ASCO 2018-SEARCHING FOR THE RIGHT IMMUNOTHERAPY COMBINATIONS

The field of cancer immunotherapy has greatly advanced during the last 7 years. Agents approved for the treatment of advanced melanoma by the U.S. Food and Drug Administration include the anti–CTLA-4 antibody ipilimumab (2011), the anti–PD-1 antibodies nivolumab (2014) and pembrolizumab (2014), ipilimumab combined with nivolumab (2015), and the oncolytic virus vaccine talimogene laherparepvec (T-VEC; 2015). In addition, the combination of the kinase inhibitors dabrafenib and trametinib was approved in 2014 for BRAF-mutant melanoma. Disease remission has been achieved in many more patients thanks to these agents. The available evidence and continuing research for efficacious combinations of therapies for melanoma treatment was the topic of the Education Session “Rational Combinations With an Immuno-Oncology Backbone,” held June 1.

Alexander M. Eggermont, MD, PhD, of Cancer Institut Gustave Roussy, France, provided an overview of treatment with multiple immunotherapies. Combining therapies does not always lead to a successful outcome. For example, the combination of dacarbazine with ipilimumab in patients with advanced melanoma was less successful than ipilimumab monotherapy. The immune-related adverse event profile of 3 mg/kg ipilimumab is well-characterized and includes colitis, hepatitis, hypophysitis, and rare cases of myocarditis and neuritis syndromes. Combination therapy may result in unforeseen events, further complicating the development of optimal treatment.

Anti–PD-1 and anti–PD-L1 antibodies have a more favorable toxicity profile compared with anti–CTLA-4 antibodies. Various combinations of ipilimumab with other immune-modulating, antiangiogenic, chemotherapeutic, or targeted agents have been investigated or are under evaluation, but nivolumab and pembrolizumab have taken center stage in the development of combination therapies.

“Monotherapy with anti–PD-1 agents has been phenomenally successful in melanoma and is actually an overachiever. Thus, it will be difficult to show that combining something with an anti–PD-1 agent in melanoma will be significantly better,” Dr. Eggermont noted.

A small increase in overall survival has been observed when the anti–PD-1 agent nivolumab was combined with ipilimumab compared with nivolumab alone. More recently, anti–PD-1 agents combined with indoleamine 2,3-dioxygenase
(IDO) inhibitors showed promising results. An interim analysis of a study of the IDO inhibitor epacadostat and pembrolizumab showed an overall response rate of 58%. This led to a phase III program that was stopped in April because of negative results. Combining the oncolytic vaccine T-VEC with pembrolizumab in patients with melanoma led to an overall response rate of 57%.

“Is this sufficient to be better than anti–PD-1 alone? I doubt it,” Dr. Eggermont said. More research is needed to obtain better insight into the optimal mechanisms and timing of combining therapies.

Biomarkers to Monitor Disease Response

Jennifer A. Wargo, MD, MMedSc, of The University of Texas MD Anderson Cancer Center, discussed ways to optimize treatment regimens based on disease response to therapy. Reverse translation follows patients longitudinally using blood and tumor samples. This methodology was used to determine potential biomarkers in a cohort of 53 patients with melanoma who received treatment with ipilimumab.

Seven patients experienced a disease response; 46 patients experienced disease progression and subsequently received anti–PD-1 therapy. Of those 46 patients, 13 demonstrated disease response and 33 had disease progression. Baseline biopsies and biopsies during treatment were obtained from all patients with molecular and immune profiling conducted at each time point. The immune signatures in the pretreatment biopsy did not predict response to therapy, but the immune signatures in the biopsies obtained during treatment were highly predictive.

“If we stress the system and look for an adaptive response during treatment, we may get a better answer, suggesting that early on-treatment biomarkers may have more utility, at least in the short-term, until we can identify better pretreatment biomarkers,” Dr. Wargo said.

Several lines of evidence suggest that the gut microbiome affects the response to immunotherapy. The microbiome is comprised of 100 trillion microbes, making up 3% of the human body mass. The gastrointestinal tract harbors the greatest number of microbes. Dr. Wargo and her team wanted to investigate the role of the gut microbiome in patients who received immune checkpoint blockade for melanoma.

Oral and gut microbiome samples and biopsies were obtained from 233 patients at baseline and after therapy. The samples underwent microbiome sequencing and immune profiling, revealing that patients who responded to anti–PD-1 therapy had a much greater diversity of gut bacteria and had prolonged progression-free survival. The results were recapitulated using fecal samples from the patients in mechanistic studies in germ-free mice. A collaborative effort is currently underway to conduct a clinical trial to further investigate the modification of the gut microbiome to elicit better response to therapy via fecal transplant and other methodologies.

“Combination therapy holds tremendous promise, but there are a lot of complexities with regard to ideal combinations, dosing schedules, and optimal biomarkers of response. As we move forward, I think we need to embrace novel biomarkers and targets,” Dr. Wargo concluded.

Radiation and Immunotherapy

Marka R. Crittenden, MD, PhD, of the Earle A. Chiles Research Institute, Providence Cancer Center, provided an update on the preclinical data of radiation with immunotherapy combinations and available clinical trial information. Several synergistic mechanisms exist that relate to radiation and the subsequent immune response. These include tumor antigen release and increased priming, tumor adjuvant release, the deletion of anergic and regulatory T cells, as well as T-cell activation, antigen processing machinery, death receptor upregulation, induction of cytokines and chemokines, and increased immune-cell trafficking.

Dr. Crittenden discussed two types of synergistic interactions between radiation therapy and the immune response. The first is the abscopal response, in which radiation acts as an in situ vaccine leading to increased control of distant disease sites. The second type of interaction is immunogenic modulation, in which changes occur in the tumor microenvironment and any residual cancer cells leading to immune-mediated clearance of remaining local disease.

Evidence to date indicates that a higher radiation dose may lead to a better endogenous vaccine effect, but an inflexion point may exist. To date, most clinical trials of combined radiation and immunotherapy have been early-phase studies. When combined with
interleukin-2, the data indicate better response with ablative doses of radiation therapy. The response rates of radiation combined with immune checkpoint inhibitors in clinical studies have not been as high as those seen in the preclinical setting.

Recent reports indicate that responses to immune checkpoint inhibition combined with radiation therapy are dependent on preexisting immunity. Although there is a solid basis for combining radiation with immuno-oncology agents to boost abscopal responses, the details are still being researched. Preclinical studies will help guide the timing, appropriate immunotherapy combinations, and the amount of optimal fractionation. In addition, immuno-oncology agents other than immune checkpoint inhibition should be investigated in clinical trials.

“Radiation struggles a lot more when a patient does not have a competent immune system, suggesting that part of why radiation works is that the immune system helps clear the last residual cells,” Dr. Crittenden said.

Patients receiving anti–PD-1 therapy have demonstrated enhanced local control of radiated tumors. PD-1 axis activation occurs following radiation as a result of PD-L1 upregulation.

“If you have patients receiving PD-1 inhibition, even if they are not responding systemically, they often show very good responses to the radiated tumor. Now we are starting to look at immunotherapy in the upfront neoadjuvant setting in combination with radiation to see if we

can start reducing our doses and perhaps spare toxicity,” Dr. Crittenden concluded.  

–Muriel Cunningham