Doroshow, James H.

We previously reported initial results of the pivotal phase II trial of atezolizumab for patients with alveolar soft part sarcoma (ASPS; ClinicalTrials.gov identifier: NCT03141684 ). Here, we report on three additional years of observation. Fifty-three patients with ASPS received atezolizumab. Median duration of response increased to 37.0 months. Objective response rate (ORR) and median progression-free survival (mPFS) remained essentially as previously reported (35.8% [95% CI, 23.1 to 50.2] and 20.8 months [IQR, 7.6-not reached], respectively). ASPSCR1::TFE3 fusion type was determined for 47/53 patients; ORR and mPFS were higher among the 41 patients expressing type 1 (43.9% [95% CI, 28.5 to 60.2] and 28.3 months [IQR, 9.2-not reached], respectively) than the six patients expressing type 2 (0% [95% CI, 0 to 45.9] and 7.5 months [IQR, 3.9-not reached], respectively, PFS HR, 3.2 [95% CI, 1.01 to 10.2]). Eleven patients chose a per-protocol drug holiday (range, 3.5-26.4 months) after ≥2 years of treatment; two experienced disease progression during the holiday. Nine eligible patients elected to receive bevacizumab plus atezolizumab after progressing on monotherapy; ORR was 0% and mPFS was 18.5 months (IQR, 7.9-21.1) in this small cohort. Long-term results support using atezolizumab to treat ASPS, even for several years; a drug holiday with careful monitoring may be an option for some patients.

Abstract Introduction: MyeloMATCH (mM), is an National Cancer Institute (NCI)-sponsored precision medicine initiative for newly diagnosed AML/MDS. It consists of an initial screening study (Master Screening and Reassessment Protocol, or MSRP) that involves centralized testing of bone marrow/whole blood, leading to assignment into several genetically driven treatment subprotocols within the mM portfolio. MSRP employs karyotype, 8-15 probe fluorescence in situ hybridization (FISH) and NCI-myeloid (NMAv2) assays to determine ploidy, translocations and mutational status needed for accurate disease subclassification, risk stratification as well as for theragnostic determination. NMAv2, a rapid next generation sequencing assay (TAT<48 hrs), interrogates 45 DNA and 35 RNA fusion driver genes to report 1661 hotspot DNA mutations and 779 targeted RNA fusions, including all relevant fusions in AML except Inv3/t(3;3)/MECOM rearrangement (Yeung et al, 2025). The initial mM MSRP workflow relied on karyotype and FISH assay results to identify fusion positive AML/MDS as per the current testing guidelines/ recommendations as well as to abide by the FDA's requirements under the investigational device exemption (IDE). Here we present concordance analysis between karyotype, FISH and NMAv2 assay to identify relevant fusions in AML/MDS. Methods: First 400 participants enrolled in the mM MSRP were included in this analysis. We examined the results from karyotype analysis analyzing 20 metaphase cells, 8-15 probe FISH analyzing 500 nuclei per probe, and NMAv2 curating fusion read counts greater than 100, performed at the mM labs to determine the prevalence of fusions in this cohort. Concordance analysis was performed to determine clinical utility of the NMAv2 assay to report relevant fusions at the time of initial diagnosis. The concordance analysis excluded biomarkers including Inv3/t(3;3)/MECOM rearrangement, KMT2A-PTD and other rare fusions that are beyond the scope of detection by NMAv2 and/or FISH assay. Results: Of the 400 patients analyzed in this cohort (median age 64, [range 20-95]; 43% female; 15.5% non-white; 9.5% Hispanic), translocations/fusions were reported in 67, 73 and 95 patients by karyotype, 8-15 probe FISH and NMAv2, respectively. The karyotypic analysis reported inv(16)/t(16;16) [15], t(11q23) [13], t(9;22) [10], inv3/t(3;3) [9], t(8;21) [6], t(15;17) [5], t(6;9) [4], t(21q22) [3], t(9q34) [1] and t(10;11) [1]. The FISH reported inv(16)/t(16;16) CBFB::MYH11 [15], t(11q23) KMT2A rearrangement [14], t(9;22) BCR::ABL1[10], inv3/t(3;3) MECOM rearrangement [10], t(8;21) RUNX1::RUNX1T1 [7], t(15;17) PML::RARA [5], t(6;9) DEK::NUP214 [5], t(21q22) RUNX1 rearrangement [3], t(11p15.4) NUP98 rearrangement [3], and t(9q34) ABL1 rearrangement [1]. The NMAv2 reported KMT2A-PTD [26], CBFB::MYH11 [15], KMT2A fusion [14], BCR::ABL1[12], RUNX1::RUNX1T1 [8], PML::RARA [5], DEK::NUP214 [5], RUNX1 fusion [4], NUP98 fusion[3], t(9q34) ABL1 fusion [1], PICALM::MLLT10 [1] and ETV6::MECOM [1]. The concordance analysis between NMAv2 and karyotype assay demonstrated positive percent agreement(PPA) of 100%, negative percent agreement(NPA) of 96.81% and overall agreement (OA) of 97.25% when using karyotype as reference. The concordance analysis between NMAv2 and FISH assay demonstrated PPA of 100%, NPA of 98.81% and OA of 99% when using FISH as reference. Of the 12 cases with discrepant results, 7 were due to presence of cryptic translocations missed by karyotype assay, 3 had suboptimal specimen submitted for karyotype/FISH analysis, 1 had false positive BCR::ABL1 fusion reported by NMAv2 due to low level contamination and 1 had minor subclonal population of leukemic blast with BCR::ABL1 fusion detected only by NMAv2. Conclusion: NMAv2 shows high concordance with karyotype and FISH assays which are the most commonly utilized assays to identify fusions/translocations in AML/MDS. NMAv2 is a faster, relatively cheaper and sample conserving method to identify fusions and is less prone to false negative results than karyotype/FISH assay from suboptimal specimen acquisition and testing. Based on the results above, mM MSRP workflow has been amended with FDA concurrence such that a combination of NMAv2, karyotype and MECOM breakapart FISH assay will be used to identify relevant fusion variants in all patients enrolled in mM, whereas additional specific FISH assay will be limited to cases where discrepant results between karyotype and NMAv2 are reported.

Abstract The increase in the complexity of cancer clinical trials over the past several decades has led to a dramatic growth in trial cost and operational burden. The extent and frequency of data collection, particularly in late-phase trials that enroll many participants, have been major contributors to this problem. The Clinical Trials and Translational Research Advisory Committee of the National Cancer Institute (NCI) recently assessed the effect of these stressors on the NCI National Clinical Trials Network (NCTN) and recommended that data collection in late-phase NCTN trials be limited to data elements essential to address the primary and secondary objectives of the trial. The purpose of this commentary is to describe the rationale for this recommendation, progress toward implementation, and the development of new streamlined standard practices for data collection for late-phase NCTN trials effective January 1, 2025.

Abstract Basket, umbrella, and platform trial designs (master protocols) have emerged over the last decade to study precision medicine approaches in oncology. First-generation trials like NCI-MATCH (Molecular Analysis for Therapy Choice) have proven the principle that studying targeted therapies on a large scale is feasible both from the laboratory and clinical perspectives. However, single-agent targeted therapies have shown limited ability to control metastatic disease, despite careful matching of drug to target. As such, newer approaches employing combinations of targeted therapy, or targeted therapy with standard therapies, need to be considered. The NCI has recently embarked on three second-generation precision medicine trials to address this need: ComboMATCH, iMATCH, and myeloMATCH. The design of these trials and necessary infrastructure are discussed in the following perspective.

PURPOSE This trial assessed the utility of applying tumor DNA sequencing to treatment selection for patients with advanced, refractory cancer and somatic mutations in one of four signaling pathways by comparing the efficacy of four study regimens that were either matched to the patient's aberrant pathway (experimental arm) or not matched to that pathway (control arm). MATERIALS AND METHODS Adult patients with an actionable mutation of interest were randomly assigned 2:1 to receive either (1) a study regimen identified to target the aberrant pathway found in their tumor (veliparib with temozolomide or adavosertib with carboplatin [DNA repair pathway], everolimus [PI3K pathway], or trametinib [RAS/RAF/MEK pathway]), or (2) one of the same four regimens, but chosen from among those not targeting that pathway. RESULTS Among 49 patients treated in the experimental arm, the objective response rate was 2% (95% CI, 0% to 10.9%). One of 20 patients (5%) in the experimental trametinib cohort had a partial response. There were no responses in the other cohorts. Although patients and physicians were blinded to the sequencing and random assignment results, a higher pretreatment dropout rate was observed in the control arm (22%) compared with the experimental arm (6%; P = .038), suggesting that some patients may have had prior tumor mutation profiling performed that led to a lack of participation in the control arm. CONCLUSION Further investigation, better annotation of predictive biomarkers, and the development of more effective agents are necessary to inform treatment decisions in an era of precision cancer medicine. Increasing prevalence of tumor mutation profiling and preference for targeted therapy make it difficult to use a randomized phase II design to evaluate targeted therapy efficacy in an advanced disease setting.

Abstract Background: Endx is a Tam metabolite with promising antitumor activity in Tam and aromatase inhibitor (AI) resistant estrogen receptor (ER) positive (+) metastatic breast cancer (MBC). Methods: This randomized phase II study compared progression-free survival (PFS) and toxicity of Endx 80 mg/day to Tam 20 mg/day in patients (pts) with ER+ MBC. Eligibility included postmenopausal women, ECOG PS 0-2, prior progression on AI but not Tam (unlimited endocrine therapy [ET] lines allowed), and a preregistration biopsy confirming ER+ (>10% nuclear staining) and HER2-negative MBC. Stratified randomization was used balancing prior CDK 4/6 inhibitor (CDK 4/6i) use and/or everolimus (yes/no), measurable disease (yes/no) and endocrine resistance (primary/secondary) between arms. Pts randomized to Tam were allowed to cross over to Endx at progression. Due to short expected median PFS, differences in PFS were assessed using approaches for interval-censored data (ICD). 40 eligible pts were to be randomized to each arm so a one-sided alpha=0.10 generalized log-rank test (GLRT) would have a 90% chance of detecting a 50% decrease in hazard of disease progression with Endx (median: 6 months) relative to Tam (median: 3 months). Secondary endpoints include clinical benefit rate (stable or partial response > 6 cycles) (CBR) for measurable and non-measurable disease. Pharmacokinetic (PK) data were obtained Day (d) 1 (4 hour), end of cycle 2, and at time of progression. Results: From March 2015 to March 2017, 108 women with endocrine refractory recurrent or MBC were preregistered. 27 pts did not register due to: biopsy demonstrating ER-/HER2- (3 pts), ER+/HER2+ (5 pts), cancer other than breast (3 pts), no cancer in specimen (6 pts), brain metastases (2 pts), acute infection (1 pt), progression on or recent use of Tam (2 pts), or pt refusal (5 pts). 4/81 pts who registered were excluded due to ineligibility (3 pts) or refusal to start protocol treatment (1 pt). The study cohort consisted of 40 pts randomized to Endx and 37 pts to Tam. The median (m) number of ETs in the metastatic setting was 2 (range 1-4) for each arm including prior CDK 4/6i (Endx: 42.5%, Tam: 29.7%) and everolimus (Endx: 35.0%, Tam: 40.5%). The m cycle number was 6 for Endx (range: 1-35) and 3 for Tam (range: 1-42). PFS for Endx was not significantly different compared to Tam (HR= 0.77; 95% CI: 0.49-1.22, GLRT p=0.309; mPFS: Endx 130 days [95% CI: 76-138 days] and Tam 42 days [95%CI: 24-129 days]). However, PFS was significantly longer in pts with no prior CDK 4/6i in the Endx arm (GLRT p=0.002; HR(no/yes)=0.31; 95%CI: 0.15-0.65) but not in the Tam arm (GLRT p=0.708) (unplanned analysis). Severe (grade (G) 3+) toxicities included: Endx G3 hypertriglyceridemia (3 pts); Tam: G3 hypertension with G2 stroke (1 pt), G3 thromboembolic event (1 pt), and G3 abdominal, bone and liver pain (1 pt). In Endx arm, d1 m Endx plasma concentration (conc) was 216 ng/ml (n=17; range: 144-400). For Tam arm, d1 m Tam conc was 17 ng/ml (n=17; range:11-23) (Endx not detectable). For the 25 pts that crossed over to Endx, CBR was 28.0% (90% CI: 14.0-46.2%) and 14 pts had pk data at progression. A lower median Endx conc (6 ng/ml range: 3.3-16.3) was observed in Tam patients at progression who then had Endx clinical benefit compared to Tam pts without clinical benefit after Endx crossover (median Endx 12 ng/ml; range 4.4-36.6).Conclusions: In endocrine-resistant breast cancer, Z-Endx was not significantly superior to Tam, but clinical benefit was observed in 28% that crossed over to Endx after Tam progression. In pts with no prior CDK 4/6i, the observation of significantly longer PFS in the Endx arm is hypothesis generating. Support: U10CA180821, U10CA180882, U24CA196171, U10CA180820 (ECOG-ACRIN), https://acknowledgments.alliancefound.org; Clinical Trials.gov Identifier:NCT02311933 Citation Format: Matthew P. Goetz, Vera J Suman, Joel M Reid, Mary Kuffel, Sarah A Buhrow, Renee M McGovern, John Black, Travis Dockter, William F Symmans, Minetta C Liu, John R Hawse, James Doroshow, Anna M Storniolo, Jerry M Collins, Howard Streicher, Matthew M Ames, James N Ingle, Ann Partridge, Lisa Carey. A randomized phase II trial of tamoxifen versus Z-endoxifen HCL in postmenopausal women with metastatic estrogen receptor positive, HER2 negative breast cancer [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 PD7-06.

5020 Background: V+C was well tolerated in a phase I trial and responses and prolonged disease stabilization were observed in BRCA + patients (pts).To assess the relative contribution of the PARP inhibitor to the efficacy observed for the combination, we conducted a randomized multicenter trial comparing the response rate (RR) of V and C to the RR of C alone in patients with deleterious BRCA mutations and recurrent ovarian, or primary peritoneal, fallopian tube or high-grade serous ovarian cancer. Methods: Pts were ≥ 18 yrs, KPS ≥ 70%, had adequate organ function, prior therapy with PARP inhibitors was allowed.Both drugs were administered orally qd; C 50 mg, V 60 mg; 21 day cycles. Pts were randomized to receive either C alone or V+C. At disease progression, pts on C alone were allowed to cross over to the combination. Radiologic imaging was performed at baseline and q 3 cycles for assessment of response. Dose reduction of V was allowed to 40 mg for gr 3 non-hematologic or gr 4 hematologic toxicities. The study design had an 88% power to detect the difference between a 15% RR for C alone versus 35% for V+C, early closure if fewer responses were observed on the combination arm in the first 65 pts enrolled (half of the total projected accrual). Results: Total of 74 pts were enrolled (36 pts C, 38 pts V+C), median age 58 (37-79 yrs), # of prior therapies: median 4 (1-9), 2 pts had prior PARP therapy. Treatment was well tolerated, Gr ≥ 2 toxicities per arm for initial regimen (# of pts): C alone: lymphopenia (2), mucositis (1); V+C: lymphopenia (4), anemia (2), leucopenia (2), neutropenia (2). Of the 74 pts evaluable for response at the interim analysis, 3 PRs observed in 36 pts on V+C and 5 PRs of 38 pts on C alone arm; thus accrual was stopped. PAR levels assessed by validated ELISA were inhibited (>80%) in PBMCs in 9/10 pts 4 hours post V, no inhibition with C alone. Conclusions: Addition of V, a PARP inhibitor, to C did not improve RR versus C alone. Exomic sequencing, gene expression studies, and Fanconi Anemia triple stain immunofluorescence (FATSI) assay for FancD2 nuclear foci formation using archival tissue are ongoing.

Lineage-specific growth factors mobilize peripheral blood progenitor cells (PBPC) and accelerate hematopoietic recovery after high-dose chemotherapy. Recombinant human thrombopoietin (rhTPO) may further increase the progenitor-cell content and regenerating potential of PBPC products. We evaluated the safety and activity of rhTPO as a PBPC mobilizer in combination with granulocyte colony-stimulating factor (G-CSF) in 29 breast cancer patients treated with high-dose chemotherapy followed by PBPC reinfusion. Initially, patients received escalating single doses of rhTPO intravenously (IV) at 0.6, 1.2, or 2.4 μg/kg, on day 1. Subsequent patients received rhTPO 0.6 or 0.3 μg/kg on days −3, −1, and 1, or 0.6 μg/kg on days −1 and 1. G-CSF, 5 μg/kg IV or subcutaneously (SC) twice daily, was started on day 3 and continued through aphereses. Twenty comparable, concurrently and identically treated patients (who were eligible and would have been treated on protocol but for the lack of study opening) mobilized with G-CSF alone served as comparisons. CD34+ cell yields were substantially higher with the first apheresis following rhTPO and G-CSF versus G-CSF alone: 4.1 × 106/kg (range, 1.3 to 17.6) versus 0.8 × 106/ kg (range, 0.3 to 4.2), P = .0003. The targeted minimum yield of 3 × 106CD34+ cells/kg was procured following a single apheresis procedure in 61% of the rhTPO and G-CSF–mobilized group versus 10% of G-CSF–mobilized patients (P = .001). In rhTPO and G-CSF mobilized patients, granulocyte (day 8 v 9, P= .0001) and platelet recovery (day 9 v 10, P= .07) were accelerated, and fewer erythrocyte (3 v 4,P = .02) and platelet (4 v 5, P = .02) transfusions were needed compared with G-CSF–mobilized patients. Peripheral blood platelet counts, following rhTPO and G-CSF, were increased by greater than 100% and the platelet content of PBPC products by 60% to 110% on the first and second days of aphereses (P < .0001) with the greatest effect seen with repeated dosing of rhTPO at 0.6 μg/kg. rhTPO is safe and well tolerated as a mobilizing agent before PBPC collection. Mobilization with rhTPO and G-CSF, in comparison to a comparable, nonrandomized G-CSF–mobilized group of patients, decreases the number of apheresis procedures required, may accelerate hematopoietic recovery, and may reduce the number of transfusions required following high-dose chemotherapy for breast cancer.

Abstract Lineage-specific growth factors mobilize peripheral blood progenitor cells (PBPC) and accelerate hematopoietic recovery after high-dose chemotherapy. Recombinant human thrombopoietin (rhTPO) may further increase the progenitor-cell content and regenerating potential of PBPC products. We evaluated the safety and activity of rhTPO as a PBPC mobilizer in combination with granulocyte colony-stimulating factor (G-CSF) in 29 breast cancer patients treated with high-dose chemotherapy followed by PBPC reinfusion. Initially, patients received escalating single doses of rhTPO intravenously (IV) at 0.6, 1.2, or 2.4 μg/kg, on day 1. Subsequent patients received rhTPO 0.6 or 0.3 μg/kg on days −3, −1, and 1, or 0.6 μg/kg on days −1 and 1. G-CSF, 5 μg/kg IV or subcutaneously (SC) twice daily, was started on day 3 and continued through aphereses. Twenty comparable, concurrently and identically treated patients (who were eligible and would have been treated on protocol but for the lack of study opening) mobilized with G-CSF alone served as comparisons. CD34+ cell yields were substantially higher with the first apheresis following rhTPO and G-CSF versus G-CSF alone: 4.1 × 106/kg (range, 1.3 to 17.6) versus 0.8 × 106/ kg (range, 0.3 to 4.2), P = .0003. The targeted minimum yield of 3 × 106CD34+ cells/kg was procured following a single apheresis procedure in 61% of the rhTPO and G-CSF–mobilized group versus 10% of G-CSF–mobilized patients (P = .001). In rhTPO and G-CSF mobilized patients, granulocyte (day 8 v 9, P= .0001) and platelet recovery (day 9 v 10, P= .07) were accelerated, and fewer erythrocyte (3 v 4,P = .02) and platelet (4 v 5, P = .02) transfusions were needed compared with G-CSF–mobilized patients. Peripheral blood platelet counts, following rhTPO and G-CSF, were increased by greater than 100% and the platelet content of PBPC products by 60% to 110% on the first and second days of aphereses (P &lt; .0001) with the greatest effect seen with repeated dosing of rhTPO at 0.6 μg/kg. rhTPO is safe and well tolerated as a mobilizing agent before PBPC collection. Mobilization with rhTPO and G-CSF, in comparison to a comparable, nonrandomized G-CSF–mobilized group of patients, decreases the number of apheresis procedures required, may accelerate hematopoietic recovery, and may reduce the number of transfusions required following high-dose chemotherapy for breast cancer.