AACR: Trio of studies highlights promising early results with new cancer therapies and targets

ABSTRACTS CT037, CT038, CT042

SAN DIEGO – Three early-phase clinical studies presented by researchers from The University of Texas MD Anderson Cancer Center at the American Association for Cancer Research (AACR) Annual Meeting 2024 show promising initial data for patients with lymphoma, gastric or gastroesophageal junction cancers, and specific molecularly selected tumors. The studies were featured in a clinical trials minisymposium highlighting novel agents and emerging therapeutic strategies. Information on all MD Anderson AACR Annual Meeting content can be found at MDAnderson.org/AACR.

Novel combination with evorpacept demonstrates promising results for patients with B-cell non-Hodgkin lymphoma (Abstract CT037)

Data from an investigator-initiated Phase I trial of the novel CD47 blocker evorpacept (ALX148) in combination with lenalidomide and rituximab (R²), presented by Paolo Strati, M.D., assistant professor of Lymphoma and Myeloma, showed promising early results for patients with relapsed or refractory B-cell non-Hodgkin lymphoma.

While historical complete response rates (CRRs) with R² monotherapy are 30%, the new combination achieved an 80% CRR with an overall response rate of 90%. After a median follow-up of 16 months, the one-year progression-free survival rate was 70% and one-year overall survival rate was 90%.

Previous work from Strati demonstrated that specific white blood cells known as SIRPα+ macrophages may mediate resistance to the R² combination, leading to the hypothesis that adding evorpacept to the R² combination could have synergistic results. Blocking CD47 prevents the ‘don’t eat me signal’ that results from the interaction of SIRPα and CD47.

“The addition of evorpacept to R² seems to significantly increase the efficacy of these therapies, with no synergistic toxicity, in patients with indolent B-cell lymphomas,” Strati said. “We look forward to continuing studies with this novel combination in order to bring effective options to our patients in need.”

The trial included 20 patients with four different types of B-cell non-Hodgkin lymphoma, 18 of whom had indolent, or slow-growing, disease. All patients previously received an anti-CD20 monoclonal antibody, and 73% received prior chemotherapy.

The most common grade 3 or higher adverse events were consistent with those typically seen with R² therapy, such as neutropenia, infections, elevated liver enzymes, skin rash and anemia, and were not increased by the addition of evorpacept. No dose-limiting toxicities were observed, and the recommended Phase II dose was identified.

A Phase II study investigating the efficacy of this combination in previously untreated patients is now enrolling.

This study was funded by ALX Oncology, the Leukemia & Lymphoma Society Scholar in Clinical Research Award, the Gilead and Kite Scholar Award and the Andrew Sabin Family Fellowship Program. A full list of collaborating authors and their disclosures can be found here.

Antibody-drug conjugate SKB264 shows potential for durable responses in heavily pretreated patients with advanced gastric or gastroesophageal junction cancers (Abstract CT038)

Preliminary data from a Phase I/II study evaluating the antibody-drug conjugate (ADC) SKB264, presented by Jordi Rodon, M.D., Ph.D., associate professor of investigational cancer therapeutics showed that pretreated patients with gastric or gastroesophageal junction cancers could have durable responses and potentially longer overall survival with SKB264 monotherapy.

Of the 41 patients able to be evaluated for response, SKB264 achieved an objective response rate of 22%, a disease control rate of 80.5%, and a median duration of response of 7.5 months.

“It is interesting to note the change in antitumor activity and safety profile that results from changing payloads and linkers, even among ADCs aiming at the same target,” Rodon said. “One of the big results of this trial is that, by using a different linker-payload combination, we did not see the interstitial lung diseases associated with other ADCs.”

SKB264 is an ADC that targets TROP2, a factor associated with poor prognosis in advanced gastric cancers. It uses a novel linker to connect the antibody with the payload, a belotecan-derivate topoisomerase I inhibitor.

Forty-eight patients were evaluable for safety, with a follow-up of at least nine weeks at the data cutoff. All received previous therapy, with 50% having received multiple prior lines of therapy. Treatment-related adverse events higher than grade 3 were seen in 52.1% of patients, with the most common being anemia, decreased white blood cell or neutrophil counts, and neutropenia. Only 18.8% of patients had to decrease dosage, and 33.3% had to delay dosing due to adverse events. No adverse events led to discontinuation of the trial or death.

Based on these results, a Phase III global study currently is being planned to evaluate SKB264 in comparison to the current standard of care in patients with at least three prior lines of therapy in gastric or gastroesophageal junction adenocarcinomas.

This study was funded by Klus Pharma and Merck & Co. (MSD). A full list of collaborating authors and their disclosures can be found here.          

Combining PARP and PI3K inhibitors shows encouraging results in Phase Ib trial for molecularly selected patients (Abstract CT042) 

Results from a biomarker-driven, tumor-agnostic Phase Ib trial of copanlisib plus olaparib showed the combination was safe and well tolerated, with a clinical benefit in 36% of molecularly selected patients who had advanced cancers harboring PIK3CA hotspot, PTEN, or DNA damage response (DDR) mutations.  

Trial results were presented by Timothy Yap, M.B.B.S., Ph.D., professor of Investigational Cancer Therapeutics, and vice president and head of clinical development in the Therapeutics Discovery division.  

Of 22 patients able to be evaluated for efficacy, six achieved partial responses and two achieved stable disease for at least six months. Notably, a patient with advanced triple-negative breast cancer with PIK3CA H1047R, PTEN and ARID1A mutations achieved a confirmed radiological partial response and was on trial for 42 months with minimal side effects.   

Preclinical studies had shown potential for the combination of PI3K and PARP inhibition in cancers with DDR and PI3K pathway alterations, prompting this investigator-initiated trial conducted through National Cancer Institute Cancer Therapy Evaluation Program (NCI CTEP), which partnered the pan-PI3K inhibitor copanlisib with the PARP inhibitor olaparib.  

The trial enrolled 28 patients, representing 12 cancer types and 11 mutation types. Ten patients had more than one qualifying mutation. This was a heavily pretreated patient population, with 61% having received three or more prior lines of therapy. The combination was safe and generally well tolerated, with the most common adverse events of any grade being mucositis, nausea, diarrhea and vomiting. 

“We observed promising antitumor activity in patients with a range of cancers with different DDR and/or PI3K pathway alterations, which may serve as novel predictive biomarkers of response,” Yap said. “Comprehensive translational analyses of longitudinally collected patient samples from the clinical trial are currently ongoing.”  

This study was funded and sponsored by the National Cancer Institute, part of National Institutes of Health. MD Anderson led the study with participation from the NCI Experimental Therapeutics Clinical Trials Network (ETCTN) (4UM1CA186688-07). AstraZeneca Pharmaceuticals and Bristol-Myers Squibb Company provided support to this study through Cooperative Research and Development Agreement between NCI and each company. A full list of collaborating authors and their disclosures can be found here.