A report by French investigators has raised concern regarding the broad application of immunotherapy in lung cancer.
Checkpoint inhibitors like ipilimumab, pembrolizumab and nivolumab have gained traction in oncology as patients with advanced melanoma, bladder, kidney and lung cancer can have dramatic and sometimes durable remissions. One problem has been the lack of biomarkers to select appropriate candidates.
The most widely used measure is PD-L1 expression that identifies the target protein on the cell. Unfortunately, many studies have shown little relationship between the presence of PD-L1 and response, leading some investigators to suggest that PD-L1 expression should not be used at all.
Clearly, there is a need for better predictors of response.
The current study from the Institut Gustave Roussy examined 406 patients who had received PD-1 or PD-L1 immunotherapy. Despite the appeal of this form of therapy, fully forty percent of treated patients had progressive disease as their best response indicating that these patients’ tumors actually grew larger during treatment. As immunotherapy patients tend to respond more slowly than their counterparts receiving chemotherapy they are generally followed for longer periods of time before they are restaged with CT, MRI or PET/CT scans.
This extra time can also provide the opportunity for tumor growth.
While patients on conventional chemotherapy usually undergo restaging by week six, immunotherapy patients are often restaged at week eight, nine, ten or beyond. Thus, immunotherapy patients who are not responding to treatment may do particularly poorly, as their progressive disease is not detected until later in its course. The term the investigators applied is "hyper-progressive disease". Patients with hyper-progressive disease were shown to have an earlier death. Clearly patients falling into this unhappy category are the ones most in need of other forms of therapy. The study did not address whether hyper-progressive disease was in any way related to immunotherapy.
That is, they did not attribute worsening disease to the immune treatments.
However, we know that cytotoxic chemotherapy can induce DNA insults and can select or even induce a state of resistance and tumor aggressiveness in patients unresponsive to the treatment. Less is known about how immunotherapies might change the tumor milieu.
Is it possible that alterations in the PD-1/PD-L1 status of the tumor microenvironment might influence tumor biology? My own recent experience with two patients comes to mind.
One with recurrent bladder cancer clinically deteriorated before the third cycle of immunotherapy and was changed to effective salvage chemotherapy. The other with lung cancer progressed extremely rapidly on a single cycle of immunotherapy and was luckily recaptured with a platinum-based doublet. The results of the French study are provocative.
First, patients on immunotherapy may require closer surveillance.
Second, we need to develop a better understanding of the impact of immunotherapy on the tumor microenvironment to ensure that our interventions aren’t adversely affecting patient outcomes.
Finally, we need better tools to select candidates for immunotherapy so that those least likely to benefit do not waste precious time receiving the wrong treatment.
As always, I appreciate your thoughts and comments.
Dr. Robert Nagourney, has been internationally recognized as a pioneer in cancer research and personalized cancer treatment for over 20 years. He is a TEDx speaker, author of the book Outliving Cancer, a practicing oncologist and triple board certified in Internal Medicine, Medical Oncology and Hematology helping cancer patients from around the world at his Nagourney Cancer Institute in Long Beach, California. For more info go to NagourneyCancerInstitute.com