For Laura Q.M. Chow, MD, medical oncologist at Seattle Cancer Care Alliance and professor of medicine in the division of medical oncology at the University of Washington, there is still much to be done to improve the quality of life and survival of patients with lung cancer until it is eradicated — starting with identification of better biomarkers to personalize therapy and development of novel therapies to improve response and survival in clinical trials. Healio recently spoke with Chow about what may be in store for lung cancer treatment and the research surrounding it. As a professor at the University of Washington treating patients with thoracic and head and neck malignancies, associate director of the phase 1 clinical trials program at the Seattle Cancer Care Alliance in Washington, and associate member of the Fred Hutchinson Cancer Research Center, Chow has dedicated her career to trying to develop better lung cancer treatments.
Laura Q.M. Chow, MD
Early in my career, we had to decide if patients with advanced/metastatic cancer would even benefit from chemotherapy, and there was a lack of differentiation in terms of which chemotherapy would be most effective for patients. During my oncology training, trials supporting adjuvant chemotherapy for post-surgery patients with earlier stages of disease became the standard of care. With subsequent trials, the idea of personalizing chemotherapy based on histology in the advanced setting changed how we administered palliative chemotherapy. Subsequently, in predominantly nonsmoking patients with nonsquamous histology, we discovered molecular driver mutations that predicted high responses and improved survival to “targeted” therapy. The presence of a single targetable ‘driver’ gene mutation driving the growth of the cancer greatly impacted the discovery of targeted tyrosine kinase inhibitors, including those for the more common epidermal growth factor receptor, EGFR, ALK, and ROS1 gene re-arrangements; for the rarer BRAF, cMET and RET gene mutations; and for the newer mutations such as NTRK mutations. Although these driver mutations are not common and more frequently observed in non-smokers, small-molecule oral molecular targeted therapies inhibiting these driver mutations and subsequent cancer growth have been highly efficacious with high response rates and improvements in survival. These therapies are generally oral and reasonably well-tolerated, allowing patients a good quality of life while on therapy. Many of these drugs also demonstrate activity in the central nervous system with the ability to target metastases in the brain. Better targeted therapies are being developed and are evolving with time. Subsequent generations of drugs demonstrate enhanced potency, broader activity, and often are developed to cover resistance mutations to restore response when resistance occurs. These newer targeted therapies under development have the potential to prolong life substantially with reasonably low toxicity.
Another way to treat patients with advanced metastatic lung cancer is with immunotherapy and PD-1 immune checkpoint inhibitors(ICIs) – a promising breakthrough in treating patients with non-small cell lung cancer. The PD-1 ICIs were the first immunotherapeutic agents that provided durable tumor regressions and improvements in survival for patients with advanced lung cancer, and we were impressed by the tolerability that allowed long-term administration. However, despite the initial excitement, there has been a plateau, as we realized that single-agent PD-1 ICIs were not the be-all, end-all. The number of patients going into complete remission is extremely low, response rates are also still low and patients who previously responded to therapy do become resistant and can progress. The focus now is to find effective combination therapies that will increase the depth and duration of response, increase the incidence of complete remission and improve survival. By finding better therapies in the advanced/metastatic setting, I believe we can move these into earlier lines of therapy and earlier settings to improve the chance of cure. There has been a substantial evolution in how we treat patients with lung cancer and more personalization in terms of enriching and predicting responders to effective therapies such as targeted therapy or immunotherapy. Compared with 15 years ago when we only had cisplatin-based chemotherapy, it is refreshing to be able to offer something more to patients.
The standard of care is evolving rapidly. The KEYNOTE-189 phase III study evaluated an immunotherapy-chemotherapy triplet combination of pemetrexed, platinum and the PD-1 ICI pembrolizumab (Keytruda, Merck) for first-line therapy for patients with advanced metastatic NSCLC with nonsquamous histology.1 Results of this randomized phase 3 trial demonstrated improvements in response and overall survival with the triplet combination across all patient groups, regardless of PD-L1 expression class, compared with chemotherapy alone. This approach has been established as the new standard of care for these patients. For patients with squamous histology, the randomized phase III KEYNOTE-407 trial demonstrated that platinum-based doublet chemotherapy plus pembrolizumab improved responses, progression-free survival and overall survival benefits compared with doublet chemotherapy alone across all PD-L1 expression categories and will likely change the standard of care for these patients.2 However, it is unclear whether patients with high PD-L1 expression (tumor proportion score ≥ 50%) should consider triplet therapy or pembrolizumab alone based off results of the phase III randomized KEYNOTE-024 trials that showed an improvement in survival for pembrolizumab versus platinum-based chemotherapy doublets in this cohort of patients.3 Clearly, individualized decisions based on patient characteristics, performance status and preferences are needed for these patients. Recent phase III trial updates have demonstrated that the combination of ipilimumab Yervoy, Bristol-Myers Squibb) and nivolumab (Opdivo, Bristol-Myers Squibb) may demonstrate benefits with improvements in progression-free survival over that of platinum-based chemotherapy in the front-line setting in patients with high tumor mutational burden.4 The results of the phase III IMpower150 study,5 demonstrated that the combination of atezolizumab (Tecentriq, Genentech), paclitaxel, carboplatin and bevacizumab (Avastin, Genentech) improved survival in patients with advanced nonsquamous NSCLC compared with bevacizumab and chemotherapy. These studies will also impact our first-line decisions when these options are FDA approved. Undoubtedly, the standard of care and the options for first-line therapy have expanded for patients, and carefully choosing the options based on biomarkers, patient characteristics and toxicity will be key to successfully improving outcomes and survival for patients with lung cancer.
The largest population now and for the future will be those patients with lung cancer who are refractory and fail to respond to PD-1 therapy or those that stabilize or respond to treatment and then subsequently progress. We do not know which mechanisms are best to target to increase the chance for response or which mechanisms lead to resistance and progression in an individual. Tumor and tissue biopsies at progression are key to better assess which pathways are likely relevant in patients who do not respond to PD-1 therapies or combinations. Unfortunately, it is not always easy to obtain adequate samples or safely obtain biopsies from patients with lung cancer to study these mechanisms of resistance. The other issue is that many pharmaceutical companies are creating such large complicated trials with multiple combinations and many novel agents being developed that deployment is challenging for most centers. Another issue is the sheer number of novel agents being combined with a PD-1 ICI and the multitude of clinical trials – now several hundred – for lung cancer. There is substantial competition for patient enrollment, and, because of the speed of development, there is often less preclinical rationale as to why agents should be combined. We need to further study why patients do not respond to treatments to better develop new treatments for them, and we need to develop biomarkers to predict for response in order to enrich for responders in future trials. The key to successful trials will be by better assessing in the laboratory the rationale for combining a novel agent with a PD-1 ICI and developing well-designed early phase clinical trials with correlatives in the laboratory assessing the mechanisms of response and progression. Furthermore, we need to present and publish negative results in addition to positive results so that we can determine why therapies are ineffective and avoid duplicating efforts.
Rather focusing on finding treatments for patients with advanced lung cancer who do not respond at all to immunotherapy, most researchers are studying the population of patients who initially have stable disease or respond to PD-1 treatment and then progress. These resistant patients are felt to be more likely to respond to combination approaches to restore or re-incite response than those who are upfront refractory to PD-1 therapy. If we can find successful agents or combinations that restore response, then there is promise and activity in moving these agents in clinical trials to earlier lines of therapy and earlier treatment settings to improve remissions and cure rates. A one-size-fits-all approach may not be possible, and we may need to better consider tissue biopsies and sampling of blood or even microbiome stool assessment to enrich for patients responding to immunotherapy in clinical trials. Similarly, at progression, biopsies and tissue samples may also yield information regarding mechanisms of resistance that can lead to personalization of therapy. For example, a patient who is progressing and has high upregulation of LAG-3 exhaustion markers and pathway may be more likely to respond to therapy with an agent affecting LAG-3. Hopefully, with the evolution of more understanding of the mechanisms of response and resistance, we will be able to find better therapies and more successful combinations leading to later-phase trials that will change the standard of care to improve the survival and ultimately cure patients with lung cancer.
Biomarker development was significant in this setting because it allowed us to move second-line therapy into the front-line therapy for advanced NSCLC patients. Identifying biomarkers will likely help us select patients in earlier curative settings who may respond better and potentially enhance cure rates. The use of biomarkers will be significant when we investigate combination treatments which may have increased toxicity, including three or four drug regimens, to minimize toxicity to those who may not benefit.
I would like to see the evolution of targeted therapy and immunotherapy for our patients and additional options for patients, in addition to chemotherapy. I suspect we will see trials of novel agents in less well-studied populations such as those with coexisting organ dysfunction, autoimmune disease, poor performance status and the elderly. Moreover, we will see better biomarker development and the advent of more personalized therapy for patients. We will continue to see tremendous development in both areas of targeted therapy with the discovery of novel targets and drugs and also in the arena of combination immunotherapy. Hopefully we will see the T-cell therapies and other immunotherapies gain in their effectiveness to improve responses and survival. Regardless, this is an exciting time and we are seeing glimpses for the first time of a future where advanced/metastatic NSCLC patients may see long term survival and cure as a reality.
Edward S. Kim, MD
Stress hormones and current research in EGFR TKIs
Karen L. Reckamp, MD, MS
The field of lung cancer has evolved significantly over the past 10 years.
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