Outliers Join the Research Fold: Technological Advances Spark Initiatives to Study Exceptional Responders

Despite numerous reports of “miracle cures” for a select few patients treated with a variety of different anticancer therapies, drugs that failed to show improvement for a large number of patients have historically been considered failures and have been shelved.

Now, major advancements in our ability to more readily and affordably perform genome sequencing on biopsied tumor samples are leading researchers to revisit the idea of exceptional responses and uncover the molecular mechanisms underlying them.

In September, the National Cancer Institute (NCI) launched an initiative to gather and analyze tissue and clinical data about exceptional responders from patients treated during studies of experimental therapies, in standard therapy settings including community practice, and from pharmaceutical industry studies.

“The increasing ability of molecular technologies to stratify tumor types by prognosis or response to treatment will result in many common cancers being separated into specific subtypes that may respond to drugs in very different ways,” Barbara A. Conley, MD, of the NCI’s Division of Cancer Treatment and Diagnosis and co-lead investigator for the study, said when the agency announced the project.

Technology Spurs Interest

At the very least, these analyses will broaden our understanding of the complex biology underlying tumor development and evolution. Many are hoping that it may prove to be a source of novel therapies and even serve as a revival for failed therapies in tumor types in which they had previously been written off.According to the current paradigm of cancer drug development, successful therapies are those that are broadly active, helping the largest number of patients, and clinical trials accordingly focus on seeking out the best responses. Yet, time and again, oncology clinical trials are peppered with reports of anomalous patients who staged a spectacular recovery.

In fact, it’s estimated that between 1% and 10% of patients are so-called exceptional responders, a subpopulation for which the NCI has developed a specific definition (Figure 1). Such patients are often heavily pretreated individuals who demonstrate remarkable and, in many instances, durable control of their cancer. With no way to decipher the molecular meaning behind these responses, researchers discounted these individuals as statistical outliers and there was little interest, particularly for pharmaceutical companies, in pursuing these anecdotal outcomes further.

Early Cases Indicate Potential

In recent years, the oncology field has come to appreciate the significant heterogeneity among tumors, even between those that are morphologically indistinguishable, and to recognize that a spectrum of therapeutic responses is to be expected. Understanding this variability may present a unique opportunity to unravel novel molecular mechanisms of sensitivity to anticancer therapies and improve our understanding of the biology of cancer to provide better therapies and diagnostics.Among the first to pursue the sequencing of exceptional responders were researchers at Memorial Sloan Kettering Cancer Center (MSK). In an overall negative phase II trial of the mammalian target of rapamycin (mTOR) inhibitor in metastatic bladder cancer, everolimus (Afinitor), there was one patient with an exceptional response— a complete disappearance of her cancer within 3 months and a continued response after 4 years of treatment.

The researchers at MSK performed whole-genome sequencing on her tumor biopsy and discovered more than 17,000 genetic aberrations that were not present in her normal cells. Among them were mutations in the tuberous sclerosis 1 (TSC1) and neurofibromin 2 (NF2) genes. Both of these mutations lead to activation of the mTORC1 component of the mTOR protein complex, which is the target of everolimus. Thus, researchers hypothesized that these mutations made the cancer cells dependent on the mTOR pathway and sensitized the tumor to mTOR inhibition.

Studying exceptional responders can be particularly helpful in identifying potential novel therapies for patients with tumors that are more rare and harder to characterize.

Vivek Subbiah, MD, an assistant professor at The University of Texas MD Anderson Cancer Center, described a striking response that one of his patients experienced after receiving sorafenib-based therapy for a difficult-to-characterize tumor that was being treated like a conventional sarcoma.

Using next-generation sequencing (NGS), the researchers were able to identify a unique fusion protein, as well as loss of the tumor suppressor protein phosphatase and tensin homolog (PTEN).

“This was the first report of a patient with that kind of tumor responding to sorafenib-based therapy,” Subbiah said in an interview with OncologyLive. “This may be extremely rare, this may be an ‘N of 1’ study, but for the next patient with a similar aberration we can probably offer the same targeted agents.”

Clinical Trial Launched

The success rate so far in identifying the mechanisms of exceptional response has been high and a range of different molecular mechanisms have been reported in numerous different tumor types (Table).Inspired by success, major forces in cancer care are taking notice. In 2013, the NCI, in collaboration with several major academic medical centers including MSK and the Dana-Farber Cancer Institute, proposed a national Exceptional Responders Initiative, to help advance this concept and, hopefully, repeat the successful paradigm on a larger scale.

Those plans became a reality this fall. The NCI has established a process for evaluating and testing specimens in which DNA and RNA from tissue samples will be isolated at the Biospecimen Core Resource at Nationwide Children’s Hospital in Columbus, Ohio, and then shipped to Baylor College of Medicine in Houston for sequencing and analysis (Figure 2).

As part of the clinical trial, researchers are seeking to successfully conduct exome sequencing from about 100 cases, which they believe would provide enough information to ferret out potential therapeutic discoveries. They may have to examine up to 300 cases in order to reach that goal.

Figure 2. Recruiting Exceptional Responders

Adapted from Abrams J et al. National Cancer Institute’s precision medicine initiatives for the new National Clinical Trials Network. Am Soc Clin Oncol Ed Book. 2014;71-76.

Since only about 3% of patients with cancer enroll in clinical trials, soliciting data on exceptional responders from practicing oncologists is extremely important to the project. The ultimate goal is to create a national database containing the information that is gathered that is accessible to all.

On the academic front, MSK announced in May the establishment of the Marie-Josée and Henry R. Kravis Center for Molecular Oncology, which will focus in part on sequencing exceptional responders. In addition, a genomics approach called MSK-IMPACT, which analyzes 341 cancer-related genes via NGS, will be used to screen every patient with metastatic disease who enrolls in an MSK-led clinical trial in the next 12 months. Likewise, The MD Anderson Cancer Center is encouraging its doctors to submit tumor samples from exceptional responders for further analysis.

Reverse Engineering Therapies

The center’s Institute of Personalized Cancer Therapy has established an Unusual Responder Program that provides support for analyzing, sequencing, and publishing these findings.The analysis of exceptional responders is reversing the “genotype-to-phenotype” drug development paradigm by retrospectively analyzing data from drugs that have already been tested and reverse engineering them to get to the molecular drivers of these responses. The hypotheses that are generated can subsequently be tested in prospective trials to see if the same response can be generated in other patients with these genomic alterations.

Alternatively, a novel clinical trial design is being developed to assist in the prospective identification of exceptional responders. Dubbed basket trials, they apply the reverse “phenotype- to-genotype” approach to prospective clinical trials. While cancer trials traditionally examine the response to a particular drug in a patient population that shares a common tumor type, basket trials do the same among those that share a common genetic target. In this way they aim to determine the optimal targeted therapy for patients who harbor the associated genomic abnormality, regardless of the type of tumor they have, so that statistically it becomes a group of parallel phase II studies.

Table. Published Examples Of Exceptional Responders

^aDulanermin is a human protein corresponding to the apoptosis ligand 2/tumor necrosis factor-related apoptosis-inducing ligand (RhApo2L/TRAIL), according to the NCI Drug Dictionary.

IGF1R indicates insulin-like growth factor receptor 1.

Subbiah is currently running a BRAF mutation basket trial of vemurafenib (Zelboraf). “We look for response signals in many tumor types, and we can then expand the study to include those particular patients who have an unusual response and shut down arms that do not respond to the BRAF inhibitor even though they have the BRAF mutation,” said Subbiah.

In fact, many basket trials are ongoing. The NCI has developed the NCI-MATCH trial, which aims to match at least 1000 individuals with a variety of cancer types with therapies that target the specific mutations found in their tumors.

Pharmaceutical companies are also beginning to get involved in monitoring exceptional responses and in developing basket trials.

Novartis has begun routinely sequencing tumors of patients for 300 known cancer gene mutations prior to enrollment in early-stage clinical studies to help explain potential exceptional responses if they should occur during the trial. The company has also developed the Signature trials, a series of pathways-based basket trials. There are currently eight ongoing phase II Signature trials involving these agents and corresponding gene alteration targets:

• BGJ398—FGFR
• Binimetinib (MEK162)—RAS/RAF/MEK
• Buparlisib (BKM120)—PI3K, PTEN
• Ceritinib (LDK378)—ALK, ROS1
• Dovitinib (TKI258)—RTK
• Encorafenib (LGX818)—BRAF V600
• LEE011—CDK4/6, cyclin D1, or p16
• Sonidegib (LDE225)—PTCHI, SMO

Likewise, Genentech has developed the My- Pathway basket trial (NCT02091141). This is an open-label phase II study evaluating four therapies— trastuzumab (Herceptin) plus pertuzumab (Perjeta) combination, erlotinib (Tarceva), vismodegib (Erivedge), or vemurafenib—in patients with advanced solid tumors harboring mutations or gene expression abnormalities that are predictive of response to these agents.

Such trials could eventually provide an opportunity to revive therapies considered to have failed in certain treatment settings.

Optimizing Bedside to Bench Approach

While extremely promising, researchers are still in the early phases of developing a paradigm for effectively translating the clinical utility of these analyses of exceptional responders and there are a number of challenges to be addressed.

Among them is the question of a broad definition of exceptional response. Currently, there is no standardized definition and many in the field believe it is likely that any definition(s) will have to be specific to the type of cancer, stage, and possibly other variables, to reflect the true heterogeneity of response. Out of necessity, the NCI developed a broad definition for its Exceptional Responders Initiative in order to provide a guide for clinicians who submit potential examples (Figure 1).

Although researchers may be able to identify the mechanism of response at the molecular level, another significant hurdle is that it may prove difficult to translate this information in a clinically meaningful way.

Tumor cells are continually evolving, and even exceptional responses are not always durable and patients can relapse. “We need to understand and study these unusual responders in depth in a dynamic way, because we are not dealing with just one target,” stated Subbiah. “The target is moving, the tumor is evolving, and we need to study these unusual responders in real-time.”

Furthermore, the drug may not have been involved in the exceptional response at all or the exceptional response might result from mechanisms beyond the tumor biology. It is also unclear from a regulatory standpoint how the findings from exceptional responder analyses and basket trials might be translated into the development of new approved therapies or the revival of failed ones.

Finally, Subbiah and others believe that, in order to gain the most benefit from this research, we should be trying to understand the whole spectrum of response, not just exceptional responders. “As well as sequencing unusual responders, we need to sequence patients who have unexpected progression,” said Subbiah. “There are also those who have mixed responses and we need to study these patients as well because the tumor is heterogeneous and polyclonal so there are likely to be bits of the tumor that respond to the treatment and bits that don’t. We need to biopsy and study both parts of the tumor so we can have an understanding about response and nonresponse.

Jane de Lartigue, PhD, is a freelance medical writer and editor based in Davis, California.

Key Research

Chang DK, Grimmond SM, Evans TRJ, Biankin AV. Mining the genomes of exceptional responders [published online March 27, 2014]. Nat Rev Cancer 2014;14(5):291-292.

Iyer G, Hanrahan AJ, Milowsky MI, et al. Genome sequencing identifies a basis for everolimus sensitivity. Science. 2012;338(6104):221.

Memorial Sloan Kettering Cancer Center. Landmark $100 million gift from Marie-Josée and Henry R. Kravis Foundation supports a groundbreaking approach to precision oncology.

Center News Magazine. http://goo.gl/SfeMW1. Published June 1, 2014. Accessed August 31, 2014.

NIH exceptional responders to cancer therapy study launched [press release]. Bethesda, MD: National Cancer Institute; September 24, 2014.

Novartis Oncology. Signature website. https://www.signaturetrial. com/en/hcp#all. Accessed October 21, 2014.

Sheridan C. Cancer centers zero in on exceptional responders. Nat Biotechnol. 2014;32(8):703-704.

Subbiah V, Westin SN, Wang K, et al. Targeted therapy by combined inhibition of the RAF and mTOR kinases in malignant spindle cell neoplasm harboring the KIAA1549-BRAF fusion protein [published online January 14, 2014]. J Hematol Oncol. 2014;7(1):8.

Subbiah V. Prospects and pitfalls of personalizing therapies for sarcomas: from children, adolescents, and young adults to the elderly. Curr Oncol Rep. 2014;16(9):401.

Willyard C. ‘Basket studies’ will hold intricate data for cancer drug approvals. Nature Med. 2013;19(6):655.