Response is a poor outcome measure of immunotherapy, according to Tanguy Seiwert, MD, who addressed this and other concerning issues in immunotherapy at the 2016 Multidisciplinary Head and Neck Cancer Symposium.
“The impact of immunotherapy, at least for PD-1 [programmed death-1] checkpoint blockade, is primarily on survival,” he said. “Response rate likely significantly underestimates its benefit, and based on what we’ve seen in other cancer types, the impact will probably be more pronounced in overall survival than in progression-free survival, given that response is not that reliable.”
According to Dr Seiwert, Associate Director of the Head and Neck Cancer Program at the University of Chicago, IL, much overall survival benefit is likely derived from patients with minor shrinkage and prolonged disease stabilization, and response is only moderately correlated with benefit of immunotherapy. “We see patients who have rapidly growing disease, and then suddenly the disease is stable,” he said. “So it can clearly modify the disease dynamic.”
In a keynote address at the symposium, Dr Seiwert offered some immunotherapy “pearls” based on his experience from treating a substantial number of patients with immunotherapy.
A Sustainable Response
Pseudoprogression is rare. “I estimate that 95% of imagery-based progression of disease is real disease,” he said. “Keeping patients on an ineffective agent for a prolonged period of time, if their disease is progressing, is potentially harmful.”
The biologic half-life of a PD-1 or its ligand (PD-L1) inhibitor is months, he added. “So if you stop the agent, you will probably still see the benefit, if such a benefit should actually occur. But in my experience, stopping the treatment and going to something like a cytotoxic agent instead is better.”
According to Dr Seiwert, unlike anti–cytotoxic T-lymphocyte antigen 4, the use of immune-related response criteria is of unclear benefit for PD-1/PD-L1.
“Dynamic of response is also important,” he said. Most responses to immunotherapy occur relatively early, but delayed responses do occur. “The majority of patients who have a response seem to have a sustainable response—not forever—but it seems to be more stable than what we see with other agents,” he said. For a faster response, he recommends the use of chemotherapy.
Immune-Related Side Effects
According to Dr Seiwert, PD-1/PD-L1 agents are exceptionally well tolerated, even in older patients and patients with poor performance, and particularly when compared with chemoradiation, chemotherapy, and radiation and surgery. The most common side effects are mild fatigue, hypothyroidism, and itchy skin. There are severe side effects, such as pneumonitis and colitis, but they are rare, and if recognized early, they are treatable. So, intensive screenings for symptoms of pneumonitis and colitis are imperative.
“Why are we so afraid?” Dr Seiwert asked. “We treat patients with some of the most toxic treatments [available], we make patients sick as hell with chemoradiation, and yet we’re so afraid of immune-related side effects? That seems very strange.”
“These side effects may actually even be a biomarker for benefit,” he continued. “What we want to do is break tolerance. We should treat more, and we shouldn’t be as afraid as we were, and I think as we learn more about these agents we might get more comfortable.”
In terms of cure and treatment duration, these questions are clearly unanswered, he said. “I think the depth of responses really may matter. If you have a very deep response, these may be patients who have long-term survival and benefit, and maybe the disease never comes back,” he said. “And when to discontinue treatment may need to be individualized.”
A Long Way to Go
“There are a lot of challenges ahead,” said Dr Seiwert. “We’ve taken a big step in the right direction, but we have a long way to go.”
“Cancer is inherently robust,” he said. “We’ve learned this over decades and decades of failure; we’ve seen it become resistant, and patients die. And this has not changed, ultimately, even though some patients do well.”
Fifty percent to 75% of patients with head and neck cancer do not derive benefit from anti–PD-1 agents. “So there we have patients who are constitutively resistant to immuno-oncology,” he stated. And a large fraction of patients who do respond may ultimately develop acquired resistance.
According to Dr Seiwert, immunotherapy is broadly active across human papillomavirus–positive and –negative cancers, including nasopharyngeal cancers, so it is an agent that can potentially be used very broadly. Additionally, responses to immunotherapy seem to be more durable, and “maybe for some patients, even for very advanced disease, we may be able to eradicate their disease completely,” he said.
“I think this is the point in time for a call to action,” he added. “We should move forward, because we actually have something that works; we just need to do better.”