Ambitious Large-Scale Efforts Aim to Bring Targeted Therapy to Understudied Tumors

Ambitious Large-Scale Efforts Aim to Bring Targeted Therapy to Understudied Tumors

More than 70 targeted drugs have been developed for use in a variety of cancers. This ever-expanding armamentarium of targeted therapies offers clinicians the promise of individualizing therapy for their patients based on tumor characteristics, in theory leading to more effective treatment. However, providers often hit critical snags that preclude use of targeted therapy, either due to the inability to test for the presence of potential targets or the inability to gain access to agents when the malignancy falls outside of approved labeling.

During the Clinical Science Symposium “Precision Medicine: Making Progress for Patient Benefit,” held June 6, attendees heard about three large-scale efforts leveraging innovative trial designs and cutting-edge technology to break critical ground in the ability to pinpoint and utilize viable targeted therapies for individual patients.

Targeted Treatment in Pediatric Oncology

“The fast penetration of tumor molecular profiling, as evident at this meeting in the exhibition hall, will increase the likelihood of off-label use and associated subsequent risks,” said presenter Gilles Vassal, MD, PhD, of the Gustave Roussy Cancer Centre.  To address these issues, the French National Cancer Institute developed the AcSé (Secured Access to Innovative Therapies) program in 2013 to promote safe access to targeted therapies outside of their approved indications for patients who otherwise face a dearth of treatment options. Through this program, French patients undergo molecular testing and, if appropriate, receive targeted therapy within the oversight of a phase II trial, provided there are no other trials for which they are eligible.

The first trial coordinated by the AcSé program in July 2013 was a proof-of-concept basket study investigating single-agent crizotinib in adults and children with an advanced-stage, incurable malignancy harboring ALK, MET, or ROS1 alterations. Crizotinib is currently only indicated in France for adults with ALK-positive non­­–small cell lung cancer (NSCLC); however, research indicates that more than 15 different malignancies in adults and children feature molecular alterations amenable to crizotinib treatment.

Dr. Vassal, who is chief investigator of the nonrandomized, open-label, phase II AcSé crizotinib trial, presented the results for children and adolescents enrolled on this study (Abstract 11509). Of 107 pediatric patients tested for structural genomic alterations in ALK, MET, or ROS1 using biomarker tests or pangenomic tumor profiling, 17 patients harbored positive tumors. Five of these patients met the eligibility criteria to enroll in a phase I trial of ceritinib, whereas 11 patients entered into the AcSé crizotinib trial.

The median age of the 11 patients enrolled onto the AcSé crizotinib trial was 9 years, (range: age 3 to 16). A variety of tumor types were represented in the group, including high-grade glioma (three patients), anaplastic large cell lymphoma (ALCL; two patients), neuroblastoma (two patients), inflammatory myofibroblastic tumor (two patients), mesothelioma (one patient), and atypical meningioma (one patient).

The youths received  280 mg/m2 of crizotinib twice daily (except patients with ALCL who received 165 mg/m2 of crizotinib twice daily) via oral suspension so long as they derived clinical benefit. With such treatment, one patient attained a complete response (CR), four patients attained a partial response (PR), and two others had stable disease (SD). Overall, the objective response rate (ORR) reached 45%, and progression-free survival (PFS) among patients with stable disease or better ranged from 5.5+ to 24.8+ months. Five patients remain on treatment.

Dr. Vassal considers this feasibility study to be a success, having “provided secured access to both biomarker testing and treatment for children and adolescents with life-threatening malignancies.” To sustain the forward momentum, another trial, AcSé eSMART, is slated to launch in the fall of 2016 throughout Europe in collaboration with the Innovative Therapies for Children with Cancer (ITCC) consortium. eSMART will be phase I/II basket-and-umbrella trial for children with relapsed or refractory disease that will explore the effectiveness of 10 investigational oncology drugs from at least three different pharmaceutical companies—as single agents and in combination—based on the results of pangenomic tumor profiling.

Dr. John D. Hainsworth
Discussant Ranee Mehra, MD, of Fox Chase Cancer Center, had complimentary remarks about the AcSé crizotinib trial. “The investigators should be congratulated for their ability to acquire the data and tissue from centers all over France and other regions in order to perform testing. [ . . . ] This is the foundation of a robust clinical trial infrastructure, and I look forward to the results of the upcoming eSMART study, which will hopefully build on this platform,” Dr. Mehra said.

Molecular Testing of Solid Tumors

Efforts similar to the AcSé program in France have been undertaken in the United States. For example, the MyPathway study, a basket-and-umbrella trial commenced at 39 U.S. treatment centers, is designed to evaluate agents targeting the HER2, BRAF, Hedgehog, and EGFR pathways in tumor types outside of the approved indications that bear the biomarker of interest.

As presenter John D. Hainsworth, MD, of the Sarah Cannon Research Institute and Tennessee Oncology, PLLC, explained, to be eligible for this nonrandomized, open-label phase IIa study, patients with a performance status of 0 to 2 had to have advanced solid tumors that progressed after exhausting all standard treatment options and potential clinical trials. In addition, patients had to have disease bearing a potentially actionable genetic alteration, as determined by a Clinical Laboratory Improvement Amendments–certified laboratory.

As of December 2015, 129 patients with tumors from 25 different primary sites received targeted treatment based on the genetic and molecular profile of their tumors. Across all tumors, 64% featured HER2 alterations, 26% BRAF mutations, 6% Hedgehog pathway mutations, and 5% EGFR mutations.

Prior to this study, patients had received a median of three prior lines of therapy (range: 0 to 10). With the current line of targeted treatment, 22% of the 129 patients achieved an objective response—the primary study endpoint—spanning 12 different tumor types outside of current indications. Another 12% of patients benefited from stable disease for at least 120 days, bringing the overall clinical benefit rate to 34%.

The vast majority of responses observed in patients were partial (28 patients) as opposed to complete (one patient). Still, the responses appear to be fairly durable. Fifteen patients have ongoing responses (range: 3+ to 11+ months), whereas the 14 patients who progressed on treatment did so after a median of 6 months (range: 2 to 14 months).

Dr. Hainsworth emphasized that four major cohorts of patients in this trial achieved particularly favorable outcomes with nonapproved/off-label targeted therapy:

  • Among 20 patients with colorectal cancer featuring HER2 amplification or overexpression, the clinical benefit rate reached 50% (35% ORR, 15% SD rate).
  • Among eight patients with bladder cancer featuring HER2 amplification or overexpression, the clinical benefit rate reached 63% (38% ORR, 25% SD rate).
  • Among six patients with biliary cancer featuring HER2 amplification or overexpression, the clinical benefit rate reached 50% (35% ORR, 15% SD rate).
  • Among 15 patients with BRAF-mutated NSCLC, the clinical benefit rate reached 33% (20% ORR, 13% SD).

Encouragingly, no new safety signals emerged among patients beyond those seen in pivotal clinical trials of the agents.

“In summary, at this preliminary report, I think we can say that this trial design is feasible, with patients accrued based on molecular profiling results rather than primary site or tumor type,” Dr. Hainsworth said. Patient accrual to the MyPathway study is ongoing, with the goal of ultimately enrolling 500 patients. “Just this past week we passed the 200 mark,” Dr. Hainsworth noted.

Dr. Alex A. Adjei
Discussant Alex A. Adjei, MD, PhD, of the Mayo Clinic, raised an important issue about the ability of basket-and-umbrella trials to facilitate expanded approval and use of targeted agents. “Can we ever have enough power to recommend treatment of a rare molecular subset, particularly if it’s with an expensive targeted agent?” he asked.

Dr. Adjei answered by indicating that such trials can be successful if, as in the MyPathway study, patients are grouped into tumor cohorts defined by tumor type and molecular alteration and undergo separate statistical analysis. “Novel designs clearly are important for accelerating drug development. But we need to be careful about maintaining statistical rigor when we plan these studies, as was done nicely in this study,” he said.

The Future of Lung Cancer Therapy

EGFR mutations and ALK rearrangements are currently the only driver mutations routinely tested in NSCLC to identify candidates for treatment with erlotinib, afatinib, crizotinib, or ceritinib. However, NSCLC adenocarcinomas often harbor other driver mutations that can be hit with alternative targeted therapies.

In a nationwide effort to improve the treatment of patients, a collection of 16 leading cancer centers across the country have banded together to form the Lung Cancer Mutation Consortium (LCMC) with the aim of prospectively examining lung adenocarcinomas for genetic and molecular abnormalities using a variety of technologies and using that information to match patients to the best possible therapies.

As described by presenter Dara Aisner, MD, PhD, of the University of Colorado School of Medicine, the latest study undertaken by the group beginning in May 2012 identified 1,020 eligible individuals with confirmed stage IV lung adenocarcinomas, a performance status of 0 to 2, and sufficient tissue for biomarker analysis. Tumor tissue from 875 of these individuals was probed for 14 different genetic and molecular abnormalities.

More than half of all patients—54%—had tumors bearing a genetic abnormality. The most common mutations fell within the KRAS (25%) and EGFR (12%) genes, followed by a smattering of other genetic abnormalities such as ALK rearrangements (4%), MET amplification (3%), BRAF mutations (2.5%), and others. In addition, MET overexpression and PTEN loss according to immunohistochemistry occurred in 59% and 15% of cases, respectively.

Closer inspection of the genetic and molecular changes revealed that 242 individuals (28% of the analyzable cohort) harbored tumors with a driver alteration. Of these patients, slightly more than one-half (131 patients) went on to receive targeted therapy. Here is where the striking differences between groups were found. Patients with a driver mutation who received targeted treatment attained a median overall survival (OS) duration of 2.7 months—an improvement of 1.2 years over patients with driver mutations who did not receive targeted therapy and 1.0 years over patients without targetable driver mutations.

When examining the influence of select mutations on patient outcomes, several other nuggets emerged as well:

  • TP53 mutations modulate the response to EGFR-targeted therapy among patients with EGFR-sensitizing mutations, conferring worse prognosis when present than when not (median OS: 2.9 months vs. not yet reached; p = 0.02).
  • KRAS mutations confer a worse prognosis in never-smokers when present than when not (median OS: 2.9 months vs. not yet reached; p = 0.011).
  • Identifying mutations is important in the subpopulation of smokers because presence, versus absence, of these mutations confers a more favorable prognosis (2.7 vs. 1.6 months; p = 0.008).

“The optimism here is that as testing and therapies co-evolve, we certainly expect to see additional improvements,” Dr. Aisner said.

Discussant Balazs Halmos, MD, of the Albert Einstein College of Medicine/Montefiore Medical Center, echoed this sentiment. “Of all the great advances in lung cancer therapy and testing over the last number of years … the future in the precision medicine of lung cancer is now. We’ve created a very solid foundation of discovery not just in biomarker testing, but in every single area of thoracic oncology, so that very drastic reduction of lung cancer mortality and morbidity could be achieved in the coming years,” he said.

Cost Considerations

All discussants and many audience members raised concerns regarding the cost of these types of novel approaches to testing and targeted-therapy treatment. For example, Dr. Mehra noted that cost-effectiveness information will be necessary to establish molecular profiling as a standard of care for pediatric patients. Dr. Adjei also pointed to potential obstacles in paying for broad sequencing efforts among adult patients with cancer. In addressing these cost concerns, some noted that it will be important to weigh the life–years gained with successful targeted treatment based on genetic and molecular testing against the life–years lost in the absence of testing and hence possibly suboptimal therapy.

–Kara Nyberg, PhD