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SAN FRANCISCO -- Research presented here at the Gastrointestinal Cancers Symposium (GICS) included promising data in mismatch repair-deficient (dMMR) locally advanced rectal cancer and BRAF-mutant colorectal cancer (CRC) but a miss in pancreatic cancer.

'Unprecedented' in dMMR Rectal Cancer

Single-agent PD-1 inhibition led to complete responses in 100% of patients with mismatch repair-deficient (dMMR) locally advanced rectal cancer in a preliminary study.

All 11 evaluable patients had complete endoscopic clearance of the primary tumor, normal digital rectal exam, and absence of radiographic evidence of residual disease 12 months after finishing treatment with dostarlimab (Jemperli). Two other patients had preliminary responses but had not reached the 12-month cutoff.

The clinical complete response rate in the first 11 patients was "unprecedented," said Melissa A. Lumish, MD, of Memorial Sloan Kettering Cancer Center in New York City. "This strategy may uniquely allow patients to avoid chemoradiation and surgery with reduced morbidity, though the durability of response requires long-term follow-up. This strategy represents a potential new paradigm for the treatment of mismatch repair-deficient rectal cancer."

About 5% to 10% of rectal cancers are associated with dMMR, and a majority of patients have Lynch Syndrome. Studies have shown a lack of response to adjuvant 5-fluorouracil and an increased risk of progression during or after neoadjuvant chemotherapy. Metastatic dMMR colorectal cancer is responsive to immune checkpoint inhibition, providing a rationale for the evaluation of single-agent dostarlimab as initial treatment.

Lumish reported these preliminary findings from an ongoing trial that ultimately will enroll 30 patients with stage II-III dMMR rectal cancer. Patients receive dostarlimab for 6 months, followed by endoscopic and radiographic evaluation. Patients who have no evidence of disease proceed with nonoperative management.

PD-1 Blocker Boosts Activity in Mutated CRC

Half of patients with metastatic BRAF^V600E-mutant CRC responded to BRAF-targeted therapy plus nivolumab (Opdivo), according to data from a small single-arm trial.

Results showed that 11 of 22 patients responded to the combination of encorafenib (Braftovi), cetuximab (Erbitux), and the PD-1 inhibitor, and all but one of the patients obtained disease control with the regimen. The cohort had a median progression-free survival (PFS) of 7.4 months and median overall survival of 15.1 months, both of which exceeded historical norms for the FDA-approved regimen of encorafenib and cetuximab (20% response rate, median PFS 4.0 months).

"Encorafenib, cetuximab, and nivolumab appears to be a safe, well-tolerated combination for patients with microsatellite stable (MSS), BRAF-mutated metastatic colorectal cancer," said Van E. Morris, MD, of the University of Texas MD Anderson Cancer Center in Houston. "The efficacy of this combination appears promising when considering the precedent of encorafenib and cetuximab in the previously reported study. To investigate this more formally, SWOG 2107 is a randomized phase II trial that is expected to activate across the United States in the coming months."

Most patients with BRAF^V600E-mutated metastatic CRC are MSS/MMR-proficient (pMMR), characterized by increased immune activation and tumor mutational burden as compared with MSS BRAF wild-type CRC, said Morris. In vitro studies of MSS BRAF^V600E-mutated CRC showed conversion from pMMR to dMMR phenotype in response to treatment with a BRAF inhibitor (such as encorafenib) and an EGFR inhibitor (such as cetuximab), suggesting a potential role for PD-1 inhibition.

No OS Boost in Pancreatic Cancer with Novel L-Asparaginase

Adding a novel formulation of L-asparaginase to chemotherapy did not significantly improve overall survival (OS) versus chemotherapy as second-line therapy for pancreatic cancer, according to a large randomized trial.

Median OS was 7.5 months with eryaspase plus chemotherapy and 7.4 months with chemotherapy alone. Median PFS was 3.7 months with eryaspase and 3.4 months without. More patients randomized to the eryaspase arm achieved disease control (57.6% vs 49.0%).

Pairing eryaspase with fluoropyrimidine/irinotecan chemotherapy led to a trend toward improved OS (8.0 vs 5.7 months) as compared with eryaspase plus gemcitabine/nab-paclitaxel (7.0 vs 6.9 months), but the difference did not achieve statistical significance.

"The TRYbeCA-1 study did not meet the primary endpoint. However, all efficacy indicators showed a trend towards improved outcome for the chemotherapy plus eryaspase arm versus chemotherapy alone," said Pascal Hammel, MD, of Hopital Beaujon in Clichy, France. "The treatment effect was very consistent and stable across all subgroups. The treatment was well tolerated, and the addition of eryaspase did not enhance the toxicity of chemotherapy."

Pancreatic cancer causes , such as constitutive activation of KRAS signaling and utilization of asparagine and glutamine. Deprivation of asparagine and glutamine leads to loss of cell viability.

L-asparaginase demonstrated against pancreatic cancer cell lines in vitro but poses challenges in the treatment of solid tumors because of a narrow therapeutic index, said Hammel. Eryaspase is red blood cell-encapsulated L-asparaginase that has prolonged activity and reduced toxicity.