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PDL-1 Antibody Sparks Adaptive Immune Response across Multiple Solid Tumor Types

PDL-1 Antibody Sparks Adaptive Immune Response across Multiple Solid Tumor Types

Virtual Meeting Clip

 

The investigational drug MPDL3280A, a human monoclonal antibody that targets PDL-1, shrunk one in five locally advanced or metastatic tumors, including melanoma, lung, renal, colorectal, and gastric cancers (Abstract 3000). Results from the phase I study indicate that some patients experienced a response within days of starting treatment, and that the responses seen were often durable, with 45% of patients still progression free at 24 weeks.

“Broad activity has been seen with ongoing responses observed in nearly all responding patients,” Roy S. Herbst, MD, PhD, of Yale University, said during the Developmental Therapeutics— Immunotherapy Oral Abstract Session, held June 3. “PDL-1 expression appears to be associated with clinical benefit, and further monotherapy and combination studies have been initiated.”

Although the immune system is capable of destroying metastatic cancers, it was not entirely understood how tumors evade attack. Recently, research has shown that tumors may utilize immune coinhibitory ligands such as PDL-1 to dampen immune attack. By pharmacologically blocking PDL-1, tumor-specific T-cell immunity is restored.

This study included 171 patients assigned to MPDL320A administered intravenously three times a week including a 3+3 dose-escalation and expansion cohorts. MPDL320A was given for a median of 127 days.

Of the 140 patients investigated for clinical efficacy, there was an overall response rate of 21%. Patients with melanoma had a 29% response rate. Patients with non-small cell lung cancer had a 22% response rate, and patients with renal cell carcinoma had a 13% response rate.

“Importantly, 26 of 29 responders at the time of this talk continue to respond at their last assessment,” Dr. Herbst said. “These were durable responses; the time on study for responders in this trial ranges from 3 months to 15 months and continues as I speak.”

In addition, Dr. Herbst pointed out that some patients had a gradual response to treatment that took multiple cycles. In fact, some patients progressed but were allowed to stay on trial and then later responded.

When Dr. Herbst and colleagues used a diagnostic test to examine archival tumor samples from 33 patients, they found that those patients with tumors positive for PDL-1 had a response rate of 36% compared with 13% in patients with PDL-1–negative tumors. However, because the diagnostic test to detect PDL-1 is still evolving, a negative result does not necessarily mean that the patient will not respond.

Safety results indicated that the dose-escalation cohort did not experience dose-limiting toxicity, and no maximum tolerated dose was identified. In addition, no treatment-related deaths occurred. During that time, 13% of patients reported a treatment-related grade 3/4 adverse event. No grade 3 to 5 pneumonitis was observed.

In response to the data from Dr. Herbst, and several other abstracts presented during the session, Discussant Padmanee Sharma, MD, PhD, of The University of Texas MD Anderson Cancer Center, spoke of the great promise immunotherapy holds for many cancer types because the therapies are not targeting a tumor-specific marker but rather a T-cell–specific molecule.

“We now have a new pillar in terms of treatment for cancer patients,” Dr. Sharma said. “We have standard chemotherapy, targeted therapy, radiation therapy, surgery, and—I propose—immune checkpoint therapy is now really here.”

For more information on the PD-1 pathway and its ligand PDL-1, read ASCO Daily News online at chicago2013.asco.org/dn. Watch the exclusive video interview with Dr. Jedd Wolchok in which he explains the pathway’s role in various cancer types including kidney and non-small cell lung cancers, as well as melanoma. In-depth information on other pathways—MEK, HER2, EGFR, VEGF, PI3K, and ALK—is also available.