乌鸦传媒

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SAN FRANCISCO -- Immune therapies continued to achieve limited success in the treatment of microsatellite stable (MSS) refractory or advanced colorectal cancer (CRC), according to studies presented here.

In a study of 180 patients with advanced, refractory CRC, the combination of PD-L1 inhibitor durvalumab (Imfinzi) plus a monoclonal antibody against CTLA-4, tremelimumab extended overall survival (OS) to a median of 6.6 months (hazard ratio 0.72, (90% CI 0.54-0.97, P=0.07) compared with a median of 4.1 months for best supportive care (BSC), reported Eric Chen, MD, PhD, University Health Network in Toronto, and colleagues.

But the combination had no effect on progression-free survival (PFS) at 1.8 months (90% CI 1.8-1.9 months) versus 1.9 months (90% CI 1.8-1.9 months) for BSC, Chen said in a presentation at Gastrointestinal Cancers Symposium (GICS).

In a separate study of 121 patients in stage IV CRC limited to liver metastases, tecemotide (L-BLP25), a vaccine that targets the MUC1 antigen, failed to have any effect on either recurrence-free survival (RFS) or OS, regardless of the level of MUC1 expression, reported Carl Schimanski, MD, PHD, on Klinikum Darmstadt in Germany, and colleagues.

"A number of large clinical trials looking at anti-PD-L1 inhibitor monotherapy, or anti-PD-L1 inhibitors given in various combinations, have all been negative in microsatellite stable CRC, and even if you select patients for PD-L1 positivity, none of the MMS patients have responded to anti-PD-1 therapy, so single agent treatment has not been successful in this population," said GICS discussant Michael Overman, MD, of MD Anderson Cancer Center in Houston.

And while he did not totally dismiss the potential benefit of treating refractory CRC with the combination of durvalumab plus tremelimumab, "I think we need confirmation of these findings to have confidence in them before this data is incorporated into any clinical practice," Overman stated.

As for the anti-cancer vaccine, tecemotide, here again, "all trials have been negative in regards to their primary OS endpoint," he said.

Thus, oncologists continue to confront challenges in the use of immune therapy in the treatment of MMS CRC, Overman said.

The Canadian CO.26 trial randomized patients with advanced CRC who had failed all standard CRC regimens to either IV durvalumab (1500 mg) every 28 days along with IV tremelimumab (75 mg) given on day 1 for the first four cycles plus BCS (n=119) or BCS alone (n=61). Over 85% of patients received at least 90% of planned doses of the active therapy arm, Chen reported.

At a median follow-up of 15.2 months, no complete responses (CRs) were observed in either arm and there was only one partial response (PR) in the combination arm. On the other hand, the disease stabilized in 22.7% of patients on the combination strategy compared with only 6.6% of those treated with best supportive care (P=0.006). Rates of grades 3 and 4 abdominal pain, fatigue and lymphopenia were all significantly higher in the active therapy arm compared with BSC (P<0.01).

Nevertheless, Chen suggested that quality of life was not adversely affected by this particular regimen, and that "Results from this study suggest that the combination of durvalumab and tremelimumab prolongs overall survival of patients with refractory colorectal cancer compared to best supportive care."

He added that "this is the first study demonstrating immune checkpoint blockade effectiveness in colorectal cancer patients unselected for mismatch repair deficiency." Colorectal tumors are classified according to their global genomic status, either microsatellite instable (MSI) or MMS. MSI is the molecular fingerprint of a mismatch repair deficiency, where immune checkpoint blockade has demonstrable activity.

In the second trial, Schimanski noted that 79 patients with stage IV CRC limited to liver metastases received tecemotide after undergoing resection of both the primary tumor and liver metastases (R0/R1). The vaccine was given as eight weekly, subcutaneous injections followed by 6-week maintenance intervals, until recurrence or a maximum of 2 years. Three days prior to the first tecemotide dose, patients were treated with cyclophosphamide at a dose of 300 mg/m² to reduce regulatory T-cells.

The remaining 42 patients served as placebo controls. At a median of 6.1 months in the tecemotide arm and 11.4 months in the placebo arm, RFS rates were not significantly different between the twp groups. Similarly, OS rates for patients treated with tecemotide were 62.8 months (45.1 months-not achieved or NA) compared with NA (53.6 months to NA) for placebo controls, a difference which was again not statistically significant between the two groups.

However at 3 years, 69.1% of patients in the vaccine arm and 79.1% of patients in the control arm were still alive. prompting Schimanski to suggest that "the unexpectedly high OS rate highlights the critical importance of both accurate staging and intensive surveillance."