June 2013, Vol 2, No 4
Anti–PD-L1 Drug Achieves Response in Variety of TumorsUncategorized
The engineered PD-L1–targeted antibody shows impressive tumor shrinkage rates in several types of cancers that had progressed on several lines of previous therapy. In a phase 1 study, the novel agent demonstrated safety and durable responses in non–small cell lung cancer (NSCLC), melanoma, and kidney, colorectal, and gastric cancers. The best responses were seen in NSCLC, melanoma, and kidney cancers. The study was presented at the 2013 ASCO Annual Meeting.
The drug, MPDL3280A, manipulates the immune system by blocking an immune checkpoint. Cancer cells frequently express the PD-L1 protein, allowing them to evade the immune system. By blocking the PD-L1 protein, the cancer cells become vulnerable to attack by T cells because they are now recognizable.
“MPDL3280A was well tolerated, with no dose-limiting toxicities and no significant side effect, particularly pneumonitis, which is of concern. Immune-related adverse events were uncommon,” explained lead author Roy Herbst, MD, Chief of Medical Oncology at Smilow Cancer Hospital at Yale-New Haven, CT. “Tumor PD-L1 expression appears to be associated with response to this agent. Further monotherapy and combination therapy studies are planned.”
The phase 1 trial enrolled patients with a variety of incurable or metastatic solid tumors. MPDL3280A was given every 3 weeks. Response was assessed by CT scan every 6 weeks.
Safety was assessed in 171 patients. “No maximum tolerated dose was seen. We were able to keep giving higher doses of the drug. There were no dose-limiting toxicities and no treatment-related deaths,” Herbst stated.
Grade 3 or 4 adverse events were reported in 43% of patients.
Only 1 patient withdrew from the trial due to a treatment-related adverse event (elevated ALT levels).
Looking at tumor shrinkage, response was achieved in 29 of 140 patients, for an overall response rate (ORR) of 21%. In tumors that expressed PD-L1, ORR went up to 36%, while ORR was 13% in tumors that tested negative for PD-L1 expression.
“Responses were seen in tumors without the PD-L1 protein. Responses occur quickly and are durable,” Herbst said.
At the time of the ASCO 2013, 26 of 29 responses were ongoing. Durable responses were seen in melanoma, renal cell carcinoma, and head and neck, colon, and bladder cancers. Responders were on treatment from 3 to 15 months.
The phase 1 study has been expanded to include 275 patients, some of them with hematologic cancers. Further study is planned, including combination therapy with targeted agents.
“This study shows that productively manipulating the immune system can achieve a response rate of 21%, lasting as long as a year in tumors that progressed on previous treatment. The clearest indications of activity in this phase 1 study are in NSCLC and melanoma, as well as in patients with tumors testing positive for the PD-L1 marker. Maybe in the future we can develop biomarkers for tumors sensitive to this approach.
This approach of unblocking this checkpoint in the immune system and allowing it to ramp up is the beginning of a new chapter in cancer therapy,” stated ASCO President-Elect Clifford A. Hudis, MD.
Combination therapy with ipilimumab and nivolumab achieved remarkable responses in a phase 1 trial of patients with aggressive advanced melanoma. Durable tumor shrinkage was observed in about half the patients. “The complete and near-complete responses we are seeing are unprecedented for an immunotherapy in melanoma. We are particularly impressed that [ Read More ]
Dr Van Loon is Assistant Clinical Professor, University of California, San Francisco (UCSF). She is a gastrointestinal cancer specialist, with a particular interest in colon cancer. Dr Atreya is Adjunct Instructor at UCSF. She is a gastrointestinal oncologist and scientist whose research focuses on the interplay between genotype and response [ Read More ]