Oncology Daily Report: 01/23/2024

Phase 3 Studies

Renal Cell Carcinoma (Advanced)

A phase III, TIVO-3 trial analyzed long-term survival in patients with relapsed/refractory advanced RCC treated with tivozanib (1). In this study, 350 patients who progressed with 2 or 3 prior systemic therapies were randomized to receive either tivozanib or sorafenib. Tivozanib demonstrated fewer grade ≥3 treatment-related adverse events (46%) compared to sorafenib (55%), with a 3-year progression-free survival rate of 12.3% vs 2.4%, and a 4-year rate of 7.6% vs 0%. Overall survival hazard ratio was 0.89 (95% CI, 0.70-1.14); showing significant improvement over sorafenib when conditioned on 12-month landmark PFS (HR, 0.45; 95% CI, 0.22-0.91).

Reference

Beckermann KE, Asnis-Alibozek AG, Atkins MB, Escudier B, Hutson TE, Kasturi V, McDermott DF, Pal SK, Porta C, Rini BI, Verzoni E. Long-Term Survival in Patients With Relapsed/Refractory Advanced Renal Cell Carcinoma Treated With Tivozanib: Analysis of the Phase III TIVO-3 Trial. Oncologist. 2024 Jan 23:oyad348. doi: 10.1093/oncolo/oyad348. Epub ahead of print. PMID: 38262444.

Castration-Sensitive Prostate Cancer (Biochemically Relapsed )

A phase III, open-label study investigated the effect of intensification of androgen blockade in 503 patients with high-risk biochemically relapsed castration-sensitive prostate cancer (BRPC) and found that both experimental arms (ADT + apalutamide, ADT + apalutamide + AAP) significantly prolonged PSA progression-free survival compared to the control arm, with a manageable safety profile (1).

Reference

Aggarwal R, Heller G, Hillman DW, Xiao H, Picus J, Taplin ME, Dorff T, Appleman L, Weckstein D, Patnaik A, Bryce A, Shevrin D, Mohler J, Anderson D, Rao A, Tagawa S, Tan A, Halabi S, Dooley K, O'Brien P, Chen R, Ryan CJ, Eggener SE, Morris MJ; EORTC-55994 Study Group. PRESTO: A Phase III, Open-Label Study of Intensification of Androgen Blockade in Patients With High-Risk Biochemically Relapsed Castration-Sensitive Prostate Cancer (AFT-19). J Clin Oncol. 2024 Jan 23:JCO2301157. doi: 10.1200/JCO.23.01157. Epub ahead of print. PMID: 38261983.

Phase 2 Studies

HER2-positive advanced breast cancer

A phase II open-label, multicenter study investigated the effect of poziotinib in 67 patients with HER2-positive advanced breast cancer who have received prior anti-HER2 regimens and found that the ORR was 30% in both groups (p = 0.98) (1). DCR was 60% vs 78% (p = 0.15) and median PFS and TTP were 4.1 vs 4.9 months (both p = 0.30) for cohorts 1 and 2, respectively. The most common treatment related adverse events (AEs) of any grade included diarrhea (88% vs 85%, p = 0.76), rash (88% vs 88%, p = 0.96), and stomatitis (64% vs 56%, p = 0.52), with grade 3-4 diarrhea occurring in 33% vs 32% of patients (p = 0.93) and grade 3-4 rash in 27% vs 35% of patients (p = 0.48) in cohort 1 vs cohort 2, respectively.

Reference

Nasrazadani A, Marti JLG, Lathrop K, Restrepo A, Leu SY, Bhat G, Brufsky A. Poziotinib treatment in patients with HER2-positive advanced breast cancer who have received prior anti-HER2 regimens. Breast Cancer Res Treat. 2024 Jan 23. doi: 10.1007/s10549-023-07236-z. Epub ahead of print. PMID: 38261228.

Castration-Sensitive Prostate Cancer (Biochemically Relapsed )

A phase II multicohort, open-label study investigated the effect of sacituzumab govitecan in combination with pembrolizumab in 41 patients with metastatic urothelial cancer that progressed after platinum-based chemotherapy and found the objective response rate was 41% (95% CI, 26.3 to 57.9; 20% complete response rate), clinical benefit rate was 46% (95% CI, 30.7 to 62.6), median duration of response was 11.1 months (95% CI, 4.8 to not estimable), and median progression-free survival was 5.3 months (95% CI, 3.4 to 10.2) (1). The study was TROPHY-U-01 (ClinicalTrials.gov identifier: NCT03547973).

 Reference

Grivas P, Pouessel D, Park CH, Barthelemy P, Bupathi M, Petrylak DP, Agarwal N, Gupta S, Fléchon A, Ramamurthy C, Davis NB, Recio-Boiles A, Sternberg CN, Bhatia A, Pichardo C, Sierecki M, Tonelli J, Zhou H, Tagawa ST, Loriot Y. Sacituzumab Govitecan in Combination With Pembrolizumab for Patients With Metastatic Urothelial Cancer That Progressed After Platinum-Based Chemotherapy: TROPHY-U-01 Cohort 3. J Clin Oncol. 2024 Jan 23:JCO2202835. doi: 10.1200/JCO.22.02835. Epub ahead of print. PMID: 38261969.

HER2-positive advanced breast cancer

A phase II single-arm trial investigated the effect of the anti-VEGF receptor tyrosine-kinase inhibitor, pazopanib, combined with the anti-PD-L1 inhibitor, durvalumab, in metastatic and/or recurrent soft tissue sarcoma and found the overall response rate was 30.4%, median progression-free survival was 7.7 months (95% confidence interval: 5.7-10.4) (1). The study was NCT03798106.

Reference

Cho HJ, Yun KH, Shin SJ, Lee YH, Kim SH, Baek W, Han YD, Kim SK, Ryu HJ, Lee J, Cho I, Go H, Ko J, Jung I, Jeon MK, Rha SY, Kim HS. Durvalumab plus pazopanib combination in patients with advanced soft tissue sarcomas: a phase II trial. Nat Commun. 2024 Jan 23;15(1):685. doi: 10.1038/s41467-024-44875-2. PMID: 38263321; PMCID: PMC10806253.

Phase 1/2 Studies

HER2-positive advanced breast cancer

A phase 1/2 clinical trial (NCT03379051) investigated the effect of venetoclax in combination with umbralisib and ublituximab (U2-VeN) in 46 patients with relapsed/refractory chronic lymphocytic leukemia and 5 with Richter transformation (1). The overall response rate for CLL was 98%, with a best response of 100% in evaluable patients (42% complete responses). The end-of-treatment rate of undetectable minimal residual disease at 10-4 in bone marrow was 77% (30/39), including a 71% rate among 14 patients refractory to prior BTK inhibitor. Adverse events included diarrhea in 50% of patients (11% grade 3/4) and aspartate aminotransferase/alanine aminotransferase elevation in 33% of patients, with 7% grade 3/4.

Reference

Hill BT, Ma S, Zent CS, Baran AM, Wallace DS, Advani A, Winter A, Winter J, Gordan L, Karmali R, Liesveld JL, Mulford DA, Rowland C, Bui A, Sportelli P, Miskin HP, Weiss MS, Friedberg JW, Barr PM. Response-adapted, time-limited venetoclax, umbralisib, and ublituximab for relapsed/refractory chronic lymphocytic leukemia. Blood Adv. 2024 Jan 23;8(2):378-387. doi: 10.1182/bloodadvances.2023010693. PMID: 37871300; PMCID: PMC10820336.

Acute Myeloid Leukemia

A phase 2/1b, Beat AML substudy investigated the effect of Enasidenib (ENA) monotherapy, and its combination with azacitidine in 60 patients with newly diagnosed IDH2-mutant AML aged ≥60 years (1). The study found a composite complete response (cCR) rate of 46% for ENA monotherapy. Seventeen patients transitioned to combination therapy, achieving a cCR rate of 41% with 1 dose-limiting toxicity. The study is registered at clinicaltrials.gov as #NCT03013998.

Reference

Cai SF, Huang Y, Lance JR, Mao HC, Dunbar AJ, McNulty SN, Druley T, Li Y, Baer MR, Stock W, Kovacsovics T, Blum WG, Schiller GJ, Olin RL, Foran JM, Litzow M, Lin T, Patel P, Foster MC, Boyiadzis M, Collins RH, Chervin J, Shoben A, Vergilio JA, Heerema NA, Rosenberg L, Chen TL, Yocum AO, Druggan F, Marcus S, Stefanos M, Druker BJ, Mims AS, Borate U, Burd A, Byrd JC, Levine RL, Stein EM. A study to assess the efficacy of enasidenib and risk-adapted addition of azacitidine in newly diagnosed IDH2-mutant AML. Blood Adv. 2024 Jan 23;8(2):429-440. doi: 10.1182/bloodadvances.2023010563. PMID: 37871309.

Phase 1 Studies

Astrocytoma (Grade 4)

A phase I study using a 3 + 3 dose escalation design investigated the effect of anti-CD3 x anti-EGFR bispecific antibody armed T cells (EGFR BATs) in combination with radiation and temozolomide in patients with newly diagnosed grade 4 astrocytoma and found the highest feasible dose was 80 × 10(9) EGFR BATs without dose-limiting toxicities in seven patients, with significant increases in glioma-specific anti-tumor cytotoxicity and NK cell activity, and increased serum concentrations of IFN-γ, IL-2, and GM-CSF (1). The study was registered at ClinicalTrials.gov (Identifier: NCT03344250).

Reference

Fadul CE, Thakur A, Kim J, Kassay-McAllister J, Schalk D, Lopes MB, Donahue J, Purow B, Dillon P, Le T, Schiff D, Liu Q, Lum LG. Phase I study targeting newly diagnosed grade 4 astrocytoma with bispecific antibody armed T cells (EGFR BATs) in combination with radiation and temozolomide. J Neurooncol. 2024 Jan 23. doi: 10.1007/s11060-024-04564-y. Epub ahead of print. PMID: 38263486.

Large B-cell lymphoma

A phase 1 clinical trial (NCT02706405) investigated the effect of autologous CD19 CAR T cells (JCAR014) combined with escalating doses of the anti-PD-L1 monoclonal antibody, durvalumab, in adults with large B-cell lymphoma (1). Patients who started durvalumab before JCAR014 infusion had later onset and shorter duration of cytokine release syndrome and inferior efficacy, associated with slower accumulation of CAR T cells and lower concentrations of inflammatory cytokines in the blood. Ongoing durvalumab therapy after JCAR014 was associated with re-expansion of CAR T cells in the blood, late regression of CD19+ and CD19- tumors, and enhanced duration of response.

Reference

Hirayama AV, Kimble EL, Wright JH, Fiorenza S, Gauthier J, Voutsinas JM, Wu Q, Yeung CCS, Gazeau N, Pender BS, Kirchmeier DR, Torkelson A, Chutnik AN, Cassaday RD, Chapuis AG, Green DJ, Kiem HP, Milano F, Shadman M, Till BG, Riddell SR, Maloney DG, Turtle CJ. Timing of anti-PD-L1 antibody initiation affects efficacy/toxicity of CD19 CAR T-cell therapy for large B-cell lymphoma. Blood Adv. 2024 Jan 23;8(2):453-467. doi: 10.1182/bloodadvances.2023011287. PMID: 37903325.

Astrocytoma (Grade 4)

A Phase 1, randomized, double-blind, placebo-controlled study investigated the effect of oral formulation (CG-750) of ivaltinostat in 25 patients with pharmacokinetic and pharmacodynamic assessment and found that CG-750 was generally well tolerated with a mean bioavailability of 10.6% (1).

Reference

Kim B, Huh KY, Yu KS, Lee S. Pharmacokinetics, pharmacodynamics and safety of oral formulation (CG-750) of ivaltinostat, a histone deacetylase inhibitor, compared to IV formulation (CG-745). Br J Clin Pharmacol. 2024 Jan 23. doi: 10.1111/bcp.15997. Epub ahead of print. PMID: 38263733.

Peripheral T-Cell Lymphoma

A phase 1 trial investigated the effect of pralatrexate combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in patients with peripheral T-cell lymphoma and found an overall response rate of 83.9% (1). Thirty-five patients (67.3%) experienced grade 3/4 treatment-emergent adverse events. This trial was registered at www.ClinicalTrials.gov as #NCT02594267.

Reference

Iyer SP, Johnston PB, Barta SK. Pralatrexate injection combined with CHOP for treatment of PTCL: results from the Fol-CHOP dose-finding phase 1 trial. Blood Adv. 2024 Jan 23;8(2):353-364. doi: 10.1182/bloodadvances.2023011095. PMID: 38029357; PMCID: PMC10788850.

Astrocytoma (Grade 4)

A phase 1 study investigated the effect of triple-targeted therapy with braf, mek, and akt inhibitors in 27 patients with BRAF V600E/V600K-mutant solid tumors and found that the treatment was well tolerated and led to partial responses in patients, but higher level drug-drug interactions affected exposure to dabrafenib and its metabolites (1).

Reference

Algazi AP, Moon J, Lao CD, Chmielowski B, Kendra KL, Lewis KD, Gonzalez R, Kim K, Godwin JE, Curti BD, Latkovic-Taber M, Lomeli SH, Gufford BT, Scumpia PO, Lo RS, Othus M, Ribas A. A phase 1 study of triple-targeted therapy with BRAF, MEK, and AKT inhibitors for patients with BRAF-mutated cancers. Cancer. 2024 Jan 23. doi: 10.1002/cncr.35200. Epub ahead of print. PMID: 38261444.