It has become routine practice to prescribe targeted drugs to patients with metastatic non-small cell lung cancer (NSCLC), whose tumors harbor molecular alterations in EGFR, ALK, and ROS. However, the majority of patients with NSCLC have no targetable mutations and lack good treatment options. Enter immunotherapy drugs, specifically ‘immune checkpoint blockade antibodies,’ to which many refer simply as ‘anti-PD-1 drugs,’ or simply ‘PD-1 drugs.’ In this post, I provide some updates on the efficacy of anti-PD-1 and anti-PD-L1 drugs in lung cancer.
PD-1 is a ‘checkpoint’ protein found on the immune system’s ‘killer’ T cells. It restrains the T cells’ function of eliminating tumor cells. Antibody drugs that bind to PD-1 prevent it from interacting with PD-L1, a protein that tumors might express as a way to evade immune system attack. By preventing this interaction, these drugs restore the killing activity of T cells. The two most advanced drugs in this category are nivolumab (Opdivo, made by Bristol-Myers Squibb) and pembrolizumab (Keytruda, made by Merck). Both have been approved by the U.S. Food and Drug Administration (FDA) for treatment of metastatic melanoma. And now, both drugs are in a tight race for approvals in other conditions and cancer types.
Opdivo has already won a recent (March 4, 2015) approval for treatment of advanced squamous NSCLC that has progressed after treatment with platinum-based chemotherapy. In the phase II clinical trial CheckMate-063, tumors shrank in 15% of patients who took Opdivo, and 26% had stable disease—remarkable results for the squamous subtype. Moreover, the phase III CheckMate-017 trial, in which NSCLC patients received either Opdivo or the chemotherapy drug docetaxel, had to be stopped after it became evident that Opdivo far outperforms chemotherapy. (Patients who had been receiving docetaxel in this trial were allowed to transfer to Opdivo). Opdivo is currently being tested as a first-line therapy for NSCLC in both squamous and non-squamous cancers, with the aim to expand its use to patients who have not yet received other treatments.
Keytruda, meanwhile, received a Breakthrough Therapy designation from the FDA for NSCLC in October 2014. This means the FDA intends to accelerate its review of the drug for approval. It is expected that an approval will indeed follow, with Merck having filed for it on April 19, 2015. The Breakthrough Therapy designation was based on the results of the KEYNOTE-001 trial, in which 20% of NSCLC patients had a reduction in tumor size or had no more tumors after treatment. However, patients whose lung tumors had high levels of the PD-L1 protein had a much higher response rate—45%. Still, some responses (10%) were observed in patients whose tumors tested negative for PD-L1.
Keytruda positively shined in a small trial conducted in patients with mesothelioma of lung: the overall disease control rate was 76%, an unheard of response rate in this lethal cancer. Immune checkpoint drugs are currently being tested in at least 30 different types of cancer, including small cell lung cancer (SCLC), which has very few treatment options.
Continuing on the subject of PD-L1, this protein itself is a worthy drug target. A drug called MPDL3280A (made by Roche) was designed to bind PD-L1 on tumor cells and prevent it from inactivating T cells through binding to PD-1. This antibody drug received a Breakthrough Therapy designation from the FDA in February of this year. The approval was based on the results of a trial in which 23% of patients overall responded to the drug. Responses were much higher (up to 80%) in patients whose tumors had high levels of PD-L1, and were also higher in smokers than in nonsmokers.
The other anti-PD-L1 drug currently being tested in trials is MEDI4736 (made by AstraZeneca), which induced tumor regression or stabilization in 16% of NSCLC patients in one trial. MEDI4736 is not as advanced in its development as MPDL3280A, but it certainly holds promise.
It will be extremely useful to be able to predict which patients may respond to immune checkpoint blockade. Clearly, expression of PD-L1 on tumor cells is one important factor that may predict response, but it is not the decisive factor. Also, lung cancers that have more mutations are more likely to shrink when treated with Keytruda. Smoking, known to increase the number of mutations in the lungs, has been found to mightily increase the chances of response to both Keytruda and MPDL3280A. The hunt for other predictive factors is on.
What’s next for checkpoint inhibitors?
Putting a brake on immune checkpoints like PD-1 is an extremely promising approach, but cumulative results strongly suggest that few patients respond to treatment with a single checkpoint antibody. Combining the checkpoint antibodies with other treatments is considered to be the most promising strategy. I wrote about it back in October 2014, and since then the number of trials exploring these combination treatments has mushroomed.
Opdivo, Keytruda, MPDL3280A, and MEDI4736 are being tested in combination with chemotherapy, targeted drugs, and radiation. The rationale is that treatments that kill tumor cells directly may improve the immune system’s rejection of tumors by increasing the ‘visibility’ to the immune system of tumor antigens (small molecules) spilled from dying cells. Targeted drugs may produce responses in the fairly high proportion of patients who have specific alterations in EGFR and ALK, but resistance usually sets in fairly soon. Checkpoint inhibitors produce responses in fewer patients, but these responses tend to be long-lasting. A combination of both may favor both the frequency and durability of responses.
Combining two different checkpoint drugs is another promising direction of exploration. The older drug ipilimumab (Yervoy), FDA-approved in melanoma, targets a different checkpoint protein on T cells: CTLA-4. In clinical trials, the combination of Opdivo and Yervoy proved to be highly effective in the treatment of melanoma. Now this and other combinations of Yervoy with anti-PD-1 or anti-PD-L1 drugs are being explored in NSCLC. Preliminary results reported last year for an Opdivo/Yervoy combo were promising, in particular because the patients’ responses did not depend on the presence of PD-L1 in their tumors. Side effects of the double treatment were fairly serious, though manageable.
Regulation of T cell function is complex, and there are a number of other proteins on these cells that either inhibit or promote their function. Several of them are being explored in the lab and in patients as potential targets for treatments to improve the immune system’s rejection of tumors.