Trial results suggest new approaches to treat rare cancers
Rare cancers are difficult targets. They have traditionally attracted little attention from researchers, and most have few treatment options. But the advent of targeted therapy and immunotherapy is changing the traditional treatment paradigm to help focus attention on less common cancer types including mesothelioma, biliary tract cancer, and certain types of melanoma.
The Annual Meeting’s second clinical trials plenary session, Hope for Rare Cancers: Novel Targeted and Immunotherapy Agents, highlighted four promising studies that suggest new treatment approaches for rare cancers. The session, which was held Sunday, April 16, can be viewed on the virtual meeting platform by registered Annual Meeting participants through July 19, 2023.
First Hippo-YAP pathway inhibitor shows success in advanced solid tumors
Timothy A. Yap, MD, PhD, reported on a study that provides the first clinical proof-of-concept for effectively drugging the Hippo-YAP pathway.
Mesothelioma and other cancers commonly have a deregulated Hippo pathway, which leads to the activation of the YAP and TAZ transcription factors. YAP/TAZ interact with DNA-binding TEAD proteins, resulting in uncontrolled tumor proliferation and impaired differentiation. Hippo-YAP has long been considered undruggable, but this first-in-class, first-in-human phase I trial has demonstrated up to an 81 percent reduction in target lesions over more than 12 months of treatment.
The study drug, VT3989, inhibits TEAD palmitoylation, which is required for the transcription function of TEAD-YAP, explained Yap, Associate Professor in the Department of Investigational Cancer Therapeutics and Medical Director at the Institute for Applied Cancer Science at The University of Texas MD Anderson Cancer Center.
The researchers have treated 69 patients to date with multiple types of mesothelioma and other solid tumors. The 3+3 dose-escalation study included five escalating doses, from 50 mg to 200 mg, using multiple continuous and intermittent dosing schedules. The primary endpoints are safety, tolerability, maximum tolerated dose, and recommended phase II dosing. Secondary endpoints include antitumor activity, pharmacokinetics, time to response, and duration of response.
Median age of study participants is 63.5 years, half are female, and they have received VT3989 for as long as 75 weeks. No dose-limiting toxicities have been seen.
Peripheral edema, nausea, albuminuria, and fatigue were the most common adverse events, Yap reported. Albuminuria and proteinuria have not been associated with any significant clinical symptoms or changes in serum creatinine, creatinine clearance, or serum albumin, and have been reversible in patients on all doses and schedules.
VT3989 has a long half-life, 12 to 15 days, and plasma concentrations are dose-proportional.
First trial of arginine-depleting therapy in cancer prolongs survival in non-epithelioid malignant pleural mesothelioma
The ATOMIC-Meso trial compared pegargiminase plus chemotherapy versus placebo plus chemotherapy in patients with non-epithelioid malignant pleural mesothelioma (MPM).
“We saw an increase in median overall survival (OS) of 1.6 months compared with standard-of-care chemotherapy for non-epithelioid MPM with pegargiminase,” reported Peter Szlosarek, MD, PhD, Professor of Medical Oncology and Group Leader at Barts Cancer Institute, Queen Mary University of London, United Kingdom. “Pegargiminase plus chemotherapy also increased the median progression-free survival (PFS).”
MPM is driven predominantly by asbestos and has one of the lowest five-year survival rates of all cancers, at 5 percent to 10 percent. Non-epithelioid MPM is even more aggressive, with a median survival of four to eight months.
L-arginine is a nonessential amino acid in normal cells that can be synthesized by the body, Szlosarek said. But it becomes an essential amino acid in cancer cell lines with an epigenetic loss of ASS1, an enzyme essential for arginine synthesis, leaving MPM cells lines sensitive to arginine deprivation. Pegargiminase converts extracellular arginine into citrulline, preventing cancer cells from receiving this arginine supply.
The trial randomized patients to receive either pemetrexed and platinum chemotherapy plus pegargiminase (125) or chemotherapy alone (124).The primary endpoint was median OS. Secondary endpoints were median PFS, pharmacodynamics, and immunogenicity. The study was stopped early on the recommendation of an independent data safety monitoring board due to positive results.
Patients in the trial were 69 years old and predominantly male, the usual pattern seen in MPM.
The disease control rate in the pegargiminase group was 85.1 percent versus 76.4 percent in the placebo group, and the difference was not significant. But the median OS was 9.3 months for pegargiminase versus 7.7 months for placebo. The pegargiminase group had more grade 3 and higher adverse events than the placebo group (28.8 percent versus 16.9 percent, respectively). The adverse events were primarily hematologic.
“The survival curves separated early, and they remained separated,” Szlosarek said. “We have seen patients on pegargiminase who have survived with no further treatment. I would urge you to see poster 1760 for more information on the first anti-metabolite regimen based on arginine deprivation for the treatment of cancer.”
Pembrolizumab plus gemcitabine and cisplatin improve outcomes for patients with biliary tract cancer
Biliary tract cancers (BTCs) are on the rise globally and generally have a poor prognosis. Most BTCs have a cold, or immune-suppressed, microenvironment, and response to immune checkpoint inhibitor monotherapy is low.
Gemcitabine and cisplatin (gem/cis) have been standard of care for BTC for more than a decade, and because they modulate antitumor immunity, there is a good rationale to combine gem/cis with checkpoint inhibition.
The phase III KEYNOTE-966 study randomized 1,069 patients with unresectable BTC to either gem/cis (536) or pembrolizumab + gem/cis (533), with a median follow-up of 25.6 months.
Study participants were about 64 years old on average, with a slight predominance of males. OS was the primary endpoint, and secondary endpoints included PFS, objective response rate (ORR), duration of response (DOR), and safety.
“We saw a 17 percent advantage in OS for pembrolizumab plus gem/cis compared to gem/cis alone,” reported Robin Kate Kelley, MD, Professor of Clinical Medicine at the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco. The benefits of adding pembro were generally consistent across prespecified subgroups.”
OS at 24 months was 25 percent for the combination arm versus 18 percent for the chemo arm. PFS at 24 months was 9 percent and 6 percent, respectively. The ORR was similar in the two arms, but the DOR was significantly better in the combination arm (8.3 months) than in the chemo arm (6.8 months) at the final analysis. Adverse events were similar in both arms and primarily hematologic, except for immune-mediated events and infusion reactions, which were higher in the combination arm.
“These data support pembrolizumab plus gem/cis as a new treatment option for patients with previously untreated metastatic or unresectable BTC,” Kelley said.
The study was published simultaneously in The Lancet.
Strong response with single-agent anti-PD-1 in metastatic desmoplastic melanoma
SWOG S1512 is the first prospective study looking at PD-1 blockade with pembrolizumab in patients with desmoplastic melanoma (DM), a rare melanoma subtype with a high tumor burden due to heavy ultraviolet light damage. A retrospective analysis of more than 1,000 cases found a strong overall response rate to PD-1 blockade, but there were no prospective data.
“We saw an overall response rate of 89 percent and clinically complete response in 33 percent of patients,” reported Kari Kendra, MD, PhD, Associate Professor of Internal Medicine at the Ohio State University Comprehensive Cancer Center.
The trial included 27 patients with unresectable DM who were treated with pembrolizumab every three weeks for two years. Follow-up for PFS and OS will continue for five years from the completion of treatment. Researchers collected tissue and whole blood samples at baseline and every nine weeks thereafter. The primary endpoint was clinical complete response (CR) rate.
A total of 21 patients discontinued protocol treatment, mostly due to adverse events (9) or disease progression (4). Overall, patients received a median of 15 cycles of pembro.
The median age of study patients was 79, and 93 percent were male, which is typical for DM.
CR was observed in nine patients, corresponding to 33 percent of the cohort. The study successfully met its primary endpoint of achieving a CR of 20 percent or higher. ORR was 89 percent. Two-year PFS was 74 percent, and two-year OS was 89 percent.
Most patients, 94 percent, had adverse events, primarily grade 1/2. The most frequent toxicities were fatigue, diarrhea, rash, pruritus, anemia, arthralgia, and decreased lymphocyte count.
“Patients with metastatic DM are exceptional responders to pembrolizumab,” Kendra said. “Based on these data, single-agent PD-1 therapy should be considered the first-line treatment of choice for most patients with unresectable DM.”
Claim Your CME/MOC Credits for the Annual MeetinG
Access to the AACR Annual Meeting 2023 virtual meeting platform and all on-demand sessions is available through July 19, 2023. To claim CME/MOC credits for qualified sessions, visit the AACR Continuing Medication Education page. Questions? Contact the AACR Office of CME at (215) 440-9300 or via e-mail at [email protected].