Extensive Lung-MAP Trial to Study 5 Novel Drugs

Vassiliki A.

Papadimitrakopoulou, MD

Five novel agents for the treatment of patients with advanced squamous cell carcinoma (SCC) of the lung will be evaluated in the recently launched Lung-MAP trial. This innovative, biomarker-driven study aims to improve the drug development process while exploring therapeutic options for this challenging malignancy.

The study, formally known as SWOG S1400, may cost up to $160 million and involve testing an additional 5 to 7 drugs beyond the agents initially selected. Plans call for enrolling up to 5000 patients through more than 200 medical centers during the next 5 years in randomized phase II substudies of the novel agents after participants have been screened through a master protocol.¹

The first round of agents to be tested include 4 targeted therapies—GDC- 0032, palbociclib, AZD4547, and rilotumumab— and the immunotherapy MEDI4736.²

The logistics of the trial have been challenging to coordinate, but academic researchers, government regulators, and pharmaceutical companies have embraced the concept, according to Vassiliki A. Papadimitrakopoulou, MD, the principal investigator. Collaborators include 6 companies, the SWOG and the National Clinical Trials Network research cooperatives, and the National Cancer Institute (NCI).

“Everybody sees the advantages in the process. We have an unprecedented willingness to participate,” said Papadimitrakopoulou, a professor in the department of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center in Houston.

“There is a realization that we’re doing things in such a fractional way in clinical research now that we’re not really fulfilling our goals of getting safe and effective drugs to the patients as fast as possible,” she said.

Key Facets of the Trial

Papadimitrakopoulou discussed the Lung-MAP trial in August in Huntington Beach, California, during the 15th Annual International Lung Cancer Congress®, where she explained the use of the master protocol design for implementing personalized medicine.The Lung-MAP trial seeks to recruit patients with advanced or incurable stage IIIB/IV SCC who have progressed after receiving one front-line platinum-containing chemotherapy regimen for metastatic disease (Table). Detailed criteria for assignment to a substudy group and then to a study drug also have been developed.²

To screen for biomarkers, investigators will conduct genomic profiling on either archived or freshly obtained tumor specimens using the Foundation- One test, which analyzes 182 genes.

After genomic evaluation, patients will be channeled into 1 of 5 substudies, depending on their biomarker status, and then randomized within that study. The substudies are:

• MEDI4736 versus docetaxel—Participants whose tumors do not harbor any of the targeted alterations will be randomized to receive either MEDI4736, a monoclonal antibody directed against the programmed death ligand-1 (PD-L1), or the standard chemotherapy docetaxel. MedImmune, a research arm of AstraZeneca, is developing the immunotherapy agent.
• GDC-0032 versus docetaxel—Patients whose tumors test positive for a PI3KCA mutation will receive either GDC-0032 or docetaxel. GDC-0032, a beta-isoform-sparing PI3K inhibitor, is an oral agent from Genentech.
• Palbociclib versus docetaxel—Patients whose tumors test positive for CDK4/6 or CCDN1/2/3 amplification will be randomized for treatment with either palbociclib or docetaxel. Palbociclib is a small molecule from Pfizer that has gained Breakthrough Therapy status in breast cancer.
• AZD4547 versus docetaxel—Patients whose tumors harbor alterations in FGFR1/2/3 will be given either AZD4547 or docetaxel. AZD4547 is a tyrosine kinase inhibitor that AstraZeneca is developing.
• Rilotumumab plus erlotinib versus erlotinib—Patients whose tumors have HGF/c-MET mutations will receive rilotumumab intravenously on day 1 and erlotinib daily, versus erlotinib daily. Rilotumumab is a monoclonal antibody in Amgen’s pipeline that inhibits hepatocyte growth factor activity. Erlotinib (Tarceva) is an epidermal growth factor receptor (EGFR) inhibitor approved in several lung cancers, including as a secondline treatment for patients who progress after chemotherapy.

Papadimitrakopoulou said 16 pharmaceutical companies competed to have their drugs included in the trial in a rigorous process that included presenting data before a selection committee.

The primary endpoint of the phase II and phase III trials is progression-free survival (PFS) as measured by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints include response rates and toxicity frequencies. Researchers also will be evaluating the percentages of screened patients who register in a specific substudy and receive at least one dose of the study drug in an effort to track successful registration and to screen failure rates.

Need for New Therapies

Agents that demonstrate sufficient efficacy to graduate from phase II to phase III could be considered for registration by the US Food and Drug Administration (FDA), while agents that do not, will be replaced by new agents or combinations.Squamous cell carcinomas represent 25% to 30% of all lung cancers and constitute the second-largest subtype of non-small cell lung cancer (NSCLC) after adenocarcinoma,³but no targeted therapies have been developed yet for patients whose tumors have this histology.

“Despite a lot of impressive therapeutic advances that we have seen in lung cancer in the last few years, most of these advances are in reference to lung adenocarcinomas in specific mutational subsets, and they do not pertain to the squamous subset of patients for whom standard therapy still remains chemotherapy,” said Papadimitrakopoulou. “In many respects, this particular subset of lung tumors remains an orphan setting.”

This situation has persisted even though genomic alterations in SCC lung cancer were fully characterized 2 years ago in research conducted through The Cancer Genome Atlas (TCGA) Network,⁴Papadimitrakopoulou noted.

In the Lung-MAP trial, researchers are using the database from Foundation Medicine, which developed the genomic profiling test being used in the study, for insight into alterations in refractory disease, as well as TCGA data derived from early-stage disease specimens.

Table. Key Eligibility Criteria for Lung-MAP

Squamous-cell NSCLC confirmed by tumor biopsy and/or fine-needle aspiration

Stage 3B/4 advanced or incurable disease

Primary squamous-cell diagnosis based on H & E slides with or without specific defined IHC characteristics

Mixed histologies containing ≥50% squamous component

Patients must have progressed after exactly 1 front-line platinum-containing metastatic chemotherapy regimen

Adequate tumor tissue available, defined as ≥20%

No known EGFR mutation

No known ALK fusion

Zubrod performance status ≤2 within 28 days prior to screening registration

Patient must provide prior smoking history

Patient consent for submitting tissue for biomaker analysis for the trial and for banking for future specimen use

H&E indicates hematoxylin and eosin; IHC, immunohistochemistry; NSCLC, non-small cell lung cancer. Source: www.ClinicalTrials.gov, NCT02 154490.

How the Collaboration Evolved

“This is the first attempt to systematically go after the alterations that we have sufficient knowledge of, and I think this is going to open up the path for additional alterations that can be targeted,” said Papadimitrakopoulou. “This trial is going to provide the largest repository of squamous lung cancer materials from patients from the refractory setting.”The impetus for organizing the Lung- MAP trial stems from many factors, including a mandate from the NCI and the Institute of Medicine to improve clinical trial designs.

“The rationale is mostly efficiency— exploring novel therapeutics in a setting where we haven’t seen any approvals of novel therapeutics that are targeting alterations so far, and trying to bring into our trials next-generation sequencing, which is a clinical reality but hasn’t been generalized in its use in other studies,” said Papadimitrakopoulou.

The trial has mobilized a network of resources throughout the United States in research, advocacy, and industry. The study is being launched through SWOG, formerly the Southwest Oncology Group, and cooperative groups represented by substudy chairs and cochairs throughout the country will lead the various substudies.

The cochairs for the study are David R. Gandara, MD, of the University of California Davis Comprehensive Cancer Center, who is SWOG’s Lung Committee chair, and Roy S. Herbst, MD, PhD, of the Yale Cancer Center in New Haven, Connecticut, who is leading the Lung-MAP steering committee.

Also playing leading roles are Fred R. Hirsch, MD, PhD, of the University of Colorado Cancer Center in Denver, Philip C. Mack, PhD, of UC Davis Comprehensive Cancer Center, and Mary W. Redman, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.

Other key players in the Lung-MAP cooperative include the Friends of Cancer Research, a Washington, DC-based advocacy group, led by Ellen V. Sigal, PhD, and the Foundation for the National Institutes of Health’s Biomarker Consortium. Among industry partners, the collaboration brings together the companies whose drugs are being evaluated and Foundation Medicine.

“I think what is enticing to the companies is, first of all, the established mechanism for screening patients up front, using the resources and the patient populations that exist within the cooperative groups,” said Papadimitrakopoulou. “It’s quite a unique resource because each company would have to recruit its own network to run similar clinical trials targeted toward any of the alterations in squamous lung cancer.”

Moreover, the FDA was directly involved in oversight and advisement regarding the design of the trial, which brings the regulatory agency into the process before any potential filings for new drug approvals.

Ultimately, the groundbreaking design is intended to steer clinical trials away from the model in which large numbers of patients are screened to find a relatively small number of individuals who may benefit from the study drug. Such trials are not only expensive and time-consuming for industry, but are also “wasted opportunities for patients,” said Papadimitrakopoulou. TT For further information about the trial, visit www.Lung-MAP.org.

References

1. Groundbreaking collaborative clinical trial launched [news release]. Lung-MAP collaborative; June 16, 2014. http://www.Lung-MAP.org/media/press/groundbreakingcollaborative- clinical-trial-launched. Accessed July 24, 2014.
2. NIH Clinical Trials registry. www.ClinicalTrials. gov website. Identifier number: NCT02154490.
3. American Cancer Society. What is non-small cell lung cancer? http://www.cancer .org/cancer/lungcancer-non-smallcell/ detailedguide/non-small-cell-lung-cancer-whatis- non-small-cell-lung-cancer. Updated April 30, 2014. Accessed July 24, 2014.
4. The Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers [published online September 9, 2012].Nature. 2012;489(7417):519-525.