Clinical Trial Profile: The OAK Study

Grace K. Dy, MD

Immunotherapies have shown great promise in the treatment of advanced cancers, including metastatic melanoma and non-small cell lung cancers (NSCLC).^1-5

These therapies include immune checkpoint inhibitors, such as the anti-cytotoxic lymphocyte antigen-4 (anti-CTLA-4) antibody, ipilimumab, and, more recently, antibody inhibitors of the programmed cell death 1 (PD-1) receptor and its ligand, PD-L1, such as pembrolizumab and nivolumab.

In early-phase trials, use of these agents in NSCLC has been associated with dramatic response rates and largely manageable toxicities. “Immunotherapies have gone through very promising development in phase I and a few phase II studies, and now there are phase III studies of immunotherapy drugs to be used in the first-line treatment setting,” said Grace Dy, MD, an associate professor in the department of medicine at Roswell Park Cancer Institute in Buffalo, New York. Dy noted that the 2 major classes of checkpoint inhibitors, anti-CTLA-4 agents and anti-PD-1 agents, are the current front-runners for development in many malignancies, including lung cancer. “It seems that the PD-1/PD-L1 pathway inhibitors appear to be better tolerated, and that’s why there is a great enthusiasm to support the development of these agents. We’ve seen, in early phases of development, that most patients tolerate [them] well without the typical chemotherapy side effects. While…some of the rare side effects can be very serious [eg, pneumonitis], people have learned how to manage them… and they are not high-frequency events.”

Roy Herbst, MD, The Benefits of Using Immunotherapy to Treat Lung CancerHerbst is a professor of medicine at the Yale Cancer Center and chief of medical oncology at Smilow Cancer Hospital at Yale-New Haven in Connecticut

Some of the immunotherapy agents currently under investigation for lung cancer include CTLA-4 inhibitors (tremelimumab and ipilimumab), anti-PD-1 agents (nivolumab and pembrolizumab ), and anti-PD-L1 antibodies (MPDL3280A and MEDI4736).^5,6These therapies hold great promise for revolutionizing the treatment of NSCLC, as they have for other cancers, such as melanoma, with durable activity and tolerability observed in multiple early-phase studies.^2,5

About the OAK Study [NCT02008227]

Previous studies examining the impact of antibody-mediated inhibition of the PD-1 ligand, PD-L1, have demonstrated durable tumor regression and disease stabilization, along with a low rate of grade 3 and 4 toxicities (9%) in patients with advanced solid tumors, including those with melanoma and NSCLC.¹MPDL3280A is an engineered human IgG1-kappa monoclonal antibody directed against PD-L1.^5,6Phase I studies with this PD-L1 inhibitor (inclusive of 85 patients with NSCLC) have shown no dose-limiting toxicities and a low rate of grade 3 and 4 adverse events (11%); a best overall response rate (ORR) of 23% was observed, and responses appeared to be durable, with most responders completing a full year of treatment with no progression.⁵

The OAK study, which began recruitment in February 2014, is a global, open-label, randomized phase III study that is comparing MPDL3280A with docetaxel for the treatment of patients with locally advanced or metastatic NSCLC, following failure with platinum-based therapy.^6,7Patients in the study will be randomized 1:1 to docetaxel (75 mg/m²IV infusion) or MPDL3280A (1200 mg IV infusion) given every 3 weeks, and treatment will continue for a total of 16 cycles or 12 months of treatment or until unacceptable toxicity or disease progression occurs.

The primary endpoint of the study is overall survival; secondary endpoints include incidence of adverse events, ORR, progression-free survival, and duration of response, determined using Response Evaluation Criteria in Solid Tumors (RECIST v. 1.1). Patients will be included in the trial if they are 18 or older and have an Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease by RECIST v. 1.1, and locally advanced, unresectable or metastatic NSCLC (stage 3B, stage 4, or recurrent) that progressed during or following a prior platinum-based regimen, or disease progression (within 6 months) on a platinum-based adjuvant/neoadjuvant regimen.  The estimated primary completion date is June 2017.⁷

Clinical Pearls

• MPDL3280A is an engineered human IgG1-kappa monoclonal antibody directed against PD-L1.
• Phase I studies with this PD-L1 inhibitor (N= 85 patients with NSCLC) have shown no dose-limiting toxicities and a low rate of grade 3 and 4 adverse events.
• A best ORR of 23% was observed, and responses appeared durable, with most responders completing a full year of treatment with no progression.
• The OAK study, which began recruitment in February 2014, is a global, open-label, randomized phase III study comparing MPDL3280A with docetaxel for the treatment of patients with locally advanced or metastatic NSCLC, following failure with platinum-based therapy.
• The primary endpoint of the study is overall survival.
• The estimated primary completion date is June 2017.

References

1. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.N Engl J Med.2012;366(26):2455-2465.
2. Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med.2010;363(8):711-723.
3. Lynch TJ, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study.J Clin Oncol.2012;30(17):2046-2054.
4. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.N Engl J Med.2012;366(26):2443-2454.
5. Creelan BC. Update on immune checkpoint inhibitors in lung cancer.Cancer Control.2014;21(1):80-89.
6. Reichert JM. Antibodies to watch in 2014: mid-year update.MAbs.2014;6(4):799-802.
7. ClinicalTrials.gov. A randomized phase 3 study of MPDL3280A (an engineered anti-PDL1 antibody) compared to docetaxel in patients with locally advanced or metastatic non-Small cell lung cancer who have failed platinum therapy — “OAK”. http://clinicaltrials.gov/show/NCT02008227. Accessed September 13, 2014.