Immunotherapy for cancer has been touted as the next big breakthrough in cancer treatment. However, before we get too excited about a “cure” for cancer, it is emerging that immunotherapy for cancer is not all it is perceived to be.
Although I do not have a strong interest in cancer research or treatment, others that I rub shoulders with do. They have been telling me for years that immunotherapy for cancer is the way of future cancer treatment. Cancer immunotherapy, is a type of cancer treatment designed to boost the body’s own natural defences to fight the cancer. It uses substances either made by the body or in a laboratory to improve or restore immune system function. However as always, despite the reports of amazing success stories, reports are beginning to emerge that all is not good.
In March this year at the 10th Future of Genomic Medicine Conference held in California, evidence is emerging that some patients become “hyperprogressors” and their cancer grows quickly soon after they start therapy. “We’ve all heard that immunotherapy is great. And there is subset of patients who do really well with long-term remission, even in the metastatic setting,” said Razelle Kurzrock, MD, from the University of California, San Diego School of Medicine. “But it’s not all good.”
“We began to notice that some patients were progressing rapidly on immunotherapy,” she explained. To illustrate her point, she showed imaging from a 73-year-old patient with metastatic bladder cancer whose cancer “just exploded” in size after starting immunotherapy.
Now the question is how to figure out not only who to treat, but who not to treat?
This will largely be done through genomics. For example, the MDM2 genes boost tumour formation in a number of cancer types when amplified. The amplification of MDM2 is also associated with hyperprogression after the initiation of immunotherapy.
The progression of the cancer is rapid. “The pace of progression is increased anywhere from five- to 40-fold.” Late last year, a European group conducted a phase 1 trial and identified a small percentage of patients who were hyperprogressors, across all types of cancers. Of the 131 evaluable patients, 9% were deemed to be hyperprogressors.
The questions now being asked are:
- Which tumour types are most likely to progress?
- How do we identify the patients who are going to hyperprogress?
- Who responds well to immunotherapy?
The more complex the tumour the better the response.
It seems odd but patients with more complex tumours and a higher tumour mutational burden (TMB) respond better. TMB is a quantitative measure of the total number of mutations per coding area of a tumour genome. Tumours that have higher levels of TMB are believed to express more neoantigens – a type of cancer-specific antigen – that may allow for a more robust immune response and therefore a more robust response to immunotherapy.
Not only does immunotherapy response correspond with high TMB, it also corresponds with the amount of circulating tumour (ct)DNA. However, for each success, there may be countless patients not even considered for a potentially lifesaving immunotherapy treatment because their TMB levels are unknown. Adding TMB to oncologists’ arsenal of information could make the difference for those patients most in need of immunotherapies. It is important to consider that TMB is not going to be a universal solution. However, in the current landscape, TMB is an essential tool that can help physicians maximize the benefits of the latest innovation in cancer care.
Use of anti-programmed death 1 (PD-1) monoclonal antibodies, including pembrolizumab (Keytruda, Merck), in the treatment of advanced melanoma has, to much acclaim, changed the management of melanoma. But the downside of the data is that most patients do not respond to treatment, a pooled analysis of an early-phase study confirms.
Of 581 patients with measurable disease at baseline, 194 patients, or 33% of the overall cohort, achieved an objective response to several different dosing regimens of pembrolizumab. Similarly, 60 of 133 patients (45%) who were treatment-naïve at baseline achieved an objective response, defined as either a complete or partial response. The numbers, which come from the KEYNOTE-001 phase 1 study of pembrolizumab, indicate that a majority of patients are non-responders.
Furthermore, only 8% of the patients achieved a complete response.
Some Cancer Patients ‘Hyperprogress’ on Immunotherapy. Medscape. Mar 09, 2017.
Downside to Melanoma Immunotherapy: 55% to 67% Nonresponders. Medscape. Apr 20, 2016.