Oncology Daily Report: 01/18/2024

Phase 3 Studies

Breast Cancer (Estrogen Receptor-Rich/ERBB2-Negative)

A Phase 3 randomized clinical trial assessed the effectiveness of neoadjuvant anastrozole, fulvestrant, or their combination in 1362 postmenopausal patients with clinical stage II to III, ER-rich/ERBB2-negative breast cancer (1). The study found endocrine-sensitive disease rates of 18.7%, 22.8%, and 20.5% with anastrozole, fulvestrant, and A+F, respectively. Neither fulvestrant-containing regimen significantly improved endocrine-sensitive disease rate or Ki67 suppression over anastrozole alone. Aromatase inhibition remains the standard-of-care neoadjuvant endocrine therapy. (ClinicalTrials.gov Identifier: NCT01953588).

Reference

Ma CX, Suman VJ, Sanati S, Vij K, Anurag M, Leitch AM, Unzeitig GW, Hoog J, Fernandez-Martinez A, Fan C, Gibbs RA, Watson MA, Dockter TJ, Hahn O, Guenther JM, Caudle A, Crouch E, Tiersten A, Mita M, Razaq W, Hieken TJ, Wang Y, Rimawi MF, Weiss A, Winer EP, Hunt KK, Perou CM, Ellis MJ, Partridge AH, Carey LA. Endocrine-Sensitive Disease Rate in Postmenopausal Patients With Estrogen Receptor-Rich/ERBB2-Negative Breast Cancer Receiving Neoadjuvant Anastrozole, Fulvestrant, or Their Combination: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2024 Jan 18:e236038. doi: 10.1001/jamaoncol.2023.6038. Epub ahead of print. PMID: 38236590; PMCID: PMC10797521.

Phase 2 Studies

Breast Cancer (Triple Negative)

A Phase II non-comparative study investigated the effect of olaparib with or without durvalumab in 45 patients with advanced triple-negative breast cancer (aTNBC) sensitive to platinum-based chemotherapy (1). The study found that the median progression-free survival (PFS) was 4.0 months (95% CI, 2.6-6.1) with olaparib and 6.1 months (95% CI, 3.7-10.1) with the combination, both significantly longer than the historical control. Clinical benefit rates were 44% (95% CI, 23-66%) for olaparib monotherapy and 36% (95% CI, 17%-59%) for the combination therapy.

Reference

Tan TJ, Sammons S, Im YH, She L, Mundy K, Bigelow R, Traina TA, Anders C, Yeong J, Renzulli E, Kim SB, Dent R. Phase II DORA Study of Olaparib with or without Durvalumab as a Chemotherapy-Free Maintenance Strategy in Platinum-Pretreated Advanced Triple-Negative Breast Cancer. Clin Cancer Res. 2024 Jan 18. doi: 10.1158/1078-0432.CCR-23-2513. Epub ahead of print. PMID: 38236575.

Intracranial Tumors

A Phase II non-inferiority, prospective, multicenter, non-randomized, off-label clinical trial compared Fluorescein-stained intraoperative confocal laser endomicroscopy (CLE) with routine intraoperative frozen section (FS) for histopathological assessment of intracranial tumors (1). Involving 210 patients from 3 participating sites, the study found that CLE had a diagnostic accuracy of 87% compared to 91% for FS. The median time expedited until intraoperative diagnosis was 3 minutes for CLE and 27 minutes for FS.

Reference

Wagner A, Brielmaier MC, Kampf C, Baumgart L, Aftahy AK, Meyer HS, Kehl V, Höhne J, Schebesch KM, Schmidt NO, Zoubaa S, Riemenschneider MJ, Ratliff M, Enders F, von Deimling A, Liesche-Starnecker F, Delbridge C, Schlegel J, Meyer B, Gempt J. Fluorescein-stained confocal laser endomicroscopy versus conventional frozen section for intraoperative histopathological assessment of intracranial tumors. Neuro Oncol. 2024 Jan 18:noae006. doi: 10.1093/neuonc/noae006. Epub ahead of print. PMID: 38243410.

Melanoma

A Phase 2b, open-label, randomised, adjuvant study conducted in the USA and Australia, compared mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in 157 patients with resected high-risk melanoma (1). The study found that recurrence-free survival was longer with the combination therapy (hazard ratio [HR] for recurrence or death, 0·561 [95% CI 0·309-1·017]; two-sided p=0·053). The 18-month recurrence-free survival was 79% (95% CI 69·0-85·6) for the combination group versus 62% (46·9-74·3) for the monotherapy group. The study was funded by Moderna in collaboration with Merck Sharp & Dohme.

Reference

Weber JS, Carlino MS, Khattak A, Meniawy T, Ansstas G, Taylor MH, Kim KB, McKean M, Long GV, Sullivan RJ, Faries M, Tran TT, Cowey CL, Pecora A, Shaheen M, Segar J, Medina T, Atkinson V, Gibney GT, Luke JJ, Thomas S, Buchbinder EI, Healy JA, Huang M, Morrissey M, Feldman I, Sehgal V, Robert-Tissot C, Hou P, Zhu L, Brown M, Aanur P, Meehan RS, Zaks T. Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study. Lancet. 2024 Jan 18:S0140-6736(23)02268-7. doi: 10.1016/S0140-6736(23)02268-7. Epub ahead of print. PMID: 38246194.

Multiple Myeloma (Relapsed and/or Refractory)

Ninkovic et al. reported the findings of a multicenter phase II study (ALLG MM018/AMN002) examining carfilzomib, thalidomide, and dexamethasone (KTd) in 93 patients with relapsed and/or refractory multiple myeloma (1). The study found a median progression-free survival of 22.3 months, with a 2-year progression-free survival rate of 46.3%. The 2-year overall survival rate was 73.8%, and the overall response rate was 88%. The treatment was well-tolerated and effective irrespective of Asian or non-Asian ethnicity.

Reference

Ninkovic S, Harrison SJ, Lee JJ, Murphy N, Lee JH, Estell J, Chen VM, Horvath N, Kim K, Eek R, Augustson B, Bang SM, Huang SY, Rajagopal R, Szabo F, Engeler D, Butcher BE, Mollee P, Durie B, Chng WJ, Quach H. Carfilzomib, thalidomide, and dexamethasone is safe and effective in relapsed and/or refractory multiple myeloma: final report of the single arm, multicenter phase II ALLG MM018/AMN002 study. Haematologica. 2024 Jan 18. doi: 10.3324/haematol.2023.284238. Epub ahead of print. PMID: 38235519.

Soft Tissue Sarcomas

A non-randomized Phase II trial evaluated the combination of eribulin and pembrolizumab in 57 patients with soft tissue sarcomas (STS), including leiomyosarcoma (LMS), liposarcomas (LPS), and other STS (1). The study found that the 12-week progression-free survival rate (PFS-12) was 36.8% for LMS, 69.6% for LPS, and 52.6% for UPS/other cohorts. All 3 patients in the UPS/other cohort with angiosarcoma achieved RECIST responses. The treatment demonstrated manageable toxicity. Higher interferon (IFN) alpha and IL-4 serum levels were associated with clinical benefit, and immune aggregates expressing PD-1 and PD-L1 were observed in a patient who completed 2 years of treatment.

Reference

Haddox CL, Nathenson MJ, Mazzola E, Lin JR, Baginska J, Nau A, Weirather JL, Choy E, Marino-Enriquez A, Morgan JA, Cote GM, Merriam P, Wagner AJ, Sorger PK, Santagata S, George S. Phase II Study of Eribulin plus Pembrolizumab in Metastatic Soft Tissue Sarcomas: Clinical Outcomes and Biological Correlates. Clin Cancer Res. 2024 Jan 18. doi: 10.1158/1078-0432.CCR-23-2250. Epub ahead of print. PMID: 38236580.

Urothelial Carcinoma (Metastatic)

TROPHY-U-01, a Phase II open-label study, investigated sacituzumab govitecan in 113 patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors (1). The study reported an objective response rate of 28% and median progression-free survival and overall survival of 5.4 and 10.9 months, respectively. Grade ≥3 treatment-related adverse events were consistent with prior reports. The safety data varied across UGT1A1 subgroups, but discontinuation rates remained low for all groups. (NCT03547973).

Reference

Kang YK, Ryu MH, Hong YS, Choi CM, Kim TW, Ryoo BY, Kim JE, Weis JR, Kingsford R, Park CH, Jang S, McGinn A, Werner TL, Sharma S. Phase 1/2a Study of Rivoceranib, a Selective VEGFR-2 Angiogenesis Inhibitor, in Patients with Advanced Solid Tumors. Cancer Res Treat. 2024 Jan 18. doi: 10.4143/crt.2023.980. Epub ahead of print. PMID: 38271925.

Phase 1/2 Studies

Acute Leukemia (Pediatric)

Merli et al. conducted a phase I-II clinical trial (NCT01810120) on TCRαβ/CD19 cell-depleted HLA-haploidentical transplantation in 213 children with acute leukemia (1). The updated analysis showed a 5-year cumulative incidence of nonrelapse mortality at 5.2% and relapse at 22.7%. The projected 10-year overall and disease-free survival rates were 75.4% and 71.6%, respectively. The study identified factors influencing disease-free survival and confirmed the efficacy of this transplantation type in reducing the risk of relapse.

Reference

Merli P, Algeri M, Galaverna F, Bertaina V, Lucarelli B, Boccieri E, Becilli M, Quagliarella F, Rosignoli C, Biagini S, Girolami E, Meschini A, Del Principe G, Sborgia R, Catanoso ML, Carta R, Strocchio L, Pinto RM, Buldini B, Falco M, Meazza R, Pende D, Andreani M, Li Pira G, Pagliara D, Locatelli F. TCRαβ/CD19 cell-depleted HLA-haploidentical transplantation to treat pediatric acute leukemia: updated final analysis. Blood. 2024 Jan 18;143(3):279-289. doi: 10.1182/blood.2023021336. PMID: 37738655.

B Cell Malignancies (CD19(+))

A phase 1/2 trial conducted by Marin et al. investigated the effect of cord blood-derived natural killer (NK) cells expressing anti-CD19 chimeric antigen receptor and interleukin-15 (CAR19/IL-15) in 37 patients with CD19(+) B cell malignancies (1). The study reported a 48.6% overall response rate at both day 30 and day 100. The 1-year overall survival and progression-free survival rates were 68% and 32%, respectively. Patients with optimal CAR-NK cell levels and persistence showed better outcomes. The trial, registered under ClinicalTrials.gov identifier NCT03056339, demonstrated significant predictors for superior outcomes and highlighted the importance of donor selection in allogeneic cell therapies.

Reference

Marin D, Li Y, Basar R, Rafei H, Daher M, Dou J, Mohanty V, Dede M, Nieto Y, Uprety N, Acharya S, Liu E, Wilson J, Banerjee P, Macapinlac HA, Ganesh C, Thall PF, Bassett R, Ammari M, Rao S, Cao K, Shanley M, Kaplan M, Hosing C, Kebriaei P, Nastoupil LJ, Flowers CR, Moseley SM, Lin P, Ang S, Popat UR, Qazilbash MH, Champlin RE, Chen K, Shpall EJ, Rezvani K. Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19+ B cell tumors: a phase 1/2 trial. Nat Med. 2024 Jan 18. doi: 10.1038/s41591-023-02785-8. Epub ahead of print. PMID: 38238616.

Non-Hodgkin Lymphoma (MYC-Aberrant)

A Phase I/II trial, named the DACIPHOR regimen, investigated DA-EPOCH-R plus ixazomib in 36 patients with aggressive MYC-aberrant non-Hodgkin lymphoma (1). The study established 3mg of ixazomib as the recommended phase 2 dose. The overall response rate after induction was 97% with a complete response rate of 69%. At a median follow-up of 18.8 months, the 12-month progression-free survival and overall survival rates were 78% and 86%, respectively. Grade ≥3 toxicities were predominantly hematologic, and 75% of patients experienced neuropathy. (NCT02481310, ClinicalTrials.gov).

Reference

Karmali R, Galvez C, Hamadani M, Gordon LI, Winter JN, Ma S, Nelson V, Fenske TS, Shah NN, Jagadeesh D, Klein AK, Helenowski I, Chen R, Mi X, Petrich A, Evens AM, Pro B. A Phase I-II Trial of DA-EPOCH-R Plus Ixazomib for MYC-Aberrant Lymphoid Malignancies: The DACIPHOR Regimen. Blood Adv. 2024 Jan 18:bloodadvances.2023011369. doi: 10.1182/bloodadvances.2023011369. Epub ahead of print. PMID: 38237077.

Solid Tumors (Advanced)

A Phase 1/2a open-label, single-arm, dose-escalating, multicenter study investigated the effect of rivoceranib, a selective VEGFR-2 angiogenesis inhibitor, in 61 patients with advanced solid tumors refractory to conventional therapy (1). The study found that the most common grade ≥3 adverse events were hypertension (32.7%), hyponatremia (10.9%), and hypophosphatemia (10.9%). The overall response rate was 15.2% in parts 1 and 2, and 33% in part 3. The recommended phase 2 dose of rivoceranib was determined to be 685 mg once daily. (NCT01497704 and NCT02711969).

Reference

Kang YK, Ryu MH, Hong YS, Choi CM, Kim TW, Ryoo BY, Kim JE, Weis JR, Kingsford R, Park CH, Jang S, McGinn A, Werner TL, Sharma S. Phase 1/2a Study of Rivoceranib, a Selective VEGFR-2 Angiogenesis Inhibitor, in Patients with Advanced Solid Tumors. Cancer Res Treat. 2024 Jan 18. doi: 10.4143/crt.2023.980. Epub ahead of print. PMID: 38271925.

Phase 1 Studies

Mature B-Cell Tumors (Relapsed or Refractory)

Song et al. conducted a phase I study of the Syk inhibitor sovleplenib in 134 Chinese patients with relapsed/refractory mature B-cell tumors (1). The recommended phase 2 dose (RP2D) was determined as 600 mg or 400 mg depending on patient weight. The objective response rate in indolent B-cell lymphoma was 50.8%, with follicular lymphoma response at 60.5%, and marginal zone lymphoma at 28.6%. The study reported acceptable safety and demonstrated the antitumor activity of sovleplenib in this patient population.

Reference

Song Y, Cao J, Zhang Q, Li C, Qiu L, Qi J, Zhang H, Li W, Liu L, Jing H, Zhou K, Zhang W, Zhang L, Li D, Zou L, Yang H, Qian W, Zhou H, Hu J, Yin H, Fu S, Fan S, Xu Q, Wang J, Jia X, Dai G, Su W, Zhu J. Phase I study of the Syk inhibitor sovleplenib in relapsed or refractory mature B-cell tumors. Haematologica. 2024 Jan 18. doi: 10.3324/haematol.2022.282401. Epub ahead of print. PMID: 38235512.

Melanoma

A Phase 1B study (NCT02298959) investigated the combination of ziv-aflibercept anti-angiogenic therapy with pembrolizumab in 10 patients with advanced melanoma resistant to anti-PD-1 treatment (1). The study found that two patients (20%) achieved a partial response, and two patients (20%) experienced stable disease (SD) as the best response. The two responders had mucosal melanoma, while both patients with SD had ocular melanoma. The combination therapy demonstrated clinical activity and acceptable safety, despite the occurrence of adverse events. The study also explored changes in plasma analytes and the association of specific subsets of γδ T cells with poor clinical outcomes.

Reference

Baginska J, Nau A, Gomez Diaz I, Giobbie-Hurder A, Weirather J, Vergara J, Abrecht C, Hallisey M, Dennis J, Severgnini M, Huezo J, Marciello I, Rahma O, Manos M, Brohl AS, Bedard PL, Renouf DJ, Sharon E, Streicher H, Ott PA, Buchbinder EI, Hodi FS. Ziv-aflibercept plus pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment. Cancer Immunol Immunother. 2024 Jan 18;73(1):17. doi: 10.1007/s00262-023-03593-2. PMID: 38236249; PMCID: PMC10796592.