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International Lung Cancer Congress

James L. Mulshine, MD, professor, Associate Provost for Research, Vice President, Rush University Medical Center discusses new USPSTF recommendations for lung cancer screening.

Mulshine says this is an important and new development for community oncologists because it promises better outcomes for their patients. Theses new recommendations, which state that “high risked” individuals should be screened for lung cancer, are based on the results of the national lung screening trial. This trial found that when comparing CT scans and X-rays, the CT scan arm had a mortality reduction benefit of 20%. This confirms previous data that states CT scans can advance the early detection of lung cancer, Mulshine says.

After reviewing these findings and thousands of other papers, the USPSTF found that the benefit of CT scans outweigh the potential harms. Some insurance providers have already started to cover this service, Mulshine says, while the remaining insurance providers have until the end of the year to submit their plan for coverage.

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Dr. Mulshine Discusses New Recommendations for Lung Cancer Screening

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

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

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

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 Papadimitrakopoulou, MD, the principal investigator. Collaborators include six 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.

Papadimitrakopoulou discussed the Lung-MAP trial in a telephone interview with 

in advance of the 15th Annual International Lung Cancer Congress, where she will explain the use of the master protocol design for implementing personalized medicine. Physicians’ Education Resource (PER) is hosting the conference July 31-August 2 in Huntington Beach, California.

The Lung-MAP trial seeks to recruit patients with advanced or incurable stage IIIB/IV squamous cell carcinoma who have progressed after receiving one frontline platinum-containing chemotherapy regimen for metastatic disease (

). Detailed criteria for assignment to a substudy group and then to a study drug also have been developed.

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

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

—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.

—Patients whose tumors test positive for a 

mutation will receive either GDC-0032 or docetaxel. GDC-0032, a beta-isoform-sparing PI3K inhibitor, is an oral agent from Genentech.

—Individuals whose tumors test positive for 

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.

—Participants whose tumors harbor alterations in 

will be given either AZD4547 or docetaxel. AZD4547 is a tyrosine kinase inhibitor that AstraZeneca is developing.

Rilotumumab plus erlotinib versus erlotinib

 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 EGFR inhibitor approved in several lung cancer settings, including as a second-line 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 trial is progression-free survival by Response Evaluation Criteria. 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 screen failure rates.

Agents that demonstrate sufficient efficacy to graduate from phase II to phase III could be considered for registration by the 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,

but 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 squamous cell lung cancer were fully characterized two years ago in research conducted through The Cancer Genome Atlas (TCGA) Network,

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, and TCGA data derived from early-stage disease specimens.

“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 sub-study chairs and co-chairs throughout the country will lead the various substudies.

The co-chairs for the study are David R. Gandara, MD, of the UC Davis Comprehensive Cancer Center in California, 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 Redman, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington. (Gandara and Herbst also serve as program directors of the PER conference this weekend, while Hirsch and Mack will offer presentations on other emerging developments in lung cancer).

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 upfront utilizing 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 their 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 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 not only are expensive and time-consuming for industry, but are also “wasted opportunities for patients,” said Papadimitrakopoulou.

For further information about the trial, visit 

			Groundbreaking collaborative clinical trial launched [news release]. Lung-MAP collaborative; June 16, 2014.  http://www.Lung-MAP.org/media/press/groundbreaking-collaborative-clinical-trial-launched. Accessed July 24, 2014.

			NIH Clinical Trials registry. www.ClinicalTrials.gov website. Identifier number: NCT02154490.

			American Cancer Society. What is non-small cell lung cancer? http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancer. Updated April 30, 2014. Accessed July 24, 2014.

			The Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers [published online September 9, 2012]. 

Five novel agents for the treatment of patients with advanced squamous cell carcinoma of the lung will be evaluated in the recently launched Lung-MAP trial

Ambitious Lung-MAP Trial Launched With Five Novel Drugs

 Annual International Lung Cancer Congress, which began today in Huntington Beach, California and will continue through Saturday, will offer an array of information presented by multidisciplinary experts—in a brand-new format.

“It’s set up to be a think tank, with 200 lung cancer experts plus participants [from the audience endeavoring] to digest what was presented earlier in the year at ASCO [the American Society of Clinical Oncology] and other conferences,” said Program Director David R. Gandara, MD, professor of Medicine in the Division of Hematology/Oncology, director of the Thoracic Oncology Program, and senior advisor to the director at the University of California Davis Comprehensive Cancer Center, in Sacramento.

Serving as a program director alongside Gandara is Roy S. Herbst, MD, PhD, Ensign Professor of Medicine (Medical Oncology), professor of Pharmacology, chief of Medical Oncology, and associate director for Translational Research at Yale Cancer Center in New Haven, Connecticut.

“We have leaders from all different specialties in lung cancer—pulmonary medicine, radiology, surgery, radiation oncology, medical oncology, molecular biology, pathology&mdash;on the faculty,” Gandara continued. “We will discuss management of cases where multiple modalities are required, such as surgery plus chemotherapy and radiation, and how to do molecular testing on patients. We’ll talk about that in panel discussions, and we’ll have a community-based multi-modality tumor board, during which we’ll talk about cases. Participants from the community can bring up cases in their practice and ask the expert panel how they would manage this sort of thing.”

, Gandara discussed some other anticipated highlights of the conference.

“Our faculty includes international experts, such as Giorgio Scagliotti, MD, PhD, of Italy, and James CH Yang, MD, PhD, from Taiwan, this year, because many of the lead studies at ASCO and other recent conferences were presented by these people,” Gandara said. “Dr. Yang announced for the first time, at ASCO, that patients with a certain EGFR mutation—the exon 19 deletion&mdash;who received afatinib had an overall survival improvement.

 Seven prior studies looked at first-generation agents, and an overall survival improvement has never been seen, so we’ll be able to discuss that among our expert faculty and the participants to reach some conclusions about how we think about those data and how they might be taken into clinical practice. This will probably lead to increased use of afatinib in the first-line setting.”

“Also exciting will be a presentation on lung cancer screening by James L. Mulshine, MD, [professor, associate provost for Research, and vice president of Rush University Medical Center in Chicago, Illinois],” Gandara said. “This has been an area of a lot of excitement and controversy over the last few months. The National Lung Screening Trial in the United States showed a 20% reduction in lung cancer death by screening with low-dose CT scan [compared to x-rays], yet [the Medicare Evidence Development & Coverage Advisory Committee] made a preliminary decision not to recommend reimbursement for screening. Dr. Mulshine is an expert in this area, and we have a number of other experts in this field who will attend and discuss this with him. That clearly will be a highlight of the meeting, which is usually focused [strictly] on lung cancer treatment.”

“Another area of tremendous interest I’d call ‘targeted immunotherapy,’ particularly with drugs against the target CDL1,” Gandara said. “There are half a dozen drugs targeting this immunotherapeutic molecular target. We’ll talk—both in lectures and panel discussions&mdash;about data, how to measure the degree of activity, and whether there is too much hype about these agents, so we’ll be able to reach some consensus.

We’ll have Vassiliki Papadimitrakopoulou, MD [professor in the Department of Thoracic/Head and Neck Medical Oncology at the University of Texas MD Anderson Cancer Center, in Houston] talk about why we must use different response measurements to determine how effective these drugs are. In immune therapy, T cells are invading the tumor initially, and with these treatments, the tumor can swell and look larger on a CT scan, so how does the physician know if the cancer is getting worse or if it’s an immune response and will get better with continued treatment? She’ll talk about this challenge.

We’ll also have sessions that are designed to talk about the unique toxicities of this sort of immune blockade. Patients and doctors tend to think that other therapies can be toxic, even drugs like erlotinib, but that immune therapies are generally not, and that’s not true for these—there can be substantial toxicities, and we’ll discuss that.”

“One of the most exciting of these will be the presentation of the 7

 Annual Addario lecture by Dr. Herbst,” Gandara said. “The Bonnie J. Addario Lung Cancer Foundation has a lung advocacy group, and each year they select someone they consider a leader in breakthrough research in the field to deliver a keynote address. Dr. Herbst will be speaking about the biology of the immune system in lung cancer. I expect that to be very well-received, and a great follow-up to last year’s keynote, in which Tony SK Mok, BMSc, MD, FRCPC, [of Hong Kong], talked about making war on cancer.”

Other keynote talks will include “Potential for ‘Curing’ Metastatic Non-Small Cell Lung Cancer,” presented by Paul Bunn, Jr., MD, and “TKI Combination Strategies,” presented by Dr. Yang.

“For Dr. Bunn, the concept is that, with targeted therapies like erlotinib in EGFR-mutated cancer or crizotinib in ALK-rearranged cancer, the response rate can be very high—70% or more&mdash;and the duration can be very long, but no patient has been cured, even with these breakthroughs,” Gandara said. “For the first time, Dr. Yang showed there was increased survival using a new drug, and in the Southwest Oncology Group we plan to combine that drug with another EGFR agent, cetuximab, for firstline treatment of EGFR-mutated cancers to see if that further boosts activity. We’re talking conceptually about how to transfer chronic disease, metastatic lung cancer, into curable disease.

In Dr. Yang’s talk, one issue is: How do you combine these therapies in a way where they are at least additive to each other, and in a way that has acceptable toxicity? Even with some of the combination immune therapies, the toxicity seems very high. So, should you give these drugs together, or sequentially? Are there ways to determine when to add a second agent based on a biomarker in the blood?”

The congress agenda will include discussions of experimental drugs in various classes: FGFR inhibitors, drugs that target the ROS1 rearrangement, PI3K inhibitors, inhibitors of HSP90, drugs targeting the cMET proto-oncogene, agents targeting the RET fusion gene, and PARP inhibitors.

“Drs. Papadimitrakopoulou and Herbst are the co-chairs of a new Lung Cancer Master Protocol, the Lung-MAP, or SWOG S1400.

 It just launched last month, and it’s an example of an umbrella trial,” Gandara said. “Patients with squamous cell lung cancer undergo next-generation sequencing of over 200 genes in their cancer, and then are placed in arms of the Master Protocol, which matches a biomarker found in their cancer with a drug against that biomarker. It’s a one-of-a-kind study, a private-public partnership between the NCI [National Cancer Institute] and cooperative groups, with the foundation of the NIH [National Institutes of Health] and also the FDA. It’s the first time we’ll do this in a way where we can actually seek approval from the FDA for each biomarker and drug [if they meet their phase III endpoints during the trial]. That will be blended into our discussions at the conference—how you put new agents into the Master Protocol.”

“An area unique to this meeting that will occur nowhere else is an entire session devoted to cooperative group trials throughout the world,” Gandara said. “In the United States, there’s been a reorganization and consolidation of cooperative groups. We’ll address new studies in all the groups and hear presentations from Europe and Asia about large, multi-institution trials being done there.”

Yang J C-H, Sequist LV, Schuler MH, et al. Overall survival in patients with advanced non-small cell lung cancer harboring common (Del19/L858R) epidermal growth factor receptor mutations: Pooled analysis of two large open-label phase III studies (LUX-Lung 3 and LUX-Lung 6) comparing afatinib with chemotherapy. 

Friends of Cancer Research. Lung-MAP - The Lung Cancer Master Protocol. FOCR website. 

The 15th Annual International Lung Cancer Congress, which began today in Huntington Beach, California and will continue through Saturday, will offer an array of information presented by multidisciplinary experts-in a brand-new format.

International Lung Cancer Congress | Conference

Dr. Mulshine Discusses New Recommendations for Lung Cancer Screening

Ambitious Lung-MAP Trial Launched With Five Novel Drugs

Lung Congress to Offer Thorough Review of Latest Research Findings