Oncology Daily Report: 01/11/2024

Gastrointestinal Cancers: Hepatocellular Carcinoma

The DOSISPHERE-01 trial, a phase II study registered under ClinicalTrials.gov identifier NCT02582034, investigated the efficacy of selective internal radiation therapy in treating nonoperable locally advanced hepatocellular carcinoma (1). The study adopted a randomized design, comparing two dosimetry approaches: personalized dosimetry approach (PDA) and standard dosimetry approach (SDA). The intent was to deliver at least 205 Gy (targeting >250-300 Gy if possible) to the index lesion in PDA, and 120 ± 20 Gy to the treated volume in SDA. The primary focus was on the 3-month response of the index lesion, with overall survival (OS) as a secondary endpoint.

The study involved 60 hepatocellular carcinoma patients with at least one lesion larger than 7 cm and more than 30% hepatic reserve. Patients were randomized into two groups: 31 in the PDA group and 29 in the SDA group, with a modified intent-to-treat population of 28 in each arm after adjustments. The median follow-up duration for this analysis was 65.8 months.

Results showed that the median OS in the modified intent-to-treat population was significantly longer in the PDA group (24.8 months) compared to the SDA group (10.7 months), with a hazard ratio (HR) of 0.51. Additionally, patients receiving a tumor dose of at least 205 Gy had a median OS of 22.9 months, significantly longer than those who received less than 205 Gy (10.3 months). A similar pattern was observed for patients with a perfused liver dose of 150 Gy or higher, as opposed to those with less than 150 Gy. Furthermore, patients who underwent secondary resection, predominantly in the PDA group, demonstrated notably better long-term OS rates, with an OS of more than 50% at 5 years, compared to those without secondary resection.

The study concluded that personalized dosimetry in selective internal radiation therapy significantly improved long-term overall survival, especially in patients downstaged towards resection, including those with portal vein thrombosis.

Reference

Garin E, Tselikas L, Guiu B, Chalaye J, Rolland Y, de Baere T, Assenat E, Tacher V, Palard X, Déandreis D, Mariano-Goulart D, Amaddeo G, Boudjema K, Hollebecque A, Meerun MA, Regnault H, Vibert E, Campillo-Gimenez B, Edeline J. Long-Term Overall Survival After Selective Internal Radiation Therapy for Locally Advanced Hepatocellular Carcinomas: Updated Analysis of DOSISPHERE-01 Trial. J Nucl Med. 2024 Jan 11:jnumed.123.266211. doi: 10.2967/jnumed.123.266211. Epub ahead of print. PMID: 38212068.

Breast Cancer: Patients with HER2-positive metastatic breast cancer

The study titled "The HER2-directed antibody-drug conjugate DHES0815A in advanced and/or metastatic breast cancer: preclinical characterization and phase 1 trial results" was a phase 1 trial focused on patients with HER2-positive metastatic breast cancer (1). This research involved the development of a novel HER2 antibody-drug conjugate (ADC), DHES0815A, which was designed to not compete with existing treatments such as trastuzumab or pertuzumab for binding. The conjugate utilized a modified PBD (pyrrolobenzodiazepine) dimer payload that alkylates but does not cross-link DNA. The efficacy of DHES0815A was demonstrated in vivo in models of HER2-positive and HER2-low cancers and was found to be well-tolerated in cynomolgus monkey safety studies.

The primary objective of the clinical trial was to evaluate the safety and tolerability of DHES0815A. Secondary objectives included characterizing the pharmacokinetics, objective response rate, duration of response, and formation of anti-DHES0815A antibodies. However, the trial was prematurely terminated due to the development of persistent, non-resolvable dermal, ocular, and pulmonary toxicities in patients at higher doses. These toxicities overshadowed the early signs of anti-tumor activity observed. The study's design was a dose-escalation study registered under ClinicalTrials.gov with the identifier NCT03451162.

Reference

Lewis GD, Li G, Guo J, Yu SF, Fields CT, Lee G, Zhang D, Dragovich PS, Pillow T, Wei B, Sadowsky J, Leipold D, Wilson T, Kamath A, Mamounas M, Lee MV, Saad O, Choeurng V, Ungewickell A, Monemi S, Crocker L, Kalinsky K, Modi S, Jung KH, Hamilton E, LoRusso P, Krop I, Schutten MM, Commerford R, Sliwkowski MX, Cho E. The HER2-directed antibody-drug conjugate DHES0815A in advanced and/or metastatic breast cancer: preclinical characterization and phase 1 trial results. Nat Commun. 2024 Jan 11;15(1):466. doi: 10.1038/s41467-023-44533-z. PMID: 38212321; PMCID: PMC10784567.

Leukemias: Acute Lymphoblastic Leukemia

In this study, the researchers conducted a Phase 1/2 clinical trial to evaluate the safety and efficacy of combining low-intensity chemotherapy (mini-hyper-CVD) with venetoclax, a Bcl-2 inhibitor, in adults with relapsed or refractory Acute Lymphoblastic Leukemia (ALL) (1). The trial included 22 patients who had previously undergone a median of 2 prior therapies, with a range of 1 to 6. Notably, 59% of the participants had previously received an allogeneic stem cell transplant (alloSCT), and 39% of the 18 patients with B-cell ALL had been treated with both inotuzumab ozogamicin and blinatumomab.

Patients were administered venetoclax at doses of either 200 mg or 400 mg daily. This was given on days 1-14 in the first cycle and on days 1-7 in subsequent consolidation cycles. The study identified 400 mg daily as the recommended Phase 2 dose of venetoclax for this regimen.

The results demonstrated a composite complete remission (CR) and CR with incomplete hematologic recovery (CRi) rate of 57% (CR 43%; CRi 14%). Additionally, 45% of those who responded achieved measurable residual disease negativity, as assessed by multiparameter flow cytometry. Four patients were able to proceed to alloSCT following the treatment. The median duration of response was reported as 6.3 months, with a median overall survival (OS) of 7.1 months and a 1-year OS rate of 29%.

The study also reported on the adverse events experienced by the participants. The most common grade 3 or higher non-hematologic adverse events included infection, which affected 17 patients (77%), and febrile neutropenia, which occurred in 4 patients (18%).

The study concluded that the combination of mini-hyper-CVD and venetoclax was active in patients with heavily pretreated relapsed/refractory ALL, suggesting the potential for further development of venetoclax-based combinations in this patient population.

Reference

Short NJ, Jabbour EJ, Jain N, Senapati J, Nasr LF, Haddad FG, Li Z, Hsiao YC, Yang JJ, Pemmaraju N, Ohanian M, Wierda WG, Montalban-Bravo G, Borthakur G, Han L, Xiao L, Huang X, Abramova R, Zhao M, Garris R, Konopleva M, Ravandi F, Kantarjian HM. A Phase 1/2 Study of Mini-Hyper-CVD plus Venetoclax in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia. Blood Adv. 2024 Jan 11:bloodadvances.2023012231. doi: 10.1182/bloodadvances.2023012231. Epub ahead of print. PMID: 38207208.

Skin Cancers: Melanoma

This study investigated the safety and efficacy of a novel immunotherapeutic approach in patients with refractory advanced melanoma. It was a first-in-human, phase I clinical trial (1). The population under study comprised patients with metastatic melanoma who were refractory to immune checkpoint-inhibitors and BRAF-/MEK inhibitors. The intervention entailed an intravenous administration of low-dose nivolumab (10 mg every 2 weeks), combined with intratumoral (IT) administration of 10 mg ipilimumab and 50 µg (0.5 mL) AS01(B) every 2 weeks. Additionally, autologous CD1c (BDCA-1)(+)/CD141 (BDCA-3)(+) myeloid dendritic cells, isolated from blood, were injected into the same metastatic lesion.

There was no specific control group in this phase I trial. The study included eight patients. The results indicated that the treatment was feasible and well-tolerated without unexpected adverse events. Efficacy outcomes showed that 50% of the patients achieved a complete response (CR) in the injected lesions, with two patients obtaining an overall CR and one patient achieving a partial response. All responses were ongoing after more than 1 year of follow-up. One additional patient exhibited stable disease. The disease control rate stood at 50%. The median progression-free survival and overall survival were 24.1 and 41.9 weeks, respectively. Baseline tumor biopsies from responders demonstrated features of T-cell exclusion, and during treatment, an increase in T-cell infiltration was observed, reducing the mean distance between T cells and tumor cells. The study concluded that combining intratumoral injection of myeloid dendritic cells with IT ipilimumab, AS01(B), and systemic low-dose nivolumab is a safe and feasible approach with promising early results.

Reference

Tijtgat J, Geeraerts X, Boisson A, Stevens L, Vounckx M, Dirven I, Schwarze JK, Raeymaeckers S, Forsyth R, Van Riet I, Tuyaerts S, Willard-Gallo K, Neyns B. Intratumoral administration of the immunologic adjuvant AS01B in combination with autologous CD1c (BDCA-1)+/CD141 (BDCA-3)+ myeloid dendritic cells plus ipilimumab and intravenous nivolumab in patients with refractory advanced melanoma. J Immunother Cancer. 2024 Jan 11;12(1):e008148. doi: 10.1136/jitc-2023-008148. PMID: 38212127.

Solid tumors/ Carcinomas: Non-Small Cell Lung Cancer, Pancreatic Cancer, Cholangiocarcinoma

This study was a phase I clinical trial investigating the combination of the anti-TIGIT antibody tiragolumab and the programmed death-ligand 1-inhibitor atezolizumab in Japanese patients with advanced or metastatic solid tumors (1). The study enrolled patients aged 20 years or older, who were administered tiragolumab (600 mg) and atezolizumab (1200 mg) intravenously every 21 days until they experienced unacceptable toxicity or disease progression. The primary endpoints of the study were safety and pharmacokinetic parameters of the combination therapy. Secondary endpoints included anti-tumor activity.

In total, three patients were enrolled in the study, diagnosed with non-small cell lung cancer, pancreatic cancer, and cholangiocarcinoma. The study found no dose-limiting toxicities, and two patients experienced treatment-related adverse events of any grade. Importantly, there were no grade 3 or higher adverse events, serious adverse events, events leading to discontinuation, modification, or withdrawal of any study drug, or events leading to death. Pharmacokinetic parameters of tiragolumab at cycle 1 showed a maximum concentration (Cmax) of 217 μg/mL, a minimum concentration (Cmin) of 54.9 μg/mL, an area under the concentration-time curve from 0 to the last measurable concentration of 2000 μg·day/mL, and a half-life (t1/2) of 17.6 days. The best overall response observed was stable disease in two patients.

The study concluded that the combination of tiragolumab and atezolizumab was well tolerated in Japanese patients with advanced/metastatic solid tumors. There were no noted differences in tiragolumab pharmacokinetic characteristics between Japanese patients in this study and non-Japanese patients in a global phase III study. These results suggest the potential for including Japanese patients in ongoing global phase III clinical trials. The study's trial registration number is jRCT2080224926.

Reference

Yamamoto N, Koyama T, Sato J, Yoshida T, Sudo K, Iwasa S, Kondo S, Yonemori K, Kawasaki A, Satake K, Shibata S, Shimizu T. Phase I study of the anti-TIGIT antibody tiragolumab in combination with atezolizumab in Japanese patients with advanced or metastatic solid tumors. Cancer Chemother Pharmacol. 2024 Jan 11. doi: 10.1007/s00280-023-04627-3. Epub ahead of print. PMID: 38206370.

Thoracic Cancers: Non-Small-Cell Lung Cancer

This study, focused on repotrectinib in treating ROS1 fusion-positive non-small-cell lung cancer (NSCLC), was a registrational phase 1-2 trial (1). The investigation included patients with advanced solid tumors, particularly those with ROS1 fusion-positive NSCLC. The intervention under examination was repotrectinib, a next-generation ROS1 tyrosine kinase inhibitor (TKI), administered at a recommended phase 2 dose of 160 mg daily for 14 days, followed by 160 mg twice daily. The study did not specify a control group.

The efficacy of repotrectinib was evaluated in two distinct patient populations: those with ROS1 fusion-positive NSCLC who had not previously received a ROS1 TKI, and those who had previously received one ROS1 TKI but had never received chemotherapy.

Among the 71 patients in the former group, 56 (79%; 95% confidence interval [CI], 68 to 88) responded to the treatment, with a median duration of response of 34.1 months (95% CI, 25.6 to could not be estimated), and a median progression-free survival of 35.7 months (95% CI, 27.4 to could not be estimated). In the latter group of 56 patients, 21 (38%; 95% CI, 25 to 52) showed a response, with a median duration of response of 14.8 months (95% CI, 7.6 to could not be estimated), and a median progression-free survival of 9.0 months (95% CI, 6.8 to 19.6). Additionally, 10 out of 17 patients (59%; 95% CI, 33 to 82) with the ROS1 G2032R mutation had a response.

The most common treatment-related adverse events were dizziness (58% of patients), dysgeusia (50%), and paresthesia (30%). A minority (3%) discontinued repotrectinib due to treatment-related adverse events. The study concluded that repotrectinib showed durable clinical activity in patients with ROS1 fusion-positive NSCLC, with adverse events that were generally low-grade and manageable for long-term administration. This study was funded by Turning Point Therapeutics, a subsidiary of Bristol Myers Squibb, and was registered under ClinicalTrials.gov number NCT03093116.

Reference

Drilon A, Camidge DR, Lin JJ, Kim SW, Solomon BJ, Dziadziuszko R, Besse B, Goto K, de Langen AJ, Wolf J, Lee KH, Popat S, Springfeld C, Nagasaka M, Felip E, Yang N, Velcheti V, Lu S, Kao S, Dooms C, Krebs MG, Yao W, Beg MS, Hu X, Moro-Sibilot D, Cheema P, Stopatschinskaja S, Mehta M, Trone D, Graber A, Sims G, Yuan Y, Cho BC; TRIDENT-1 Investigators. Repotrectinib in ROS1 Fusion-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2024 Jan 11;390(2):118-131. doi: 10.1056/NEJMoa2302299. PMID: 38197815.

Urological Cancers: Prostate Cancer

The study was a Phase II prospective, single-arm, non-randomized trial investigating the use of multiparametric (mp)MRI and in-bore biopsy during active surveillance in prostate cancer (PCa) (1). It focused on 82 men diagnosed with low-risk PCa. The research aimed to compare two biopsy strategies: the first involved an in-bore and Transrectal Ultrasound (TRUS) biopsy in men who showed suspicious findings on mpMRI; the second was a TRUS biopsy performed on all 82 participants, conducted without knowledge of the mpMRI results.

In the study, 27 out of 82 men displayed suspicious mpMRI findings. Among these, clinically significant PCa (csPCa) was detected in 8 of the 27 men using different biopsy strategies. Specifically, two cases were identified exclusively through in-bore biopsy, three exclusively via TRUS biopsy, and three cases were detected by both methods. In the group of 55 men without suspicious mpMRI results, who underwent only TRUS biopsies, two were found to have csPCa. The study revealed that using TRUS biopsy for the entire cohort would have diagnosed 80% of the men with csPCa, requiring all 82 men to undergo biopsies. However, employing both in-bore and TRUS biopsies in men with suspicious mpMRI findings also led to the detection of 80% of csPCa cases but only required biopsies in 27 men. The results indicated that combining TRUS and in-bore biopsies, focusing on men with suspicious mpMRI findings, achieved a similar csPCa detection rate as performing TRUS biopsies on all participants, but with significantly fewer men undergoing biopsy procedures. The study did not provide information on the follow-up duration.

Reference

Langbein BJ, Berk B, Bay C, Tuncali K, Martin N, Schostak M, Fennessy F, Tempany C, Kibel AS, Cole AP. A Phase II Prospective Blinded Trial of MRI and In-Bore Biopsy in Active Surveillance for Prostate Cancer. Urology. 2024 Jan 11:S0090-4295(23)01122-6. doi: 10.1016/j.urology.2023.12.017. Epub ahead of print. PMID: 38218388.