MPDL3280A produced durable responses in studies in patients with forms of locally advanced/metastatic cancers, including smokers with NSCLC who customarily have poorer responses to cancer therapies than nonsmokers.
Jean-Charles Soria, MD
The engineered PD-L1 antibody MPDL3280A produced rapid and durable responses in recent studies in patients with several forms of locally advanced and metastatic cancers, including smokers with non-small cell lung cancer (NSCLC) who customarily have poorer responses to cancer therapies than do nonsmokers.1,2
Treatment with the immunotherapy MPDL3280A (referred to as MPDL) resulted in “remarkable” responses in the first study to suggest a relationship between smoking history and benefit from PD-1 pathway inhibitor therapy. The drug appeared to perform better in smokers than in nonsmokers in a phase I study reported at the European Cancer Congress 2013, in late September, held in Amsterdam, The Netherlands.1
“After 30 years of research in immunotherapy for lung cancer, bingo! We have one that works and it works in smokers,” said lead investigator Jean-Charles Soria, MD, from the Institut Gustav Roussy, Villejuif, France. Soria presented preliminary data for a cohort of 85 patients with metastatic NSCLC whose disease included tumors of both squamous and adenocarcinoma histology. The patients were a part of a larger, ongoing study with MPDL.
A total of 37 patients were evaluable for efficacy. (The entire cohort of 53 were evaluable for safety.) Patients received MPDL by IV infusion every 3 weeks for a median of 106 days (range, 1-450 days). Study patients were heavily pretreated: more than one-half (55%) had received at least three prior therapies. A large number of patients (84%) were smokers or former smokers. The median duration of therapy was 48 weeks.
The objective response rate (ORR) was 24% in patients with NSCLC. Seventeen percent of patients who responded remained stable over 24 weeks. The 24- week progression-free survival (PFS) rate was 44% in patients with squamous cell NSCLC and 46% in patients with nonsquamous cell NSCLC.
In an assessment of the impact of smoking status on objective responses, the investigators determined that current or former smokers had an ORR of 25% (n = 43), whereas never-smokers had an ORR of 16% (n = 10).
MPDL treatment was particularly impressive in two responders that Soria displayed for the audience. After 1 year of treatment, nearly complete resolution of tumors was evident in imaging visuals.
The majority of adverse events (AEs) were mild with MPDL use. No grade 3-5 cases of pneumonitis or diarrhea were reported, and no dose-limiting toxicities were observed in this study.
An analysis of biomarker data from archival tumor samples revealed PD-L1 tumor status to be highly correlated with response to MPDL. In patients with PD-L1-positive tumors by immunohistochemistry (IHC), the ORR was 100%. Patients who were PD-L1 tumor-negative had an ORR of 15%.
Although the data are preliminary, Soria said at the conclusion of his presentation, the trends are “extremely promising.” Excitement with these results was less muted among other experts: Trial discussant Paul Bass, MD, PhD, from The Netherlands Cancer Institute suggested that “perhaps we should leap to a phase III trial… bypassing phase II.”
Treatment with MPDL resulted in a 21% response rate in the efficacy analysis from a phase I study in heavily pretreated patients with locally advanced or metastatic solid tumors, including NSCLC, melanoma, renal cell carcinoma, colorectal cancer, and gastric cancer.2
Responses were often rapid. In several patients, tumor shrinkage occurred within days of the initiation of therapy, according to Roy S. Herbst, MD, PhD, from Yale University, whose presentation was one of several to generate excitement at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting for its suggestion that PD-1 pathway inhibitors could “open up a whole new avenue of therapy in cancer,” as one individual commented.
“We are seeing responses in difficult- to-treat patient groups: the RAS-mutated patients; patients who have had EGFR or ALK abnormalities. Not only do patients respond, but we’re seeing very durable responses that can last a long period of time,” Herbst said. “Even after the patient stops the drug, the response [can] continue.”
This phase I study evaluated the safety and tolerability of MPDL in a 3 + 3 design. The drug was given intravenously every 3 weeks for a maximum of 16 cycles or 1 year. ORR was assessed by RECIST v1.1.
No dose-limiting toxicities were seen throughout the administered dosages of ≤1, 3, 10, 15, and 20 mg/kg. Most AEs were grade 1 and 2 and did not require intervention, Herbst said. Although 39% of patients reported a grade 3 or 4 AE, only 13% of these were thought by the investigators to be treatment-related. No grade 3-5 pneumonitis was seen throughout the trial. Immune-related grade 3 or 4 AEs, consisting of AST/ALT elevations, colitis, and hyperglycemia (with pre-existing diabetes) occurred in only four patients (2%).
In the overall population, 29 (21% of 140) patients were evaluable for efficacy: 22% for NSCLC; 29% for melanoma; 13% for renal cell cancer. “Importantly, 26 of 29 responders…continue in response,” Herbst said. “The time onstudy for responders in this ongoing trial ranges from 3 to 15 months…and continues as I speak.”
Using an antibody against PD-L1, the investigators also looked at the tumor microenvironment in this study. “We were able to look at PD-L1 positive and PD-L1 negative tumors, [and] when this assay was used, the response rate for the overall population went up to 36%. Also, importantly, 50% of patients had stable disease in the PD-L1- positive group.” In the PD-L1-negative group, the response rate was 13%.
This search for biomarkers of response is ongoing but may be complicated. “Most of the biomarker data that have been presented, such as with MPDL, suggests that you can enhance the positive response rate if you use a marker. If you look for 5%, 10% staining with a marker, you can probably get your response rate from 20% up to about 40%,” Herbst said. However, even using a marker such as [PD-L1 positivity], there may be responses in the 13% to 15% range in marker-negative patients.
It appears that the marker will play a role, Herbst suggested in comments following his presentation. However, he added, “I am interested in learning [whether] there are other markers.Maybe the type of mutation makes a difference; maybe it is something about the host genome…and about the patient’s T cells.”
This is going to become more important as we think about combinations, he added. “We can be somewhat empirical about how we combine agentswe should be—but especially as we target the immune system and the tumor cell, we are going to have to use the best science we have to think about how to do this in the best possible way.”