Innovations in cancer treatments start with discoveries in the laboratory – which is where Fox Chase Cancer Center has made powerful inroads for more than 100 years to advance care for patients in the local community and throughout the world.
Through innovative applications of our understanding of cancer cell genetics, physicians and scientists are learning more about how to reach and destroy cancer where previously it was difficult or impossible to do so without damaging healthy tissue. In the past few years, that approach has started to transform the understanding of the difficult riddle of lung cancer – particularly non-small cell lung cancer (NSCLC), which comprises up to 90 percent of all cases.
Committed to solving that riddle at Fox Chase are Dr. Hossein Borghaei, Chief of Thoracic Medical Oncology and the Gloria and Edmund M. Dunn Chair in Thoracic Oncology, and Dr. Julia Judd, Assistant Professor in the Department of Hematology/Oncology, who specializes in Thoracic Medical Oncology.
“The data in the U.S. suggests that maybe about 30 percent and perhaps more of NSCLC patients in the U.S. could have an actionable mutation also called a biomarker such as EGFR,” says Dr. Borghaei, referring to a common driver of NSCLC. Treating that EGFR mutation, as well as other shifts in the way NSCLC is understood on a genetic level, have led to studies with pronounced results, upending long-established survival rates for what is currently the nation’s leading cause of cancer death.
As a result, the use of immunotherapy or targeted therapy has rapidly become a critical part of lung cancer care, enabling physicians to shrink the cancer, contain its spread, and occasionally make it possible to remove the cancer surgically without pursuing treatment routes that may be physically harder on the patient. As Drs. Borghaei and Judd continue to unlock these structures, they’re providing new hope to those for whom a diagnosis of lung cancer may have previously left them with little.
The revolution in NSCLC treatment can be traced to a deeper understanding of the disease at the molecular level. The new science of genetic testing, when applied to NSCLC, has uncovered mutations that drive cancer growth. Critically, this includes the commonly occurring EGFR mutations, which drive cancer growth by signaling to cells to continue multiplying.
Targeted therapies can tackle the EGFR mutations without significantly affecting surrounding tissue, in contrast with traditional treatments such as radiation and chemotherapy. Known as EGFR inhibitors, they block the mutation’s signal to slow or halt cancer progression. These include therapies such as osimertinib, which “when given for up to about three years clearly showed a survival advantage in keeping the disease away when given after surgical resection,” Dr. Borghaei says.
Immunotherapies have similarly revolutionized NSCLC treatment by harnessing the body’s own defenses. NSCLC tumors often evade the immune system by exploiting a protein, known as PD-L1, that regulates the body’s immune response. Drugs like pembrolizumab, durvalumab and nivolumab block these checkpoints, allowing the immune system to recognize and attack tumor cells — demonstrated in a large study led by Dr. Borghaei that showed nivolumab improved long-term outcomes for patients with advanced NSCLC.
“The immunotherapy works by taking the brakes off the immune system and creating an immune response against the cancer,” Dr. Judd says. Immunotherapy also enables T-cells to better identify and attack even those cancer cells that have spread to distant areas, significantly reducing the risk of recurrence and improving long-term outcomes.
Because the positive effects of these therapies occur over time, they’re often thought of as a treatment used to prevent recurrence. In NSCLC, they were initially applied primarily to combat metastatic cancer. But surprisingly, early-stage treatment with immunotherapy and targeted therapies has proved particularly effective for NSCLC.
“We learned from advances in metastatic settings that immunotherapy is effective,” Dr. Judd says, explaining that once they saw results in managing late-stage cancer, they began to pursue trials in treating early-stage disease and were surprised by how effective the treatments were.
“We’re seeing immunotherapy create lasting immune responses, particularly when used in early-stage disease,” Dr. Borghaei says. Why would a drug be as effective, or even more effective, in an early stage versus a late stage? According to Dr. Borghaei, one reason may be that by the time a tumor becomes metastatic in stage IV, it has acquired additional mutations that make it more resistant to treatment than in early stages.
In addition, a critical challenge in treating NSCLC is its tendency to spread early through micro-metastatic sites — small, undetectable clusters of cancer cells that are not visible through imaging. Even after successful surgery, these clusters can grow and lead to recurrence, making them a significant target in NSCLC treatment. Immunotherapy offers a powerful solution, as it activates the body’s immune system to work systemically, hunting down and destroying cancer cells beyond the primary tumor.
“The neoadjuvant approach stimulates the immune system not just to attack the tumor, but also to address any potential micro-metastatic disease,” Dr. Borghaei says. It’s possible that the earlier the patient receives the immunotherapy, the greater the impact on these micro-metastatic sites.
Now, targeted therapies and immunotherapies are increasingly used before and after surgery to improve outcomes, and the results are changing NSCLC treatment from beginning to end. (Note: Targeted therapy is not FDA-approved before surgery, only after.) For example, neoadjuvant chemotherapy combined with immunotherapy has shown promise in shrinking tumors, making surgery less invasive.
“Patients with fairly advanced disease, like stage III, could benefit from chemo-immunotherapy. In fact, the benefit in that group might be even higher,” Dr. Borghaei says. “We are seeing some cases where surgery can be minimized to just a lobectomy.” For example, what previously would have required a pneumonectomy (removal of an entire lung) could now be treated with a lobectomy, preserving greater lung function.
In other cases, these therapies can be used in place of chemotherapy – meaning they’re improving quality of life, with immunotherapy often causing fewer side effects than traditional chemotherapy. “The toxicity profile of immunotherapy is more manageable than chemotherapy,” Dr. Judd says. “Moreover, the toxicity profile of neoadjuvant chemo-immunotherapy is manageable for most patients. The addition of immunotherapy did not significantly increase the incidence or severity of side effects beyond the addition of immune-related toxicities, as expected from prior experience with immunotherapy.”
Perhaps even more important is that the impact of immunotherapy and targeted therapies on the success of NSCLC treatment has been profound. For the first time, physicians are seeing significant improvements in survival rates, particularly in early-stage disease. Multiple large, randomized trials have shown that combining chemotherapy and immunotherapy before surgery led to higher complete pathological response rates — meaning no viable tumor cells remained at surgery — compared with chemotherapy alone.
“In one study, a 22 percent improvement over chemotherapy alone was reported, which is clinically meaningful because patients who are found to have a pathologic complete response to treatment at the time of surgery are much more likely to be cured of their NSCLC,” Dr. Judd says.
Additionally, treatments like osimertinib have revolutionized care for patients with EGFR mutations, offering hope for long-term survival. “Osimertinib was clearly shown to extend survival in the ADAURA trial,” Dr. Borghaei says, with Dr. Judd adding: “It showed a 50 percent reduction in the risk of death at five years. That’s huge.”
The recency of these discoveries means the field of NSCLC treatment is still evolving. Researchers are focused on discovering further biomarkers or refining biomarkers like PD-L1, which both Drs. Borghaei and Judd describe as imperfect because of the difficulties in correctly determining its presence in the tumor.
Ongoing research is also exploring the further use of combination therapies to have success without the presence of PD-L1. Even patients with low levels of the protein present in their tumor can respond well to immunotherapy. “We know that when chemotherapy is combined with a checkpoint inhibitor, it is active even in PD-L1-negative tumors,” Dr. Judd says.
As the understanding of NSCLC’s molecular landscape deepens, the future promises even more personalized treatments tailored to each patient’s tumor biology. The revolution in lung cancer care is still unfolding, offering new hope.
“It’s rapidly evolving,” Dr. Judd says. “This was a very, very busy year in the world of lung cancer knowledge and therapy.”
Fox Chase is home to some of the nation’s top lung cancer specialists, with a robust research program and cutting-edge clinical trials that are not easily accessible elsewhere. As the science is accelerating to detect and effectively treat lung cancer, new techniques are becoming available that are likely not only to prolong life, but also to maintain quality of life.
That is the ultimate goal of the studies by clinicians and researchers like Drs. Borghaei and Judd – and a key benefit of Fox Chase’s elite standing as an NCI-designated Comprehensive Cancer Center, currently one of only 51 in the nation. These extraordinarily talented physicians thrive in an environment that is ideal for making fundamentally important discoveries.
With its long history of breakthrough research, Fox Chase continues to lead the field with seminal scientific discoveries that have key translational implications. The insights gleaned from these laboratory studies can be directly applied to patient care while safely evaluating new approaches to preventing and treating cancer through clinical trials, which may eventually drive standard protocols with far-reaching implications.
Through support from its partnership with Temple Health’s oncology research, treatment and prevention programs, Fox Chase Cancer Center makes a world of difference in Northeast Philadelphia and all other communities it serves.
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