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P T. 2014;39(10): 698-703, 714

Lung Cancer Research Is Taking On New Challenges

Knowledge of Tumors’ Molecular Diversity Is Opening New Pathways to Treatment
Susan Worley

Lung cancer treatment has evolved in the past decade, leading to remarkable growth in the number and variety of therapeutic options. Clinicians and patients have witnessed a shift from a relatively small arsenal of mostly chemotherapeutic therapies to an expanding array of targeted treatments (Table 1) and treatment combinations. This change reflects, in part, a significant refinement in the molecular categorization of lung cancer and the increasingly successful exploitation of the molecular diversity of lung tumors.

“We clearly can no longer think of lung cancer as a monolithic entity,” says Corey Langer, MD, Director of Thoracic Oncology and Professor of Medicine at the University of Pennsylvania. “With the identification of a significant number of actionable or potentially actionable molecular drivers—including not just mutations but translocations and other molecular aberrations, most of which we weren’t aware of even 10 years ago—lung cancers really break down into distinct entities, each of which should be recognized as having separate cancer behaviors.”

Corey Langer, MD

“As lung cancers are further subdivided and characterized according to histology and molecular fingerprints,” Dr. Langer adds, “we may see an increasingly specific and beneficial impact on treatment, as we have already begun to see in our patients with adenocarcinoma, about 25% of whom have some molecular abnormality that directs their treatment.”

As breakthroughs in identifying oncogenic drivers of lung cancer continue, researchers should be in an increasingly better position to revisit persistent problems, such as the dearth of treatments for patients with squamous non–small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC); intransigent overall survival rates among patients with all types of lung cancer; and the need to assess potential new treatments more rapidly and efficiently.

Featured presentations at the 2014 meeting of the American Society of Clinical Oncology (ASCO) reflected progress in some of these areas, primarily in the NSCLC realm: Trials of novel targeted therapies for advanced lung cancers, including squamous NSCLC; agents designed to overcome resistance to approved targeted therapies; and promising new immunotherapies were among the highlights.

In June 2014, shortly after the ASCO meeting concluded, a study likely to address several unmet needs in the field was launched. While initially testing new targeted treatments and an immunotherapeutic agent in the second-line treatment of patients with squamous NSCLC, the Lung-MAP study is expected to match lung cancer patients more quickly and efficiently with investigational treatments.

Despite recent advances in NSCLC treatment (Figure 1), options for patients with SCLCs remain limited. SCLC, which represents about 15% to 20% of lung cancers and occurs mostly in patients who have a significant smoking history, has the most aggressive clinical course of any type of lung cancer, with a median survival from diagnosis of less than five months.

“Unfortunately,” says Dr. Langer, “in 25 years we have made virtually no progress with regard to small-cell lung cancer. Although it often responds well to treatment initially, small-cell cancer quickly becomes resistant to treatment, and we have not figured out how to tackle it other than with the use of standard chemotherapeutic agents. It’s the chemo-resistant population of cancer cells that determines patient survival.”

Dr. Langer and other experts trace treatment difficulties in part to multiple genetic mutations in small-cell cancers, which are still poorly understood but are due in part to damage caused by smoking. These multiple mutations increase the likelihood that SCLC will become resistant to treatment. New SCLC research efforts have focused primarily on the use of prophylactic cranial irradiation to reduce brain metastases1 and some moderately successful efforts to develop new platinum-based combination treatments. Lung cancer experts are cautiously optimistic that this type of cancer may eventually benefit from advances in molecular research,2 a better understanding of SCLC tumorigenesis,3 and recent innovations in clinical trials.

Developments in Treating Advanced NSCLC

Among the most widely discussed lung cancer presentations at ASCO 2014 was a retrospective analysis of phase 3 trial data for afatinib (Gilotrif, Boehringer Ingelheim), an FDA-approved treatment for patients with activating epidermal growth factor receptor (EGFR) mutations.4 Afatinib is an irreversible tyrosine kinase inhibitor (TKI) of the human epithelial receptor (HER) family, which includes EGFR, and was approved based on data from the LUX Lung 3 study. LUX Lung 3 demonstrated significant response rates and superior progression-free survival (PFS) among patients who received afatanib compared with those who received chemotherapy. The Boehringer Ingelheim analysis of LUX Lung 3 and LUX Lung 6 data presented at ASCO was notable for showing that afatinib significantly improves overall survival (OS) compared with chemotherapy, particularly for patients whose tumors harbor exon 19 deletions. While this survival benefit was encouraging, some experts have questioned whether, in the molecular era, new EGFR TKIs should continue to be compared with chemotherapy.5

Howard West, MD

“The most important question we face when treating patients with advanced lung adenocarcinoma and an activating EGFR mutation is whether a new EGFR TKI provides incremental value over the agent or agents it would replace,” says Howard (Jack) West, MD, Medical Director of the Thoracic Oncology Program at the Swedish Cancer Institute in Seattle, Washington. According to Dr. West, the most relevant comparison in the U.S. today should be between afatinib and erlotinib (Tarceva, Genentech). He points to the LUX Lung 7 trial, which randomized patients to first-line treatment with afatinib or gefitinib (Iressa, AstraZeneca), as the first trial that has attempted a direct comparison.

“The question of whether there is a significant difference between EGFR TKIs will likely be answered when we begin to see the results of the LUX Lung 7 trial,” says Dr. West. “This trial already has been completed, and we should expect to see results in 2015.”

Dr. West points to another study involving an EGFR TKI, presented at ASCO by Kato and colleagues,6 which was noteworthy for establishing the value of adding bevacizumab (Avastin, Genentech) to erlotinib for the first-line treatment of patients with advanced EGFR mutation–positive nonsquamous NSCLC.

“Although this study is still in the early stages and hasn’t yet reported on survival, the difference in PFS is more than six months, and I would say that’s a very clinically significant difference,” says Dr. West.

Presentations of early data from studies of several novel targeted treatments were also featured at ASCO. These included necitumumab (Eli Lilly),7 a human immunoglobulin G1 anti-EGFR monoclonal antibody being tested for the treatment of patients with stage 4 squamous NSCLC; onartuzumab (MetMab),8 a humanized monovalent antibody to the MET receptor, used in conjunction with erlotinib to treat patients with stage 3b or 4 NSCLC; and ramucirumab (Cyramza, Eli Lilly),9 a monoclonal antibody that targets the extracellular domain of VEGFR-2, used with docetaxel in the second-line treatment of patients with stage 4 NSCLC.

Julie Brahmer, MD

Overcoming Resistance to Targeted Treatments

While targeted treatments approved in recent years, including erlotinib and crizotinib (Xalkori, Pfizer), for tumors with anaplastic lymphoma kinase (ALK) protein mutations, have been associated with remarkable response rates, most patients who respond to these treatments will eventually develop resistance to them. Research geared toward identifying and targeting mechanisms of resistance in these patients has begun to yield promising potential treatments.

“At ASCO 2014,” Dr. West says, “among the most important presentations in this area were those that featured novel agents for patients whose tumors harbor the T790 mutation, which is seen in about 60% of patients who develop acquired resistance.”

Two of these, AZD9291 (AstraZeneca) and rociletinib (formerly CO-1686, Clovis), are third-generation TKIs that show activity against T790 in vitro and have earned breakthrough status from the FDA. Phase 3 clinical trials are under way for both drugs.

“In clinical studies conducted to date, there have been response rates in the range of 50% to 60% with these agents, with many of the other patients participating in these trials showing at least minor responses or stable disease,” Dr. West says. “So there are very striking benefits in patients, many of whom are experiencing prolonged responses. We don’t really know yet how prolonged these responses will be, because the studies are still in the early stages. The encouraging results with both of these agents suggest we are in the midst of breaking that impasse of not having anything constructive to offer patients with acquired resistance. And, although in the past there has not been a good answer to the question of whether to do a repeat biopsy, these drugs offer a clear reason to repeat molecular testing.”

Also reported at ASCO were clinical trial results for ceritinib (Zykadia, Novartis), which targets crizotinib-resistant tumors with ALK mutations and received FDA approval earlier this year.10

Immunotherapy: A New Direction

Discouraging early efforts to develop effective immunotherapeutic treatments for lung cancer, with agents such as interferon, interleukin 2, Bascillus Calmett-Guérin, and various cancer vaccines, caused many experts until recently to regard lung cancer tumors as nonimmunogenic.11 However, a deeper investigation of the methods by which lung tumors are able to escape destruction by the immune system has led to the development of a new generation of immunotherapeutic agents called immune checkpoint inhibitors.12,13 This class of drugs comprises monoclonal antibodies that suppress inhibitory signaling in the immune system and allow T cells to recognize and destroy tumor cells.

Preliminary clinical trial results for several new immunotherapies, including nivolumab (Bristol-Myers Squibb) and pembrolizumab (Merck), both of which target the T-cell protein programmed death-1 (PD-1), as well as for combinations of agents in this class, were reported at ASCO. Although these agents act in slightly different ways, patients have generally experienced early and durable responses with them, and they have been shown to have tolerable safety profiles. Bristol-Myers Squibb and Merck are conducting phase 3 trials of these agents. Selected investigational treatments are listed in Table 2.

Lung cancer experts have been particularly impressed by sustained responses among patients who respond to these drugs; many patients who benefit continue to do so for prolonged periods, in some cases even after treatment is discontinued following a single dose. Investigators hypothesize that these responses occur as T cells essentially become memory cells and some resetting of the immune system occurs. Interestingly, these agents have proven to be effective for some patients who are not PD-L1 positive, an unexpected development that suggests uncertainty regarding which patients are most likely to benefit.

“I think some of these inconsistencies can be explained by the variability among all of the tests being used to screen patients for these biomarkers,” says Julie Brahmer, MD, Associate Professor of Oncology and Interim Director of the Thoracic Oncology Program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, who anticipates that approximately 20% of lung cancer patients will be able to benefit from immunotherapies. “We also know that PD-L1 expression can change over time, and that PD-L1 expression can be heterogenous within a tumor. Expression does seem to concentrate where the tumor interacts with the surrounding tissue, so it is possible to biopsy the wrong spot; there are many variables that must be taken into account when you are drawing information from one small tumor sample. It is also possible that we’ll discover other factors that come into play for particular patients, which may affect their responses to these agents.”

Some experts have expressed concern that enthusiasm over the new immunotherapeutic treatments may contribute to a public misperception that these agents lack side effects.

“No drug is without side effects,” says Dr. Brahmer. “While it is refreshing for patients and clinicians that these agents are not associated with those we typically see with chemotherapy, they are associated with other side effects, such as inflammatory reactions that may range from arthritis to thyroiditis. So the use of these drugs will require rethinking, and patient and provider education will play a key role in determining how best to monitor and manage side effects of immunotherapies. It is important to note that if you compare, for example, just grade 3 and 4 side effects of nivolumab with the same grade of side effects for chemotherapies, the rates of these categories of side effects are much lower with nivolumab.”

Testing Treatments Faster: The Lung-MAP Study

The pace and sophistication with which new oncological drivers of lung cancer are currently identified, particularly for adenocarcinoma,14,15 and the speed with which corresponding investigational treatments are subsequently developed, are steadily outgrowing the inflexible machinery of traditional clinical trials. The Lung-MAP study, a model of clinical testing that launched in June 2014, is designed to address this problem by simultaneously testing large numbers of patients for a range of molecular aberrations and efficiently matching these patients with appropriate experimental treatments.

“Traditional clinical trials, which have long been limited by challenges related to start-up time, recruitment, accrual, expense, and the need to identify particular subpopulations of patients, often result in frustratingly slow results,” says Roy Herbst, MD, PhD, Chief of Medical Oncology at the Yale Cancer Center and co-chair of the Lung-MAP study.

Roy Herbst, MD, PhD

“Let’s say a particular mutation is present in approximately 10% of patients with lung cancer. It would be necessary to screen at least 100 patients to find 10 who qualify for a trial, 400 patients to conduct a trial with 40 patients—and that’s assuming that everyone who tests positive is otherwise healthy enough to participate. Screening that many patients for a single trial can require an enormous investment of time and resources, even when multiple sites are involved, and many patients who test negative will be frustrated if they are left without the opportunity to try a new drug. With the master protocol, which follows an umbrella design, many patients are tested at once and subsequently assigned to an appropriate treatment, and no one receives a placebo. Everyone is assigned to a treatment.” (Figure 2)

Dr. Herbst is one of the lead organizers of the Lung-MAP study, which has been made possible by a unique collaboration among government, industry, private foundations, and advocacy groups.16 The first five pharmaceutical companies to enter into this pre-competitive partnership are Amgen, Genentech, Pfizer, AstraZeneca, and AstraZeneca’s global biologics research and development arm, MedImmune.

The trial will initially test five experimental drugs, including an anti–PD-L1 immunotherapy in the second-line treatment of squamous NSCLC. Foundation Medicine will provide next-generation sequencing to identify more than 200 cancer-related genomic alterations. Approximately 500 to 1,000 patients will be screened per year, and patients in each treatment subgroup will be randomly assigned to a targeted treatment or to chemotherapy.

“Patients are currently being enrolled,” says Dr. Herbst, “and each trial is a phase 2/3 trial, so we will await meaningful results in each subgroup to see if we can move forward to phase 3. The phase 2 endpoint, an improvement in PFS of at least twofold, is determined after 56 events. This protocol is not only an efficient mechanism for getting new drugs to lung cancer patients quickly, it will also tell us when to discontinue the investigation of drugs that aren’t going to work.”

Earlier Detection of Lung Cancer

Most experts agree that the single greatest obstacle to significantly improving OS rates for all types of lung cancer lies in the fact that most patients have locally advanced or metastatic disease at the time of diagnosis (Figure 3). Prognosis is strongly tied to the stage of disease at diagnosis, and only about 15% of patients are diagnosed with localized disease.

Although the U.S. Preventive Services Task Force recommends low-dose computed tomography (CT) screening in high-risk patients,17 based largely on findings that such screening reduces mortality by approximately 20% among patients at high risk, several aspects of screening for this disease are a source of controversy.18,19 In the U.S. a fully effective national program of screening for lung cancer remains a major unmet need.20

“Lung cancer is the primary cause of cancer mortality for both men and women in the U.S.,” says Michael Unger, MD, Professor of Medicine at the Sidney Kimmel Medical College of Thomas Jefferson University, who is among a growing number of researchers dedicated to improving screening techniques. “Deaths from this cancer exceed those from colon, breast, and prostate cancers combined—cancers for which we already have established screening programs.” Echoing the sentiments of all clinicians and researchers interviewed for this article, Dr. Unger adds, “The screening and detection of this disease at earlier stages will provide opportunities to reduce overall mortality and, in some patients, potentially cure the disease.”

Research efforts in this realm are focused on addressing the markedly high rates of false-positive results associated with current screening practices.21 A primary aim is to develop noninvasive techniques for detecting biomarkers in biological specimens—such as blood, breath, or sputum—that can assist in resolving the status of indeterminate pulmonary nodules. Detecting lung cancer at its earliest stages, perhaps prior to CT screening, is a longer-term goal. Despite occasional media reports of success in this area,22 most investigational studies still require extensive validation. Furthest along in development are so-called breathalyzer tests,23 which involve the analysis of volatile organic compounds in exhaled air, and blood tests, including one that exploits signals by which the presence of a tumor is communicated to the immune system.24

According to Pierre Massion, MD, Professor of Cancer Research at Vanderbilt University, it is unlikely that any single novel screening method will provide sufficient information on its own. “Currently,” says Dr. Massion, “CT screening is the only modality that has been proven to work. Although imaging will likely become more sophisticated, indeterminate pulmonary nodules and indolent tumors will continue to present challenges. Ultimately it may be necessary to combine methods to develop a successful multidisciplinary model of screening—one that brings the strength of clinical data, or molecular markers, to the time-tested value of imaging data.”

Figures and Tables

Treatment Algorithm for Patients with Non–Small-Cell Lung Cancer (NSCLC)

* Avoid pemetrexed or bevacizumab

Consider second-line EGFR TKI or maintenance erlotinib (BR.21, SATURN)

Docetaxel, pemetrexed, or erlotinib as second-line therapy (based on what has not been previously administered)

Source: Courtesy of Anne Tsao, MD, MD Anderson Cancer Center, Houston; and Howard West, MD, Swedish Cancer Institute, Seattle

The Lung-MAP Study: Squamous Cell Lung Cancer, Second-Line Therapy

CT = chemotherapy (docetaxel or gemcitabine), E = erlotinib; NGS = next-generation sequencing; OS = overall survival; PFS = progression-free survival

After genomic evaluation, patients will be assigned to one of these five substudies, depending on their biomarker status:

  • MEDI4736 (immunotherapy) versus docetaxel—Patients 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 standard chemotherapy (docetaxel).
  • GDC-0032 versus docetaxel—Patients whose tumors test positive for the 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 status in breast cancer.
  • AZD4547 versus docetaxel—Patients whose tumors harbor FGFR1/2/3 alterations will be randomized to receive either AZD4547 or docetaxel. AZD4547 is a tyrosine kinase inhibitor from AstraZeneca.
  • Rilotumumab plus erlotinib versus erlotinib—Patients whose tumors have HGF/c-MET mutations will receive rilotumumab intravenously on day 1 and erlotinib daily, or erlotinib daily. Rilotumumab is a monoclonal antibody from Amgen that inhibits hepatocyte growth factor activity. Erlotinib (Tarceva) is an EGFR inhibitor already approved for the treatment of lung cancer.

Source: Roy Herbst, MD, PhD, Chief of Medical Oncology, Yale Cancer Center; co-chair of the Lung-MAP study

Percent of Lung Cancer Cases by Stage at Diagnosis

Surveillance, Epidemiology, and End Results Program, SEER 18, 2004–2010, all races, both sexes by SEER Summary Stage 2000

FDA-Approved Targeted Treatments for Lung Cancer

Generic (Brand) Manufacturer Mechanism of Action/Indication 30-Day Cost*
Erlotinib (Tarceva) Roche Metastatic NSCLC tumors with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations $7,454
Bevacizumab (Avastin) Genentech Vascular endothelial growth factor-specific inhibitor of angiogenesis for unresectable, locally advanced, recurrent, or metastatic nonsquamous NSCLC (with carboplatin and paclitaxel) $12,090
Gefitinib (Iressa) AstraZeneca Selective inhibitor of EGFR tyrosine kinase domain for locally advanced or metastatic NSCLC $2,042
Afatinib (Gilotrif) Boehringer Ingelheim Tyrosine kinase inhibitor for metastatic NSCLC tumors with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations $7,193
Certinib (Zykadia) Novartis Kinase inhibitor for patients with ALK-positive metastatic NSCLC tumors who have progressed on or are intolerant to crizotinib $16,197
Crizotinib (Xalkori) Pfizer Kinase inhibitor for ALK-positive metastatic NSCLC tumors $14,383

ALK = anaplastic lymphoma kinase; EGFR = epidermal growth factor receptor; NSCLC = non–small-cell lung cancer

*Based on average wholesale prices from Red Book and regimens in prescribing information for each medication

Based on intravenous administration of 15 mg/kg to an 85-kg patient every 21 days, extrapolated to a 30-day cost of bevacizumab alone

Investigational Lung Cancer Drugs

Agent Manufacturer Mechanism of Action/Indication Stage of Development
Nivolumab Bristol-Myers Squibb Anti-PD-1; MAb Phase 3
Pembrolizumab Merck Anti-PD-1 checkpoint inhibitor; MAb Phase 3
AZD9291 AstraZeneca EGFR mutation-positive acquired resistance Phase 2
Rociletinib Clovis Oncology EGFR mutation-positive acquired resistance Phase 2/3
Selumetinib AstraZeneca KRAS mutation-positive NSCLC Phase 3
MEDI4736 Medimmune Anti-PD-L1 immune checkpoint inhibitor; MAb Phase 1/2
MPDL3280A Roche/Genentech Anti-PD-L1 immune checkpoint inhibitor; MAb Phase 3
Nintedanib Boehringer Ingelheim VEGFR2 inhibitor Phase 3
Ganetespib Synta HSP90 inhibitor Phase 3
Veliparib AbbVie PARP inhibitor Phase 3
Bavituximab Pelegrine Phosphatidylserine inhibitor; MAb Phase 3
Necitumumab Lilly EGFR; MAb Phase 3 (completed)
Ramucirumab Lilly VEGFR; MAb Phase 3 (completed)

EGFR = epidermal growth factor receptor; HSP = heat shock protein; MAb = monoclonal antibody; NSCLC = non–small-cell lung cancer; PARP = poly ADP ribose polymerase; PD-1 = programmed death-1; PD-L1 = programmed death ligand-1; VEGFR = vascular endothelial growth factor receptor

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