Oncologists looking to learn about immunotherapy did not have to go very far at ASCO 2015. Many of the highest-impact presentations this year, including a plenary session, the Karnofsky Award, and the Science of Oncology Award, focused on cancer therapy’s most exciting field.
Checkpoint blockades and their immunologic cousins have come a long way, lately extending beyond melanoma, lung cancer, and renal-cell carcinoma. Immunotherapy in oncology is now being introduced in many cancers, including head and neck, bladder, gastric, breast, and ovarian cancers.
It is not only the list of tumor targets that is expanding. Although checkpoint inhibitors remain the star of the show, other immuno-oncology approaches are emerging, including oncolytic viruses, vaccines, and chimeric antigen receptor T-cells.
Use in Multiple Tumor Types
The phase 3 CheckMate 067 trial made national headlines by demonstrating an almost doubling in median progression-free survival (PFS) when 2 checkpoint inhibitors were paired in advanced melanoma. Patients who received nivolumab plus ipilimumab had a median PFS of 11.5 months versus 6.9 months with nivolumab alone and 2.9 months with ipilimumab alone. In patients with PD-1 ligand 1 (PD-L1) expression of ≥5%, the median PFS was 14 months with the combination.
Michael B. Atkins, MD, Deputy Director, Lombardi Comprehensive Cancer Center of Georgetown University, Washington, DC, discussed CheckMate 067 at the plenary session, concluding, “In my opinion, ipilimumab can no longer be considered a standard first-line immunotherapy for patients with advanced melanoma. This clearly has important implications for the field and for our patients.”
The results of a randomized, phase 3 clinical trial comparing nivolumab with docetaxel set a new standard of care for patients with previously treated nonsquamous non–small-cell lung cancer, when those who received nivolumab gained almost 3 months in overall survival time. Another study showed promise for pembrolizumab in head and neck cancer, demonstrating a clinically significant 24.8% overall response rate in patients with recurrent or metastatic carcinoma.
“This is twice as good as our best targeted therapy in this early preliminary report,” said study investigator Tanguy Seiwert, MD, Assistant Professor of Medicine, University of Chicago.
There were even promising data for hepatocellular cancer. A phase 1/2 study showed a potential new role for nivolumab in advanced liver cancer, a disease for which only 1 agent has been approved by the US Food and Drug Administration. Approximately 1 in 5 patients responded to this anti–PD-1 drug.
Receiving the 2015 David A. Karnofsky Memorial Award, Suzanne L. Topalian, MD, Professor, Oncology and Surgery, Johns Hopkins University School of Medicine, and Director of the Melanoma Program, Sidney Kimmel Comprehensive Cancer Center, Baltimore, spoke about discovering a common denominator for cancer therapy—anti–PD-1.
“The immune system is in many ways the ‘ideal’ anticancer weapon,” Dr Topalian said. “There are diverse modes of attack through different cells and antibodies, which can recognize cancer cells. This system is very precisely targeted, and it has recall. So, if we can educate or prime the immune system the right way to recognize cancer, this immunity should last for a lifetime.”
According to Dr Topalian, drugs blocking PD-1 or PD-L1 have shown durable, objective tumor response rates in clinical trials for a variety of cancers, including:
- Hodgkin lymphoma (87%)
- Melanoma (17%-40%)
- Lung cancer (10%-30%)
- Kidney cancer (12%-29%)
- Bladder cancer (25%)
- Ovarian cancer (6%-23%)
- Head and neck cancer (14%-20%).
“We have found a single molecular pathway that, if we target it, these drugs can have an unprecedented activity spectrum and provide a common denominator for cancer therapy,” said Dr Topalian.
Immune checkpoints are molecules that are expressed on the surface of activated immune cells. Their role is to terminate immune responses at the right time to avoid normal tissue damage; however, as Dr Topalian pointed out, they are susceptible to manipulation by cancer.
“Our job as cancer immunotherapists is to block these checkpoints and therefore turn on immune responses in the right way,” she explained.
The use of blocking antibodies to obstruct either the PD-1 receptor on T-cells or PD-L1 on tumor cells has shown success so far in interrupting this interaction and turning on the T-cell activity.
The PD-1 inhibitors nivolumab and pembrolizumab have performed extraordinarily well as monotherapies and in combination compared with ipilimumab, which was the previous benchmark and targets the CTLA-4 pathway. Combination therapies, in particular, appear to enhance the effects of these drugs and render resistant tumors sensitive to treatment.
According to Dr Topalian, however, these drugs will not be alone in the marketplace for long. Currently, 6 drug companies are investigating 8 unique PD-1 pathway–blocking medications, with more on the way.
Along with its promise, immunotherapy also brings new challenges for the healthcare industry, including physical and financial toxicities. Questions also remain regarding the proper sequencing of these drugs with targeted agents, and the use of biomarkers to identify appropriate patients for these medications. None of these issues, however, seemed to dampen the enthusiasm surrounding this new approach in the fight against cancer. Immunotherapy is here to stay.
“Immunotherapy has now earned its place as one of the pillars of oncology, alongside more traditional modes of treatment,” Dr Topalian concluded.