When it comes to immunotherapy for cancer, "everyone likes to talk about the 'super-responders'," said an expert here at the 10th Future of Genomic Medicine Conference. But 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.
"We need to figure out not only who to treat, but who not to treat. This will largely be done through genomics," Dr Kurzrock said.
For example, the MDM2 genes encode an oncoprotein that turns off p53 and other tumor-suppressor genes, boosting tumor formation in a number of cancer types when amplified. The amplification of MDM2 is also associated with hyperprogression after the initiation of immunotherapy.
We've noticed now that all our patients with MDM2 amplification have responded this way," she reported, adding that progression is rapid. "The pace of progression is increased anywhere from five- to 40-fold."One patient with MDM2 amplification assessed at the UC San Diego Center for Personalized Cancer Therapy was a 65-year-old woman whose endometrial stromal sarcoma progressed quickly on nivolumab, an anti-programmed death 1 (PD-1) monoclonal antibody immunotherapy. Another patient with MDM2 amplification, a 44-year-old woman with triple-negative breast cancer, underwent craniotomy and radiation therapy for brain metastases and then started pembrolizumab therapy, which also targets the PD-1 receptor. A few months later, her cancer progressed
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," said Shubham Pant, MD, from the M.D. Anderson Cancer Center in Houston. Of the 131 evaluable patients, 9% were deemed to be hyperprogressors, he told Medscape Medical News (Clin Cancer Res. Published online November 8, 2016).
Those patients with hyperprogressive tumor growth did not have a significantly higher baseline tumor burden. However, hyperprogression was associated with older age (P < .05) and worse overall survival.
"It's a very interesting clinical question, but these are still early days," Dr Pant explained. It also raises questions: Which tumor types are most likely to progress? How do we identify the folks who are going to hyperprogress? And who responds well to immunotherapy?
Higher Mutational Burden, Better Response
It sounds counterintuitive, but sometimes people with more complex tumors and a higher tumor mutational burden respond better, Dr Kurzrock said.
"We did a study where tumor mutational burden — across tumor types — was linearly correlated to checkpoint inhibitors," she noted. "That makes sense. Once you reactivate the immune system, if there are a lot of neoantigens, the system has something to respond to."
Anti-PD1 and anti-programmed death ligand (PD-L1) checkpoint inhibitors might help "get the immune system out of check" in patients with a high mutational burden, she suggested.
Table. Responses to Immunotherapy
| Tumor Mutational Burden | Response Rates to Immunotherapy, % |
| Low | 4 |
| Intermediate | 26 |
| High | 45 |
| Very high | 67 |
Not only does immunotherapy response correspond with tissue tumor burden, it also corresponds with the amount of circulating tumor (ct)DNA, said Dr Kurzrock, whose center has performed ctDNA analysis on more than 1500 patients to date.
One of these patients — a 49-year-old woman with high-grade neuroendocrine cervical cancer — presented with a very large abdominal tumor associated with a partial ureteral obstruction and impending bowel obstruction.
Liquid biopsy revealed "a whole lot of alterations. Most patients have two or three alterations in their ctDNA, but she was just packed," Dr Kurzrock explained.
Subsequent tissue-sample biopsy confirmed that the woman had 23 genetic mutations and a very high tumor burden but was a super-responder to nivolumab and radiation, she reported. "We believe at 15 months that she is in complete remission."
Dr Kurzrock reports receiving research funding from Genentech, Merck Serono, Pfizer, Sequenom, Foundation Medicine, and Guardant; receiving consultant or advisory board fees from Actuate Therapeutics and XBiotech; and having ownership interest in Novena and Curematch. Dr Pant has disclosed no relevant financial relationships.
10th Future of Genomic Medicine (FOGM) Conference. Presented March 2, 2017.
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