Oncology Daily Report: 01/10/2024

The study, conducted between March 2014 and June 2018, involved 105 patients, but was prematurely stopped due to slow recruitment. Out of these, 53 patients were assigned to the CRS-A group and 52 to the CRS + H group. However, treatment stopped before CRS in 55 patients, mainly due to disease progression or death. The results showed that the median OS was the same for both groups, with no significant difference. However, the PFS and MFS were significantly better in the CRS + H group. The incidence of grade ≥3 adverse events (AEs) was similar in both groups.

In conclusion, the study found no difference in overall survival between the CRS + H and CRS-A groups. Despite this, the CRS + H group exhibited significantly better progression-free survival and metastasis-free survival, which warrants further investigation. Importantly, the addition of HIPEC did not result in an increase in adverse events.

Reference

Rau B, Lang H, Koenigsrainer A, Gockel I, Rau HG, Seeliger H, Lerchenmueller C, Reim D, Wahba R, Angele M, Heeg S, Keck T, Weimann A, Topp S, Piso P, Brandl A, Schuele S, Jo P, Pratschke J, Wegel S, Rehders A, Moosmann N, Gaedcke J, Heinemann V, Trips E, Loeffler M, Schlag PM, Thuss-Patience P. Effect of Hyperthermic Intraperitoneal Chemotherapy on Cytoreductive Surgery in Gastric Cancer With Synchronous Peritoneal Metastases: The Phase III GASTRIPEC-I Trial. J Clin Oncol. 2024 Jan 10;42(2):146-156. doi: 10.1200/JCO.22.02867. Epub 2023 Oct 31. PMID: 37906724.

Gastrointestinal Cancers: Gastric Cancer with Synchronous Peritoneal Metastases

The study titled "Effect of Hyperthermic Intraperitoneal Chemotherapy on Cytoreductive Surgery in Gastric Cancer With Synchronous Peritoneal Metastases: The Phase III GASTRIPEC-I Trial" was a randomized, controlled, open-label, multicenter phase III trial conducted to explore the impact of hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery (CRS) on overall survival (OS) in patients with gastric cancer (GC) and peritoneal metastasis (PM) (1). Adult patients with GC and histologically proven PM were the population under investigation. These patients were randomly assigned in a 1:1 ratio to either perioperative chemotherapy with CRS alone (CRS-A) or CRS plus HIPEC (CRS + H). The HIPEC involved administering mitomycin C and cisplatin in a saline solution. The primary endpoint of the study was OS, while secondary endpoints included progression-free survival (PFS), other distant metastasis-free survival (MFS), and safety.

The most common adverse events were all-grade diarrhea (90.9%), nausea (54.5%), and constipation (54.5%). Grade 3 diarrhea was reported in 22.7% of patients, but there were no grade 4 adverse events and no diarrhea-related treatment discontinuations. Two grade 5 adverse events occurred, which were not related to neratinib.

This study concluded that neratinib offers durable responses and disease control in HER2-mutant metastatic/recurrent cervical cancer patients. The results suggest the potential of next-generation sequencing and tailored therapy in advanced cervical cancer treatment, particularly for those with endocervical adenocarcinoma. Further investigation of neratinib in this context is recommended. The study did not specify a control group or follow-up duration.

Reference

Friedman CF, D'Souza A, Bello Roufai D, Tinker AV, de Miguel M, Gambardella V, Goldman J, Loi S, Melisko ME, Oaknin A, Spanggaard I, Shapiro GI, ElNaggar AC, Panni S, Ravichandran V, Frazier AL, DiPrimeo D, Eli LD, Solit DB. Targeting HER2-mutant metastatic cervical cancer with neratinib: Final results from the phase 2 SUMMIT basket trial. Gynecol Oncol. 2024 Jan 10;181:162-169. doi: 10.1016/j.ygyno.2023.12.004. Epub ahead of print. PMID: 38211393.

Gynecological Cancers: Metastatic Cervical Cancer

In the phase 2 SUMMIT basket trial, neratinib was evaluated for its efficacy in treating HER2-mutant metastatic cervical cancer (1). This study specifically targeted patients with metastatic or recurrent cervical cancer who had progressed following platinum-based treatment. A total of 22 patients, predominantly with endocervical adenocarcinoma, were enrolled. The intervention under investigation was neratinib administered at a dosage of 240 mg/day, accompanied by mandatory loperamide in the first cycle.

The primary outcome measure was the confirmed objective response rate (ORR), with secondary endpoints including duration of response (DoR), clinical benefit rate (CBR), progression-free survival (PFS), and safety profile. The study found that 18.2% (4 patients) achieved a confirmed partial response, while stable disease for 16 weeks or longer was observed in 27.3% (6 patients), leading to a CBR of 45.5%. The median DoR was 7.6 months, and the median PFS was 5.1 months.

The objective response rates (ORRs) were similar in both groups: 28.9% in the ofra-vec arm and 29.6% in the control arm. The study also found that response to CA-125, a cancer antigen, was a significant prognostic factor for both PFS and OS in both treatment groups. Specifically, in the ofra-vec arm, the HR for PFS in CA-125 responders compared to nonresponders was 0.2428 (CI, 0.1642 to 0.3588), and for OS, it was 0.3343 (CI, 0.2134 to 0.5238). The safety profile of the treatment was characterized by transient flu-like symptoms, such as fever and chills.

In conclusion, the addition of ofra-vec to paclitaxel did not significantly improve PFS or OS in patients with PROC. The PFS and ORR in the control arm were higher than expected based on previous studies, and the study highlighted the importance of CA-125 response as a prognostic biomarker for patients with PROC treated with paclitaxel.

Reference

Arend RC, Monk BJ, Shapira-Frommer R, Haggerty AF, Alvarez EA, Amit A, Alvarez Secord A, Muller C, Casado Herraez A, Herzog TJ, Tewari KS, Cohen JG, Huang M, Yachnin A, Holeman LL, Ledermann JA, Rachmilewitz Minei T, Buyse M, Fain Shmueli S, Lavi M, Harats D, Penson RT; OVAL/GOG-3018 Investigators. Ofranergene Obadenovec (Ofra-Vec, VB-111) With Weekly Paclitaxel for Platinum-Resistant Ovarian Cancer: Randomized Controlled Phase III Trial (OVAL Study/GOG 3018). J Clin Oncol. 2024 Jan 10;42(2):170-179. doi: 10.1200/JCO.22.02915. Epub 2023 Oct 31. PMID: 37906726.

Gynecological Cancers: Platinum-Resistant Ovarian Cancer

This study, titled "Ofranergene Obadenovec (Ofra-Vec, VB-111) With Weekly Paclitaxel for Platinum-Resistant Ovarian Cancer: Randomized Controlled Phase III Trial (OVAL Study/GOG 3018)," aimed to assess the efficacy of ofranergene obadenovec (ofra-vec, VB-111) combined with paclitaxel in patients with recurrent platinum-resistant ovarian cancer (PROC) (1). The study was designed as a placebo-controlled, double-blind, phase III trial, and it randomly assigned patients in a 1:1 ratio to receive either intravenous ofra-vec every 8 weeks with weekly IV paclitaxel or a placebo with paclitaxel, continuing until disease progression. The primary endpoints of the study were overall survival (OS) and progression-free survival (PFS), assessed by a Blinded Independent Central Review.

The trial enrolled 409 patients between December 2017 and March 2022. The results showed that the median PFS was 5.29 months in the ofra-vec arm and 5.36 months in the control arm, with a hazard ratio (HR) of 1.03 (95% Confidence Interval [CI], 0.83 to 1.29; P = .7823). Median OS was 13.37 months for patients receiving ofra-vec and 13.14 months for those in the control group, with an HR of 0.97 (CI, 0.75 to 1.27; P = .8440).

The study reported that the most common grade 3/4 adverse events during maintenance were leukopenia, neutropenia, and thrombocytopenia, which were described as transient and manageable. Only four patients experienced infections, all of which were grade 1-2. In terms of outcomes, the 1-year and 2-year moderate/severe chronic GVHD rates were 4% (95% CI, 0.3-18%) and 22% (95% CI, 9-40%), respectively. After a median follow-up of 25 months among survivors, the median overall survival (OS) was not reached. The 2-year OS, progression-free survival, non-relapse mortality, and cumulative incidence of relapse rates in the 22 patients who received Ven/Aza maintenance were 67% (95% CI, 43-83%), 59% (95% CI, 36-76%), 0%, and 41% (95% CI, 20-61%), respectively. Furthermore, immune monitoring showed no significant impact on T cell expansion, but a reduced B cell expansion compared to controls was noted. The study concluded that prophylactic Ven/Aza maintenance is safely administrable in high-risk MDS/AML patients, but emphasized the need for a randomized study to properly assess any potential benefit.

Reference

Garcia JS, Kim HT, Murdock HM, Ansuinelli M, Brock J, Cutler CS, Gooptu M, Ho VT, Koreth J, Nikiforow S, Romee R, Shapiro RM, DeAngelo DJ, Stone RM, Bat-Erdene D, Ryan JA, Contreras ME, Fell G, Letai A, Ritz J, Lindsley RC, Soiffer RJ, Antin JH. Prophylactic maintenance with venetoclax/azacitidine after reduced intensity conditioning allo-transplant for high risk MDS and AML. Blood Adv. 2024 Jan 10:bloodadvances.2023012120. doi: 10.1182/bloodadvances.2023012120. Epub ahead of print. PMID: 38197938.

Leukemias:Myelodysplastic Syndromes (MDS)/Acute Myeloid Leukemia

In this phase 1 trial, researchers investigated the safety and efficacy of prophylactic maintenance therapy with venetoclax and azacitidine (Ven/Aza) in patients diagnosed with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) (1). These patients had undergone reduced intensity allogeneic hematopoietic stem cell transplantation (allo-SCT) with venetoclax and FluBu2 conditioning (Ven/FluBu2 allo-SCT), combined with tacrolimus and methotrexate for graft-versus-host disease (GVHD) prophylaxis. The study included 27 patients, of which 55.6% had prior venetoclax exposure, and 96% were positive for molecular measurable residual disease (MRD). Out of these, 22 patients received the maintenance therapy, which was administered in two different schedules: either 42-day cycles for 8 times or 28-day cycles for 12 times. The maintenance regimen involved azacitidine 36 mg/m^2 intravenously on days 1-5 and venetoclax 400 mg orally on days 1-14.

The study reported three course-1 dose-limiting toxicities (DLTs) including hematologic complications, anorexia, and elevated transaminases. Additionally, there were 23 serious adverse events, 78% of which were fever-related. Of the participants, five patients (21%) completed one year of therapy, with nine discontinuing due to disease progression, two due to DLTs, and eight by choice. The best overall response observed included two partial responses (PR) and four minor responses (MR). The median time-to-progression was 19.8 months, and three patients remained progression-free for over four years without any additional therapy. The study concluded that the MTD of DFMO with this regimen was 6750 mg/m²/day. The follow-up duration was not explicitly mentioned, but the results indicated a progression-free period of over four years for some patients. The findings suggested that high-dose DFMO can be tolerable when added to chemotherapy in heavily pre-treated patients, leading to the ongoing randomized Phase 2 trial of DFMO added to chemoimmunotherapy (NCT03794349).

Reference

Hogarty MD, Ziegler DS, Franson A, Chi YY, Tsao-Wei D, Liu K, Vemu R, Gerner EW, Bruckheimer E, Shamirian A, Hasenauer B, Balis FM, Groshen S, Norris MD, Haber M, Park JR, Matthay KK, Marachelian A. Phase 1 study of high-dose DFMO, celecoxib, cyclophosphamide and topotecan for patients with relapsed neuroblastoma: a New Approaches to Neuroblastoma Therapy trial. Br J Cancer. 2024 Jan 10. doi: 10.1038/s41416-023-02525-2. Epub ahead of print. PMID: 38200233.

Pediatric Cancers: High-risk Neuroblastoma

The study was a Phase 1 trial designed to establish the maximum tolerated dose (MTD) of DFMO in combination with celecoxib, cyclophosphamide, and topotecan for patients with relapsed neuroblastoma (1). The patient population under investigation included individuals aged 2 to 30 years with relapsed/refractory high-risk neuroblastoma. The intervention under investigation involved oral DFMO at doses up to 9000 mg/m²/day, combined with celecoxib (500 mg/m² daily), cyclophosphamide (250 mg/m²/day), and topotecan (0.75 mg/m²/day) IV for 5 days, extendable up to one year with G-CSF support. There was no mention of a control group in this phase 1 study.

The study enrolled 24 patients with a median age of 6.8 years, who received a total of 136 courses of the treatment. Adjustments in the course duration were made from 21 days to 28 days due to slow platelet recovery observed in the initial dose levels.

The study reported an objective response rate of 36% (95% Confidence Interval [CI]: 18-57.5%). The median progression-free survival was 6.7 months, with the upper limit of the 95% CI not estimable.

In conclusion, the combination of sitravatinib and tislelizumab demonstrated manageable safety and tolerability profiles in patients with anti-PD-(L)1 refractory or resistant unresectable, advanced, or metastatic melanoma. The therapy also showed promising antitumor activity. The study is registered under the identifier NCT03666143 at ClinicalTrials.gov.

Reference

Wang X, Pan H, Cui J, Chen X, Yoon WH, Carlino MS, Li X, Li H, Zhang J, Sun J, Guo J, Cui C. SAFFRON-103: a phase Ib study of sitravatinib plus tislelizumab in anti-PD-(L)1 refractory/resistant advanced melanoma. Immunotherapy. 2024 Jan 10. doi: 10.2217/imt-2023-0130. Epub ahead of print. PMID: 38197138.

Skin Cancers: Advanced/ Metastatic Melanoma

The SAFFRON-103 study, an open-label, multicenter, multicohort investigation, focused on the efficacy and safety of sitravatinib in combination with the anti-PD-1 antibody tislelizumab in patients with unresectable, advanced, or metastatic melanoma (1). This phase Ib study enrolled 25 patients who had previously shown disease progression on or after first-line anti-PD-(L)1 monotherapy. The key objective was to evaluate the combination of sitravatinib, administered daily, and tislelizumab, given every three weeks. The primary endpoint was the assessment of safety and tolerability.

All participants experienced treatment-emergent adverse events (TEAEs), with more than half (52%) encountering TEAEs of grade 3 or higher. However, these events were mostly mild to moderate in severity, and there were no fatal TEAEs. A small portion of the cohort (12%) discontinued treatment due to TEAEs.

A total of 643 patients were enrolled, with 320 receiving canakinumab and 323 receiving placebo. At a median follow-up of 6.5 months, the median PFS was 6.8 months for both groups (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.67 to 1.09; P = .102). At a median follow-up of 21.2 months, the median OS was 20.8 months with canakinumab versus 20.2 months with placebo (HR, 0.87; 95% CI, 0.70 to 1.10; P = .123). Safety profiles were consistent with expectations; infection rates were similar between groups, though the canakinumab group had higher frequencies of neutropenia and alanine aminotransferase (ALT) increase (grade ≤2). Patients with higher baseline C-reactive protein and IL-6 levels had shorter PFS and OS. Canakinumab-treated patients experienced delays in the deterioration of lung cancer symptoms.

In conclusion, the addition of canakinumab to first-line pembrolizumab and CT did not significantly improve PFS or OS in patients with advanced NSCLC.

Reference

Tan DSW, Felip E, de Castro G, Solomon BJ, Greystoke A, Cho BC, Cobo M, Kim TM, Ganguly S, Carcereny E, Paz-Ares L, Bennouna J, Garassino MC, Schenker M, Kim SW, Brase JC, Bury-Maynard D, Passos VQ, Deudon S, Dharan B, Song Y, Caparica R, Johnson BE. Canakinumab Versus Placebo in Combination With First-Line Pembrolizumab Plus Chemotherapy for Advanced Non-Small-Cell Lung Cancer: Results From the CANOPY-1 Trial. J Clin Oncol. 2024 Jan 10;42(2):192-204. doi: 10.1200/JCO.23.00980. Epub 2023 Dec 1. PMID: 38039427.

Thoracic Cancers: Advanced Non-Small-Cell Lung Cancer

The CANOPY-1 trial was a phase III, randomized, double-blind study that investigated the efficacy of canakinumab, an anti-interleukin (IL)-1β antibody, in combination with pembrolizumab and platinum-based doublet chemotherapy (CT) for the first-line treatment of advanced or metastatic non-small-cell lung cancer (NSCLC) without EGFR or ALK mutations (1). The study compared canakinumab (200 mg subcutaneously every 3 weeks) versus placebo, both in combination with pembrolizumab (200 mg intravenously every 3 weeks) and platinum-based CT. The primary endpoints were progression-free survival (PFS) and overall survival (OS), with secondary endpoints including overall response rate, safety, and patient-reported outcomes.

The median DFS was 35.0 months in the canakinumab arm and 29.7 months in the placebo arm, with a hazard ratio of 0.94 (95% CI, 0.78 to 1.14; one-sided P = .258). Subgroup analyses of DFS did not reveal any meaningful differences between the two groups. Adverse events of grade ≥3 were reported in 20.8% of patients in the canakinumab group and 19.6% in the placebo group, leading to discontinuation in 4.3% and 4.1% of patients, respectively. No new safety concerns were identified with canakinumab use. Additionally, although canakinumab led to a decrease in C-reactive protein and IL-6 levels, this did not correlate with differential clinical outcomes. Since the primary endpoint of DFS was not met, overall survival was not formally tested.

In conclusion, the study found that adding canakinumab after surgery and adjuvant cisplatin-based chemotherapy did not provide a benefit in disease-free survival for patients with resected, stage II-III NSCLC.

Reference

Garon EB, Lu S, Goto Y, De Marchi P, Paz-Ares L, Spigel DR, Thomas M, Yang JC, Ardizzoni A, Barlesi F, Orlov S, Yoshioka H, Mountzios G, Khanna S, Bossen C, Carbini M, Turri S, Myers A, Cho BC. Canakinumab as Adjuvant Therapy in Patients With Completely Resected Non-Small-Cell Lung Cancer: Results From the CANOPY-A Double-Blind, Randomized Clinical Trial. J Clin Oncol. 2024 Jan 10;42(2):180-191. doi: 10.1200/JCO.23.00910. Epub 2023 Oct 3. PMID: 37788412.

Thoracic Cancers: Non-Small-Cell Lung Cancer

In a second report on the same agent, the CANOPY-A study, a phase III clinical trial, investigated the effectiveness of canakinumab as adjuvant therapy in adult patients with completely resected non-small-cell lung cancer (NSCLC) (1). The study was a randomized, double-blind, multicenter trial comparing canakinumab to a placebo. The participants were patients with stage II-IIIA or IIIB NSCLC who had undergone complete surgical resection and received adjuvant cisplatin-based chemotherapy. A total of 1,382 patients were enrolled, with 693 receiving 200 mg of canakinumab and 689 receiving placebo every three weeks for 18 cycles.

The primary outcome of the study was disease-free survival (DFS), and the key secondary outcome was overall survival (OS). However, the study did not meet its primary endpoint.