The Peaks and Valleys in Lung Cancer Therapeutics Research

Paul Bunn
Dr. Paul A. Bunn Jr.

By Paul A. Bunn Jr., MD
Posted: May 27, 2019

It is indeed an exciting time in lung cancer therapeutics, and we have reasons to be optimistic. To put these advances in context, I remember the early days (1970s) of lung cancer research at the National Cancer Institute, when we conducted 12 consecutive phase II trials without a single response. The chemotherapeutic survival improvements were not documented until the 1980s. With as much improvement as we have seen, we still must put this recent excitement in the context of both our goals and those of our patients. The ultimate goal is to cure patients with as little toxicity as possible. Improving survival and lessening toxicity are valuable goals, but they are not the end goal. So where does that put us regarding success of molecular and immunotherapies?

Molecular Therapies
There is no question that patients with advanced NSCLC should undergo next-generation sequencing (NGS) panel testing for driver alterations that include at least EGFR, ALK, ROS1, BRAF, and TRK and that additional alterations may be actionable in the near future, including RET fusions, MET mutations, and HER2 mutations. Testing for KRAS mutations, the most common mutation, is not useful at present, but it may be in the future.

What is the long-term outcome of patients with NSCLC with driver alterations who are treated with the appropriate TKIs? It is clear from the early Lung Cancer Mutation Consortium study and many phase II trials that objective response rates exceed 50%, progression-free survival may be as long as 3 years, and overall median survival may exceed 6 years for patients with some alterations, such as ALK.1,2 Th is is unprecedented. In addition, patients may be spared the horrors of central nervous system and leptomeningeal metastases. This is marked progress indeed.

Despite much progress, these patients still are not cured, rarely have complete remissions, and virtually always experience relapse. Therefore, we must urgently understand the biology of disease persistence and the mechanisms of resistance, and we must develop rational drug combinations. We must understand the nature of the drivers in the other 75% of lung cancers. What about patients with early-stage disease? Could these therapies be added to standard surgery, radiation therapy, and chemotherapy to improve cure rates? The answers are unknown, but we eagerly await the results of ongoing adjuvant and neoadjuvant studies.

There is no question that checkpoint inhibitors have had a profound effect on outcomes for patients with lung cancer of any histology who lack driver genetic alterations. Long-term survivors are emerging. Nonetheless, only a minority of patients have disease that responds, predictive biomarkers are not fully defined, and cure remains elusive. On the positive side, assessment of PD-L1 expression is useful, at least in NSCLC histologies. Thus, all patients with advanced NSCLC should have PD-L1 testing prior to initiation of therapy. Fortunately, this immunohistochemistry testing requires only two unstained slides.

Patients with either squamous or non-squamous histology whose tumors express PD-L1 on more than 50% of cells have improved survival with single-agent pembrolizumab compared to platinumbased chemotherapy (KEYNOTE-042 and KEYNOTE-024).3,4 This, too, is unprecedented. Never before has any therapy supplanted our standard platinum-based chemotherapy in advanced NSCLC. Despite the fact that a minority of patients have disease that responds, 2- and 3-year survival rates are quite impressive. Other studies have compared chemotherapy alone to chemotherapy plus checkpoint inhibitors in patients whose tumors have greater than 50% PD-L1 expression, and the combinations with immunotherapy have proven superior (KEYNOTE-189, KEYNOTE-407, IMpower131, and IMpower150) with respect to overall survival.5-9 Unfortunately, there are no randomized trials directly comparing checkpoint inhibitors alone to chemotherapy plus checkpoint inhibitors. Although cross-trial comparisons are fraught with issues, the objective response rates and toxicity rates are higher with the combination, whereas long-term survival rates seem somewhat comparable. Thus, at present, it may be reasonable to treat the majority of patients whose tumors have greater than 50% PD-L1 expression and who have slowly progressive and non–life threatening cancers with immunotherapy alone, and reserve the combination for those patients who are highly symptomatic and who require an immediate response.

For patients with either squamous (KEYNOTE-407 and IMpower131) or non-squamous histology (KEYNOTE-021 Cohort G,9 KEYNOTE-189, and IMpower150) and whose tumor cells express PD-L1 on less than 50% of cells, the combination of chemotherapy plus a checkpoint inhibitor (pembrolizumab or atezolizumab) has been shown to be superior to chemotherapy alone. This means that the majority of patients with advanced NSCLC (those without a driver genetic alteration) will receive either a checkpoint inhibitor alone or a checkpoint inhibitor with chemotherapy, depending on PD-L1 expression levels.

Although checkpoint inhibitors have clearly improved survival for many patients with NSCLC, they are not without expense and toxicity, they rarely produce complete responses, and they are unlikely to cure a large fraction of patients. Toxicities are common, may occur at any time during therapy, require discontinuation of treatment in as many as 10% of patients, and are more frequent when combined with chemotherapy.

On the Horizon
Other potential predictive biomarkers such as tumor mutation burden from tissue or blood, gene expression profiles, and protein profiles are experimental and are under investigation.

With the goal of increasing the cure rate, there is evidence that administering a checkpoint inhibitor (durvalumab; PACIFIC trial)10 after chemotherapy and radiation therapy will improve survival in patients with unresectable stage III NSCLC. We still await 5-year survival rates from this and other trials in stage III disease. For surgically resectable disease, there are preliminary data that the addition of either neoadjuvant or adjuvant checkpoint inhibitors to surgery with or without chemotherapy may improve survival. These studies suggest that the neoadjuvant use of checkpoint inhibitors alone or with chemotherapy prior to surgical resection produce much higher pathologic complete response rates compared to chemotherapy alone. The results of ongoing randomized trials are eagerly awaited.

There are far fewer trials of immunotherapy in SCLC, and there are no established biomarkers for immunotherapy in this histology. Nevertheless, one published trial (IMpower133)11 demonstrated that the addition of atezolizumab to etoposide/ platinum-based chemotherapy in the first-line setting improved survival compared to chemotherapy alone. Although there have been some negative randomized trials in the second-line and maintenance settings, other first-line trials in extensive-stage disease, as well as combination trials in limited-stage disease, are ongoing.

In summary, we are only beginning to scratch the surface with immunotherapy. The available immunotherapies have improved survival in advanced disease, albeit with considerable expense and toxicity and with marginally effective predictive biomarkers. There is much to learn about the immune system and cancer therapy, and many new approaches are under investigation, including new immunotherapies, T-cell and vaccine therapies, and molecular targeted therapies for KRAS, HER2, RET and MET. Thus, in 2019, there are new, improved therapies for all lung cancer histologies, and biomarkers are required for all patients with advanced-stage disease before initiating therapy. Progress is definite, and, in the past decade, the pace of progress has expanded radically, but we must be realistic. We must continue to better understand the underlying biology before we can reach that elusive goal of cure for most patients. ✦

About the Author: Dr. Bunn is distinguished professor of medicine and the James Dudley Endowed Professor of Lung Cancer at the University of Colorado School of Medicine. Dr. Bunn is a prior IASLC President and was CEO of the IASLC from 2003-2013.

1. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. Kris MG, Johnson BE, Berry LD, et al. JAMA. 2014;311(19):1998-2006.

2. Natural history and factors associated with overall survival in stage IV ALK rearranged non-small cell lung cancer. Pacheco JM, Gao D, Smith D, et al. J Thorac Oncol. 2018 Dec 29. [Epub ahead of print]

3. Lopes G, Wu Y, Kudaba I, et al. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/ metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: Open-label, phase 3 KEYNOTE-042 study. J Clin Oncol. 2018;36:18_ suppl, LBA4.

4. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016;375(19):1823-1833.

5. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 2018;378(22):2078-2092.

6. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med. 2018;379(21):2040-2051.

7. Jotte RM, Cappuzzo F, Vynnychenko I, et al. IMpower131: Primary PFS and safety analysis of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC. J Clin Oncol. 2018;36:18_suppl, LBA9000.

8. Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288-2301.

9. Borghaei H, Langer CJ, Gadgeel S, et al. 24-Month Overall Survival from KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin with or without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous Non-Small Cell Lung Cancer. J Thorac Oncol. 2019;14(1):124-129.

10. Antonia SJ, Villegas A, Daniel D, et al. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med. 2018;379(24):2342-2350.

11. Horn L, Mansfi eld AS, Reck M, et al. Phase I/III trial of atezolizumab with carboplatin and etoposide in ES-SCLC in first-line setting (IMpower133). J Clin Oncol. 2017;35:15_suppl, TPS8584.