By Mark Terry
AstraZeneca and MedImmune announced that their Phase III ARCTIC clinical trial in locally-advanced or metastatic non-small cell lung cancer (NSCLC) in patients who received a least two prior treatments failed to hit its primary endpoint.
The trial was looking at a combination of Imfinzi (durvalumab) and tremelimumab, as well as Imfinzi and tremelimumb by themselves, compared to standard-of-care chemotherapy in patients with PDL1-low/negative. It also looked at Imfinzi alone versus standard chemo in patients with high PDL-1.
Sub-study B, which was in PDL-1-low/negative lung cancer, the combination of Imfinzi and tremelimumab did not meet the primary endpoints, which were progression-free survival (PFS) and overall survival (OS) compared to standard of care.
The company stated that “sub-study A was not powered for statistical significance,” but goes on to say Imfinzi by itself had a clinically-meaningful decrease in the risk of death compared to standard chemotherapy.
“While we are disappointed that the combination of Imfinzi plus tremelimumab did not result in a statistically-significant benefit in this heavily pre-treated patient population, we are encouraged by the activity of Imfinzi monotherapy observed in this trial and look forward to presenting the full data form the ARCTIC trial at an upcoming medical meeting,” stated Sean Bohen, AstraZeneca’s executive vice president, Global Medicines Development and chief medical officer.
The ARCTIC trial was a randomized, open-label, multi-center, global Phase III trial. Tumor PD-L1 expression was evaluated using the Ventana PD-L1 (SP263) assay with PD-L1 high defined as 25% or more tumor cells with membrane staining.
Imfinzi is a human monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80. It basically keeps tumors from hiding from the body’s immune system. Tremelimumab is also a fully human monoclonal antibody, in this case, against CTLA4. It is an immune checkpoint blocker.
The U.S. FDAapproved Imfinzi for patients with unresectable, Stage III NSCLC whose disease hadn’t progressed after platinum-based chemo and radiation therapy. It’s also been granted accelerated approval in the U.S. for locally-advanced or metastatic urothelial carcinoma after disease progression after platinum-based chemo, or in patients whose disease progressed within a year of receiving platinum-containing chemo before or after surgery.
Following in the footsteps of HIV treatment, immuno-oncology has been working on the value of combination therapies, but the results of this study undercut the possibilities—although not by too much. Reutersnoted, “The results of the study, known as ARCTIC, is disappointing but not a huge surprise, since evidence has been building that there may be little value in using a so-called CTLA-4 drug like tremelimumab on top of a PD-L1 such as Imfinzi.”
Like most therapies, monotherapy or combinations, it depends on the diseases and the drugs. Because Imfinzi showed some efficacy, but adding tremelimumab didn’t, there’s a possibility that adding tremelimumb offset Imfinzi’s efficacy. Immuno-oncology therapies with traditional chemo appear to be effective, but adding multiple immuno-therapies together, at least as demonstrated by this study, do not seem terribly effective.
Reuters went on to write, “A year ago, the notion of combining the two medicines was the big hope driving AstraZeneca’s stock price—but that hope was dealt a major blow in July when its main first-line lung cancer trial, called MYSTIC, failed to slow disease progression.”
AstraZeneca is planning to report overall survival data from the MYSTIC trialin the second half of this year. MYSTIC is evaluating Imfinzi alone or in combination with tremelimumb compared to standard chemo in patients with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) wild-type locally-advanced or metastatic (Stage IV) first-line NSCLC.
As of this writing, AstraZeneca stock is up about 1.3% in trading, hitting $35.08. It dropped slightly at opening, but is recovering.