a dismal prognosis (ORR 27.3%, P=0.002; PFS 3.9 mo., P=0.001, OS 9.7 mo., P=0.02).ConclusionsA comprehensive assessment of KRAS subtypes and TP53 mutations allows a highly relevant prognostic differentiation of patients with metastatic, PD-L1 high LuAD treated upfront with pembrolizumab.

Larotrectinib versus Prior Therapies in Tropomyosin Receptor Kinase Fusion Cancer: An Intra-Patient Comparative Analysis.

Simple SummaryClinical trials for new drugs to treat rare diseases are difficult to evaluate due to the limited patient population available for recruitment. Growth modulation index (GMI) is a very useful tool in these instances, as this calculation compares the patient’s outcome on the current drug to the same patient’s outcome on their most recent prior therapy, using the patient as their own control. GMI is the ratio of progression-free survival on the current therapy to time to progression on the last prior line of therapy and offers a method to determine if the investigational drug provides a benefit compared to the patient’s last prior treatment. Using a GMI ≥ 1.33 as the threshold of meaningful clinical activity, we found that larotrectinib, a tropomyosin receptor kinase (TRK) inhibitor approved to treat patients with TRK fusion cancer, improves progression-free survival for most patients with TRK fusion cancer compared with prior therapy.Randomized controlled basket trials investigating drugs targeting a rare molecular alteration are challenging. Using patients as their own control overcomes some of these challenges. Growth modulation index (GMI) is the ratio of progression-free survival (PFS) on the current therapy to time to progression (TTP) on the last prior line of therapy; GMI ≥ 1.33 is considered a threshold of meaningful clinical activity. In a retrospective, exploratory analysis among patients with advanced tropomyosin receptor kinase (TRK) fusion cancer treated with the selective TRK inhibitor larotrectinib who received ≥1 prior line of therapy for locally advanced/metastatic disease, we determined the proportion of patients with GMI ≥ 1.33; patients who had not progressed by data cut-off were censored for PFS. Among 72 eligible patients, median GMI was 2.68 (range 0.01–48.75). Forty-seven patients (65%) had GMI ≥ 1.33; 13/25 patients (52%) with GMI < 1.33 had not yet progressed on larotrectinib. Kaplan–Meier estimates showed a median GMI of 6.46. The probability of attaining GMI ≥ 1.33 was 0.75 (95% confidence interval (CI), 0.65–0.85). Median TTP on previous treatment was 3.0 months (95% CI, 2.6–4.4). Median PFS on larotrectinib was not estimable ((NE); 95% CI, NE; hazard ratio, 0.220 (95% CI, 0.146–0.332)). This analysis suggests larotrectinib improves PFS for patients with TRK fusion cancer compared with prior therapy.

Survival outcomes associated with different palliative systemic therapies (PSTs) in patients with metastatic bladder cancer (mBC).

450 Background: Cisplatin-based (Cis) chemotherapy (C) is considered standard first-line regimen for treating mBC. In individuals medically unfit for Cis, carboplatin-based (Cb) regimens may be considered. Alternative PSTs include immunotherapy (I) as first or second-line treatments. The purpose of this study is to investigate current trends and clinical outcomes of PSTs in patients with mBC. Methods: A retrospective analysis was conducted on patients initially diagnosed with bladder cancer from Sep 2014 to Dec 2016 and had de novo or recurrent mBC. Kaplan-Meier method and Log-Rank test were used to compare survival outcomes among patients receiving different PSTs. Results: In 273 patients, 123 (45.1%) had de novo and 150 (54.9%) had recurrent disease. The median overall survivals (mOS) were 5.3 (95% CI: 3.7-8.2) and 6.5 months (95% CI 5.1-8.9), respectively (p=0.54). Patients received one of the following: C (23.1%), I (6.2%), C followed by I (C/I, 10.6%), and no treatment (NT, 60.1%). The mOS were 9.5 (95% CI: 7.1-12.5), 9.2 (95% CI: 6.1 - not estimable (NE)), 23.9 (95% CI: 16.30-NE), and 3.5 months (95% CI: 3.03-4.30), respectively. Each treatment group had a longer mOS than the NT group (p&lt;0.01 in all three pairwise comparisons). Additionally, patients receiving C/I had a longer mOS than those receiving either C or I (p&lt;0.001 and p=0.0497, respectively). The mOS were not statistically different between C vs I (p=0.2649). In patients receiving any C, 50.0% received Gemcitabine (G) plus Cis and 30.4% received G plus Cb. The mOS were 11.0 (95% CI: 8.7-19.7) and 14.4 months (95% CI:10.7-19.2), respectively, which were not significantly different (p=0.36). Conclusions: Despite the general preference for G plus Cis over Cb, this study showed that G plus Cb as a PST may be a comparable and efficacious treatment. While C currently remains the preferred initial line of PST, patients receiving I had similar survival outcomes to the C group despite many of the patients having Cis ineligibility. Real-world mOS of 2 years in patients who receive both C and I is unprecedented and indicates efficacy of PST. This study provides further evidence for immunotherapy as first or second-line regimen in treating mBC.

956P - Randomized phase III trial of avelumab + axitinib vs sunitinib as first-line treatment for advanced renal cell carcinoma: JAVELIN renal 101 Japanese subgroup analysis

956P - Randomized phase III trial of avelumab + axitinib vs sunitinib as first-line treatment for advanced renal cell carcinoma: JAVELIN renal 101 Japanese subgroup analysis

Long-Term Survival and Local Control Outcomes in Oligometastatic Colorectal Cancer Treated with Liver Stereotactic Body Radiation Therapy

The purpose of the present study was to evaluate clinical outcomes following stereotactic body radiation therapy (SBRT) in patients with liver metastases (LM) due to colorectal cancer (CRC). This was a single-institution retrospective study of patients included in a prospectively maintained institutional database. Outcome endpoints included overall survival (OS) and local control (LC). We also performed assessments for predictors of LC and OS including evaluation of BED10 less than or greater than 150. Eligible patients had LM due to CRC, were treated with SBRT between 2007-2018, and had at least 3 months of follow up. Median SBRT dose was 54 Gy (range 32-60 Gy) in 3 fractions (range 3-5), and median BED10 was 151.0 Gy. All survival times were calculated from the start date of SBRT. Kaplan-Meier curves were used to estimate actuarial survival times, and Cox regression was used for multivariable analysis (MVA) of predictors of OS. We identified 67 eligible patients and 15/67 (22%) of patients had prior partial hepatectomy. Median number of chemotherapy regimens prior to SBRT was 1 (range 0-3). The majority of patients (79.6%) had a solitary liver metastasis; 2 had extrahepatic disease at the time of SBRT. The maximum number of treated LM was 3. Median tumor diameter was 2.7 cm (range 0.4-5.6). At a median follow up of 42.5 mos (range 3-96), 27/67 patients (40.2%) of patients had died. The median estimated OS (KP method) in this patient cohort was 64.0 months (95% CI 41.6 - Not Estimable (NE)). Estimated median KP duration of local control was 71.4 months (95% CI: 38.5, NE) in the entire patient cohort. Duration of local control was statistically significantly better in patients with liver SBRT treatment where the BED was > 150. The median duration of LC in patients with liver SBRT plans with BED10 > 150 was 74.4-months (95% CI: 40.1, NE) vs 26.1 month (95%: CI 11.6 – NE) in those with liver SBRT plan with BED < 150 (p=0.0006). The median KP estimated OS was 82.4 months (95% CI: 41.4 – NE) in patients with SBRT plan > 150 vs 62.8 months (95% CI: 36.2 mo. – NE) in those with BED < 150 (p= 0.697). Duration of local control was found to significantly correlate with OS. The hazard of death was reduced by 5.1% for each additional month of local control. GTV size (cc), diameter of treated metastases, and presence of K-ras mutation did not appear to be a predictor of LC in our patient cohort. SBRT is very effective in the management of hepatic oligometastases and was associated with an estimated median OS greater than 5 years in select patients. In this study, we found that duration of local control was significantly associated with overall survival. Additionally, it appears from this series that BED10 > 150 is associated with increase in local control.