Lung Cancer: Advances in Current Treatment Modalities and Patient Classification

Overview

Like other cancers of the internal organs not often diagnosed until late stages of disease, lung cancer is among the deadliest. In the U.S., the 5-year survival rate after diagnosis is lower than 15%. Lung cancer is also among the most common cancers, in part because of the continued prevalence of tobacco smoking. The American Cancer Association estimates that in 2014, 224 210 people will be newly diagnosed with lung cancer and 159 260 deaths will be associated with the disease. On March 25, 2014, the Biochemical Pharmacology Discussion Group convened physicians and scientists for the Lung Cancer: Advances in Current Treatment Modalities and Patient Classification symposium, to discuss advances in treatment as well as new information about genetic heterogeneity that may inform future trials. Despite poor outcomes for current treatments, the speakers were optimistic that therapeutic innovations will gradually improve prognoses for this seemingly intractable disease.

From refinements in surgical techniques to drugs targeting specific oncoproteins, the range of precision therapeutic tools to combat lung cancer is growing. Several speakers cautioned, however, that technological innovation alone will not dramatically transform lung cancer treatment. Rather, physicians must tailor treatments for each patient and deploy tools discriminately, biopsying and sequencing each tumor, for example, and choosing the most appropriate drugs among many. Roy Herbst and Balazs Halmos both related adaptive treatments that resulted in several rounds of remission in patients. However, successes like these have been achieved in large medical centers where clinicians had access to drug trials. Adapting protocols for personalized medicine in a wide range of clinical settings remains challenging.

In his introduction to the symposium, Shashidhar S. Jatiani of the Forest Research Institute reviewed the sub-classification of lung cancer into small cell and non-small cell types. The former is a grim diagnosis: patients almost always present with advanced disease because metastasis occurs early. Chemotherapy is the standard treatment. More common, however, is a diagnosis of non-small cell lung cancer (NSCLC), which accounts for approximately 85% of new cases. The speakers focused on the treatment of NSCLCs, which usually arise in the epithelium of the branched lung, most commonly as an adenocarcinoma.

When NSCLC is identified as a pre-metastatic tumor, the most effective treatment is surgery. Jessica S. Donington of NYU Langone Medical Center explained that a balance must be achieved between complete removal of cancerous cells and preservation of lung function. The standard of care is removal of the lobe containing the tumor, one of five lobes in the lungs. A complete lobectomy is an invasive procedure, requiring the surgeon to break several ribs to access the thoracic cavity. The average age of patients at diagnosis is 70 years old, and many patients require substantial care to recover from such a surgery. But it has become possible to perform more precise surgery: rather than remove the lobe entirely, many surgeons now resect a minimal amount of tissue, directed by the branched morphology of the lung, in a procedure called a segmentectomy. In addition, the use of laparoscopic cameras in a technique known as video-assisted thoracic surgery (VATS) now limits the size of the incision to the circumference of the tumor itself. An increasing number of hospitals now support robot-assisted surgery using the da Vinci Surgical System, which can also be used to achieve less-invasive segmentectomies. Both techniques decreased morbidity and mortality when compared to open thoracic surgery. Although purchasing and maintaining a da Vinci system is a substantial investment, significantly less money is required for postoperative intensive care and respiratory therapy when VATS and robot-assisted surgery are used compared to open surgery.

New technologies in the operating room, such as the robotic da Vinci Surgical System pictured above, allow surgeons to remove malignant tissue more precisely. Laparoscopic and robot-assisted surgeries yield faster patient recoveries and fewer post-operative expenses. (Image courtesy of Jessica S. Donington)

Inoperable tumors that arise close to the main airways, or in patients too frail to undergo surgery, are treated with radiation therapy. In an adaptation of a radiotherapy technique originally applied to brain tumors, lung tumors are now targeted more precisely and with higher doses of radiation using hypo-fractionated stereotactic body radiation therapy (SBRT). In the Netherlands, where practitioners have aggressively phased out older modes of radiation therapy in favor of SBRT, a greater than 36% increase in 8-month survival has been observed concurrent with the change.

Underlying the success of VATS, robot-assisted surgery, and SBRT is the theme that "less is more," Donington said. Less healthy tissue is destroyed, less time and resources are required for patient recovery, and patients are ideally better prepared to undergo adjuvant therapy.

When the primary tumor has metastasized, as in more advanced cases, chemotherapy is often prescribed in addition to surgical or radiological interventions. Unfortunately, in most patients traditional chemotherapy regimens afford delayed progression at best and are rarely curative. No progress has been achieved in developing more potent chemotherapies or combinations of cytotoxic drugs for lung cancer in over ten years. In response, many physician-scientists, including symposium speakers Roy S. Herbst, Balazs Halmos, and Suresh S. Ramalingam, have begun studying the efficacy of new drugs targeting specific oncogenic pathways. Through whole exome sequencing of lung tumors, a portrait of the most common genetic aberrations has emerged. Mutations in KRAS have been known to occur in lung adenocarcinomas for at least ten years, and comprehensive sequencing efforts have additionally implicated oncogenes, including the receptor tyrosine kinases EGFR, MET, RET, NTRK1, ROS1, and HER2; the serine threonine kinase BRAF; and the atypical receptor tyrosine kinase ALK. In fact, only 37% of examined lung adenocarcinomas do not harbor mutations in any of these genes.

Molecular testing of biopsied lung tumors is necessary to match patients with the best therapeutic options. Through clinical trials and collaborative sequencing efforts, a comprehensive list of the mutations that drive lung cancer is emerging. As shown above in data reported by the Lung Cancer Mutation Consortium, these mutations are frequently in oncogenes, particularly receptor tyrosine kinases. (Image courtesy of Suresh S. Ramalingam)

Providing some historical perspective, Roy S. Herbst of Yale School of Medicine told participants that the first-generation receptor tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib entered the clinic in 1997, delivering modest response rates of less than 10%. Ten years later, with the emergence of deeper tumor exome sequencing, it became clear that responders were much more likely to harbor specific EGFR mutations, such as deletion of exons 19 or 21, which encode parts of the catalytic domain. Tumors with EGFR exon 19 deletion, in particular, exhibit susceptibility to erlotinib, which functions as a competitive inhibitor at the ATP binding site. Balazs Halmos of Columbia University Medical Center observed that based on the specificity of the TKIs, the conscientious clinician will need to become something of a "mutation aficionado," to be able to match the most efficacious TKI to each patient. At present, such choices are largely confined to clinical trials because erlotinib, gefitinib, imatinib, and afatinib are the only TKIs approved for lung cancer. Physician training will be needed as more of these drugs achieve FDA approval. To illustrate the complexity of genetics-based drug choice, Herbst mentioned the BATTLE-2 clinical trial, which he oversees. It compares several TKIs and employs a full-time statistician to conduct a Bayesian learning method to help oncologists to make the best drug/tumor match.

Receptor tyrosine kinase (RTK) inhibitors may target the mutated pathways that manifest in many lung adenocarcinomas, but a considerable proportion of tumors do not exhibit obvious mutations. From a therapeutic perspective, therefore, drugs must be developed to target more general molecular pathways that are active in tumor cells. Suresh S. Ramalingam of Emory University reviewed one such strategy, which targets the heat-shock protein HSP90. Heat-shock proteins bind and stabilize client proteins, including oncoproteins, thus preventing their degradation through the proteasome. Drugs that inhibit HSPs, such as the second-generation HSP90 inhibitor ganetespib, should theoretically facilitate the indirect degradation of oncoproteins. Moreover, such drugs will only target cancer cells, because HSP90 remains at very low levels in healthy tissue. Ramalingam outlined an active phase III study of ganetespib, the GALAXY-2 trial.

The TKIs are indeed revolutionary tools in the field of molecular oncology, but frustratingly, these novel agents only delay disease progression and do not increase survival rates among lung cancer patients. Selective pressures in the tumor microenvironment favor either cells that acquire subsequent mutations or the activation of downstream effectors that thwart the loss of the RTK. As Halmos explained, these mutations often occur in the RTKs themselves. In the case of epidermal growth factor receptor (EGFR), insertions into exon 20, or a threonine to methionine substitution in a part of the protein encoded by exon 20, render the mutant receptor resistant to TKIs. The speakers speculated that combinations of drugs targeting several oncoproteins may circumvent the problem of tumor resistance, but available agents are limited and there are no obvious putative combination therapies.

Rolf Brekken of UT Southwestern Medical Center outlined the rationale for using immunotherapy to combat lung cancer. A hallmark of tumor cells is their evasion of immune detection, achieved in part by the presentation of phosphatidylserine (PS) in the outer cell membrane. In healthy cells, this phospholipid is confined to the inner leaflet of the cell membrane. When PS becomes externalized, as in normal apoptosis, PS receptors in macrophages that detect the dying cell trigger the release of immunosuppressive cytokines. Brekken hypothesized that if this process can be inhibited, an adaptive immune response might ensue. The monoclonal antibody bavituximab, developed by Peregrine Pharmaceuticals, targets glycoprotein-bound PS. Preclinical data using bavituximab to combat a rodent tumor model is encouraging, with tumors completely regressing in some rats. Brekken's lab has observed several lines of evidence suggesting that an innate immune response occurred in bavituximab-treated rats, leading to the development of anti-tumor T cells. As several speakers noted, the best test of this therapy would be to reintroduce tumor cells to the rats and observe whether the cells are targeted and destroyed by an immune response. Such a result would be astonishing. Indeed, the potential of immunotherapy in cancer treatment has recently received considerable attention from the popular media. Several antibodies have entered clinical trials, including bavituximab, which is in a phase III NSCLC trial called SUNRISE.

From new developments in surgery and radiation therapy to a rapidly expanding collection of drugs in the field of molecular oncology, we are poised to improve the prognosis for many lung cancer patients. Key to success will be a continued emphasis on personalized medicine, augmenting the standard diagnostic regimen to include molecular testing to match each patient with a targeted therapeutic approach.

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Presentations available from:
Rolf Brekken, PhD (UT Southwestern Medical Center)
Jessica S. Donington, MD (NYU Langone Medical Center)
Balazs Halmos, MD (Columbia University Medical Center)
Roy S. Herbst, MD, PhD (Yale School of Medicine)
Shashidhar S. Jatiani, PhD (Forest Research Institute)
Suresh S. Ramalingam, MD (Emory University)

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