When it comes to learning about recent breakthroughs in cancer treatment, there is no more important event than the annual meeting of the American Society of Clinical Oncology (ASCO), to be held this year in Chicago, from May 29-June 2.
Because so much new information about immunotherapy is likely to be unveiled—including the results of clinical trials that have a direct bearing on patients—I have prepared a summary of what I consider to be the top areas to watch.
Immunotherapy for Lung Cancer
Once thought of as an unlikely candidate for immunotherapy, lung cancer has emerged as a very promising target for this approach. Already, one immunotherapy is FDA approved—nivolumab (Opdivo), made by Bristol-Myers Squibb—for a type of lung cancer called ‘squamous’ non-small cell lung cancer (NSCLC). About 25%-30% of NSCLC cases are the squamous type, while the rest are ‘non-squamous.’ Results from clinical trials indicate that patients with the more common non-squamous NSCLC also benefit from this type of immunotherapy, broadly known as checkpoint blockade.
In April, a phase III trial directly comparing nivolumab to standard chemotherapy for non-squamous NSCLC was stopped early because an independent review of the results determined that the trial had reached its goal—namely, superior overall survival for patients receiving nivolumab. At ASCO, the full results of the trial will be unveiled the morning of Saturday, May 30. The principal investigator of this trial is Julie Brahmer, M.D., of Johns Hopkins University School of Medicine. Dr. Brahmer is a member of the CRI-SU2C Cancer Immunology Dream Team.
Nivolumab is one of several PD-1/PD-L1-targeting checkpoint inhibitors currently being studied as a treatment for lung cancer. Another is pembrolizumab (Keytruda), made by Merck. The results of a large phase Ib study of pembrolizumab in NSCLC were presented at this year’s meeting of the American Association of Cancer Research (AACR), held in Philadelphia last month, and they were impressive. The objective response rate (ORR) for all patients was 19.4%, while the response for those patients with high PD-L1 expression was 45.2%. PD-L1 is the binding partner for the PD-1 receptor, which is found on T cells and serves as a brake, or checkpoint, on the immune response. PD-L1 is sometimes made by cancer cells and immune cells in tumors. When PD-L1 binds to the PD-1 receptor on T cells, the brake is engaged and the immune response against cancer is halted. PD-1/PD-L1 checkpoint inhibitors “release the brakes” on the immune system, allowing it to fight the cancer. At ASCO, the results of several other trials involving pembrolizumab in lung cancer will be presented, including one in small cell lung cancer (SCLC), and one where pembrolizumab is combined with ipilimumab, a CTLA-4-blocking antibody, as second-line therapy for NSCLC.
Merck KGaA, in cooperation with the drug company Pfizer, also makes a PD-L1-blocking antibody called avelumab (MSB0010718C), that it is testing in a phase Ib trial for NSCLC. PD-L1 blocking drugs work by preventing cancer cells (and other cells in the tumor) from activating the PD-1 “brake” on T cells. They represent the “flipside” of the PD-1-targeting approach. Some evidence suggests that targeting PD-L1 vs. PD-1 might lead to fewer side effects, especially an autoimmune complication called pneumonitis. A second PD-L1-targeting drug, MPDL3280A, made by Genentech, is being tested in a phase Ib trial in combination with chemotherapy for patients with NSCLC.
Considering the human toll of lung cancer, it is very exciting to see so many immunotherapy options being explored for patients with this disease.
Powerful Combinations: Ipi + Nivo and more
Much excitement in the field right now revolves around combination therapies—putting two or more drugs together that act in a complementary fashion. The prototype combination, which showed the great potential of this approach, is ipilimumab (ipi) plus nivolumab (nivo), for the treatment of advanced melanoma. This combination has been under intense study for several years, and at this year’s ASCO we will learn the results of a very important phase III trial.
Here’s what you need to know by way of background: ipilimumab is an immune checkpoint inhibitor that blocks a braking molecule on T cells called CTLA-4. It is currently standard of care for advanced melanoma, and has been since 2011, when it was approved by the FDA. Nivolumab is another checkpoint inhibitor that blocks a different immune checkpoint on T cells, called PD-1. Two years ago, at ASCO, we learned that a phase I study showed that the ipi + nivo combination was highly effective in a majority of patients, and later results from the same trial showed that the combo greatly improved the 2-year survival rate as compared to historical results with standard chemotherapy. Last month at the AACR annual meeting, we learned the results of a phase II study directly comparing the ipi + nivo combination to ipi alone. The objective response rate was 61% for the combo compared to just 11% for ipi alone—a big improvement. Next week at ASCO, on Sunday, May 31, the results of an ongoing phase III trial of this combination will be unveiled. This particular study is a three-way comparison of ipi + nivo vs. ipi alone vs. nivo alone. This trial will establish not only whether the combination is better than each of the individual drugs given separately, but also whether the drugs are synergistic—providing a benefit that is more than just the sum of the parts.
Phase III trials are the last stop before FDA approval, and while it is unwise to make predictions, a favorable review of this trial by the FDA could mean a new treatment option for certain patients with advanced melanoma. The trial results will be presented by Jedd D. Wolchok, M.D., Ph.D., chief of the Melanoma and Immunotherapeutics Service and director of the Ludwig Collaborative Laboratory at Memorial Sloan Kettering Cancer Center who also directs CRI’s clinical program.
Another promising combination is the anti-CTLA-4-blocking antibody tremelimumab plus the anti-PD-L1 blocking antibody MEDI4736, which is being tested in a phase I trial for a variety of solid tumors. Preliminary data from trials with PD-L1-targeting drugs suggest that PD-L1 inhibitors may have less toxicity than PD-1-targeting drugs. For that reason, PD-L1-targeting drugs might be preferable when used in combination with other therapies, such as anti-CTLA-4 drugs. This trial, which is funded under CRI’s Clinical Accelerator, where we partner with Ludwig Cancer Research for clinical trials management, represents an important step in making combination immunotherapies available for a broad range of cancers.
Yet another combination is giving the anti-PD-L1 drug MEDI4736 along with one or two targeted therapies in patients with advanced melanoma. The two targeted therapies are dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor. About half of all melanomas contain a mutated BRAF protein, which leads to aggressive cancer growth. BRAF and MEK inhibitors block the action of this mutated protein, shrinking tumors. BRAF and MEK inhibitors are often very effective ways to quickly and consistently treat melanoma. The problem is that often the cancer becomes resistant to these drugs when given singly and grows back after a period of months. The idea behind combining immunotherapy and targeted therapies is that the approaches will work synergistically, each drug boosting the efficacy of the other, while also preventing resistance—much the way that combining anti-retroviral drugs helps combat HIV drug resistance. The challenge is knowing how and when to combine the drugs to enhance the beneficial effects while minimizing toxicity. Antoni Ribas, M.D., Ph.D., a professor of medicine at the Jonsson Cancer Center at the University of California, Los Angeles, who is also a co-leader of the CRI-SU2C Dream Team, will be presenting results from a phase I study of this combination in advanced melanoma. Early results indicate that the three-drug combo is well-tolerated and shows activity in patients with both normal and mutated BRAF proteins.
CAR T Cells: Getting Beyond Leukemia
Some of the most eye-popping clinical results—complete responses of 90% in some trials—have come from the use of chimeric antigen receptor (CAR) T cell therapy. CARs are genetically engineered receptors that join the antigen-binding region of an antibody to the signaling domain of a T cell receptor; they turn a patient’s own T cells into powerful weapons against cancer. To date, most CARs have been designed to target a protein called CD19, found on the surface of all B cells in the body, including those from which B cell leukemias arise. CD19 represents in some ways a perfect target for CAR T cell therapy, since this molecule is easily recognized by CAR T cells, and since all CD19-expressing cells in the body can be safely eliminated without threatening life (provided patients receive supplemental immunoglobulin therapy).
The same cannot be said of other targets on cancer cells. Most cell types in the body from which cancer arises cannot be safely eliminated completely. And surface markers that are truly unique to cancer cells are rare. Currently, the best we can do is find targets that are highly expressed on cancer cells but rare in normal tissues. One molecule that fits this bill is mesothelin—a protein that is almost universally expressed on pancreatic cancer cells (and certain other cancers), but not very highly expressed elsewhere in the body. The Cancer Research Institute, in collaboration with the Lustgarten Foundation, is funding a phase I trial looking at the safety and anti-tumor activity of mesothelin-directed CAR T cells in metastatic pancreatic cancer. This is one of the first trials to look at the safety and efficacy of this promising form of immunotherapy in a cancer type that has one of the lowest 5-year survival rates—less than 6%—and for which there is great urgency for better treatments. We will learn the initial results of this trial in an oral session on Monday afternoon, June 1.
A second indication for which CAR T cells may be effective is multiple myeloma—using the existing CD19-targeting approach. Although multiple myeloma cells do not themselves express CD19, they arise from cells that do, which makes this a potentially viable approach to treating this blood cancer. As one scientist involved with the approach has said, “This is using CAR T cells to attack myeloma at its source.”
New Targets for PD-1/PD-L1 Checkpoint Blockade: Brain and Ovarian Cancer
The brain cancer called glioblastoma multiforme (GBM) is an underserved cancer indication with few effective treatment options. Newly diagnosed GBM patients live, on average, just 15 months with current standard of care therapies, which may include surgery, radiation, chemotherapy, and targeted therapy. But there is reason to hope that immunotherapies might improve these grim survival odds.
CRI’s Clinical Accelerator, where we partner with Ludwig Cancer Research for clinical trials management, is funding another important phase II trial of an MEDI4736, an anti-PD-L1 checkpoint inhibitor, in patients with GBM. This trial will have three different cohorts. One cohort will receive MEDI4736 after standard surgery and radiation therapy. The idea behind combining MEDI4736 with radiation is that the radiation will cause tumor cells to die, and these dying cells will release antigens that are recognized by the immune system as dangerous, increasing the efficacy of MEDI4736. In other words, the radiation may act like an endogenous vaccine, jumpstarting an immune response against the cancer. The anti-PD-L1 therapy then will then release the brakes on the immune system, allowing it to fight the cancer.
The list of cancers being treated in clinical trials with PD-1/PD-L1-blocking antibodies is long and growing. At last month’s AACR meeting, we learned that triple-negative breast cancer (TNBC) could respond favorably to this type of treatment and that the drug maker, Genentech, would be proceeding directly to a phase III of its anti-PD-L1 drug, MPDL3280A, in this indication. At ASCO, we will learn the results of several trials testing PD-1/PD-L1 targeting drugs in ovarian cancer, another hard-to-treat cancer. Results of a phase Ib trial of the PD-L1-blocking drug, avelumab (made by Merck KGaA/Pfizer), in patients with previously treated refractory ovarian cancer will be presented in a poster session on Monday afternoon, June 1. At that time, we will also learn the results of a phase Ib trial of pembrolizumab in patients with PD-L1-positive ovarian cancer. Ovarian cancer is an indication where having an effective immunotherapy would be a game-changing option, since many women with ovarian cancer who are treated with existing chemotherapies eventually become resistant to these drugs and see their cancer return. The fact that PD-1/PD-L1 therapies seem to have activity in women who have been heavily pretreated with other drugs is encouraging news indeed.
Other cancer indications for which PD-1/PD-L1-blocking antibodies are in testing include stomach, head and neck, esophageal, colorectal, and bladder cancer.
Check back here on the CRI blog for daily reports during the ASCO meeting.