Oncologists may be accustomed to looking for commonalities in patients, but highly personalized therapies are now being developed based on mutational analysis of tumors.
According to data presented at the Cedars-Sinai annual symposium on New Therapeutics in Oncology: The Road to Personalized Medicine, technologic advances have made it possible to profile abnormalities in the genetic code of tumors, and clinicians at the Center for Personalized Therapy are beginning to use this information to tailor treatments to individual patients.1
Every tumor is like a malignant snowflake, both complex and unique.— Razelle Kurzrock, MD
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“No two cancers are alike, just as no two people are alike,” said Razelle Kurzrock, MD, Senior Deputy Director of Clinical Science and Director of the Center for Personalized Cancer Therapy at Moores Cancer Center, University of California, San Diego (UCSD). “Our goal is to transform cancer therapy by using advanced technologic tools to predict who will respond to a specific treatment and to match each patient with the best drug for a particular tumor.”
“There may be a tendency to consider genomics and immunotherapy separately,” Dr. Kurzrock added, “but these two approaches are intimately wed. We can—and should—use genomics to find the best immunotherapy match.”
Bridging Genomics and Immunotherapy
Initiated in 2012, the Molecular Tumor Board, a multidisciplinary group of physicians and scientists, meets three times per month at Moores Cancer Center to discuss specific patients and advise one another on optimal treatment plans.
“We’ve tried to embed molecular profiling in the cancer center with the aim of actually treating patients on the basis of this profiling,” said Dr. Kurzrock, who noted that clinical-grade molecular profiling has been conducted in approximately 5,000 patients. In the context of precision medicine, this includes next-generation DNA sequencing, protein analysis, immune-signature analysis, and liquid biopsy (ie, detection of cancer DNA in the blood).
“Our emphasis has been on genomics, but as we’re learning more about tumors and as technology quickly improves, we’re also looking at transcriptomics, proteomics, and epigenetic changes, and to a variable extent, we’re using those as well,” she explained.
The fundamental premise of this approach, supported by the center’s early data, is that every tumor is both complex and unique: No two patients are alike despite their commonalities.
“Most patients have a complex array of alterations,” said Dr. Kurzrock. “Even though some have commonalities—15% had PIK3CA alterations, for example—when you look at the rest of the profile, for all intents and purposes, it’s different. Every tumor is like a malignant snowflake, both complex and unique.”
Predicting Response
Given the immune system’s highly personalized and precise nature, the challenge for Dr. Kurzrock and colleagues is to elucidate what, exactly, it recognizes and responds to. For the moment, their focus is on the mutanome.
“We’re learning that the immune system responds to the mutanome,” she said. “That may not be the only thing, but it’s really important. Response to mutations and certainly alterations like high mutational burden can be very important to predicting responses.”
Although confounded by several unresolved issues, emerging data also suggest that patients whose tumors overexpress programmed cell death ligand 1 (PD-L1) by immunohistochemistry have improved clinical outcomes with anti–programmed cell death protein 1 (PD-1)-directed therapy.2 Across studies and molecules, PD-L1–positive patients responded at a rate of 36% to 100%, said Dr. Kurzrock. Complicating the issue, however, is the fact that patients with low levels of PD-L1 expression have responded at rates of up to 17% as well.
“It’s not a perfect dichotomy,” said Dr. Kurzrock, “but it’s certainly a biomarker that can help us better select patients.”
The importance of tumor mutational burden has also been supported by recent studies in melanoma and lung cancer and is backed by the center’s own analysis of circulating tumor DNA, which can be taken from a small tube of blood or urine. Even though the number of patients treated with immunotherapy is small (62), there appears to be a trend (P = .07) for patients with at least 6 alterations to achieve response, compared to patients with a lower number of alterations, Dr. Kurzrock reported.3
In patients with a high tumor mutation burden, just “taking the brakes off” the immune system may be enough to elicit a response, she said. In patients with an intermediate mutation burden, the immune system may need more assistance. Patients with a low mutation burden, on the other hand, “may be more ideal for genomically targeted therapy, but we’re still learning how to fit these drugs into different stratifications,” she explained.
In addition, high microsatellite instability, which leads to high mutation burden, has been shown to predict immunotherapeutic response in colorectal cancer.4
Predicting Resistance and Hyperprogression
Having an understanding of this landscape enables clinicians to combine genomically oriented therapy and immunotherapy in a customized way to amplify responses, but mutational analysis of tumors can also predict which patients may be resistant to immunotherapy.
Antoni Ribas, MD, PhD
As Dr. Kurzrock reported, a recent paper by Antoni Ribas, MD, PhD, in The New England Journal of Medicine indicates that JAK1-inactivating alterations may initiate resistance to immunotherapy.5 Preliminary data from UCSD suggest that patients with epidermal growth factor receptor (EGFR) alterations show resistance to anti–PD-1/PD-L1 immunotherapy, at least when given alone, as well.
Genomic analysis could also save patients from the rare phenomenon of disease acceleration on immunotherapy. This phenomenon is just being recognized, but hyperprogression was described recently by another group.6 In six patients at UCSD, with MDM2/4 amplification, Dr. Kurzrock and colleagues observed a short time to progression, and four of these patients had a dramatic increase in the rate of progression in the 2 months following initiation of immunotherapy (P = .001). All patients with documented accelerated progression were treated with single-agent anti–PD-1/PD-L1 drugs.
“In spite of the small number of patients, the P value is significant,” said Dr. Kurzrock. “It’s not a complete story, but it may predict for something new.… Personally, I would be very cautious in treating patients with MDM2 amplification with single-agent anti–PD-1/PD-L1 immunotherapy.”
Finally, according to Dr. Kurzrock, these alterations may be important in diseases other than the histologies in which they’ve been approved. In patients with a high mutational burden, off-label use of checkpoint inhibitors has yielded anecdotal success, including “super-responders.”
I think it’s early for this kind of therapeutic approach, but the future is promising.— Barry E. Rosenbloom, MD
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Session moderator Barry E. Rosenbloom, MD, Clinical Professor of Medicine at Cedars-Sinai Medical Center and the University of California, Los Angeles, said that, while based on good science and good judgment, extrapolation of efficacy data from approved indications to other tumor sites often involves a “leap of faith.”
“When we take a molecular result and try to extrapolate to a patient’s situation, there are sometimes a myriad of malignant mutations such that picking one can be very confusing,” said Dr. Rosenbloom. “I think it’s early for this kind of therapeutic approach, but the future is promising.” ■
Disclosure: Dr. Kurzrock has received consultant fees from XBiotech and Actuate Therapeutics; has received research funds from Genentech, Pfizer, Sequenom, Guardant Health, Foundation Medicine, and Merck Serono; and has an ownership interest in CureMatch Inc. Dr. Rosenbloom reported no potential conflicts of interest.
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