What a difference 20 years have made! In the year 2000, the results of the ECOG 1594 trial were reported at the plenary session of the ASCO Annual Meeting. The study demonstrated comparable outcomes between four different platinum-based chemotherapy regimens for the treatment of metastatic non–small cell lung cancer (NSCLC).1 The objective response rates were approximately 20%, and the median overall survival was a mere 8 months. Just a year earlier, docetaxel had been approved as salvage therapy for advanced NSCLC, based on response rates of less than 10% and a median survival of 8 months.
There was a debate as to whether systemic therapy should even be offered to patients with
advanced-stage NSCLC. The only possibility for long-term survival or cure for lung cancer was diagnosis at a surgically resectable early stage. However, only a small proportion of lung cancers were diagnosed early due to the lack of effective screening methods.
Suresh S. Ramalingam, MD, FACP, FASCO
It is difficult to think that even the most optimistic thoracic oncologist could have foreseen the sea of change that followed, resulting in a dramatic repositioning of lung cancer as a beacon of individualized treatment paradigms to provide long-term survival for patients with advanced-stage cancer.2 Mortality for lung cancer has been reduced by 3% to 6% annually since 2013, a major contributor to the 29% overall reduction in cancer mortality in the United States since 1991—translating into 3 million fewer cancer-related deaths during the past 3 decades.
In the year 2020 alone, the U.S. Food and Drug Administration approved nine new indications for lung cancer; four represented novel agents approved for the first time (selpercatinib, pralsetinib, lurbinectedin, capmatinib), and three were new indications for immunotherapy agents. In all, the treatment of NSCLC has been transformed in the past few years. Long-term survival without compromising quality of life is a realistic treatment goal for a large subset of patients with advanced-stage NSCLC. Molecular testing through next-generation sequencing approaches allow for detection of at least seven “molecular drivers” that can be treated with targeted therapies. These novel agents provide objective tumor response rates of between 50% and 85% and median progression-free survival ranging from 10 months to 25 months.
First Steps to Personalized Therapy: EGFR and ALK Inhibitors
The first steps toward personalized therapy began with the development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and the demonstration that the presence of activating mutations was associated with sensitivity to therapy.3 Subsequently, new generations of EGFR inhibitors were developed to improve the efficacy profile and to overcome mechanisms of acquired resistance. An increase in specificity to the mutated receptor improved the safety profile of the tyrosine kinase inhibitors. Improved activity against brain metastasis was also a key contributor to the success of the newer generation of EGFR tyrosine kinase inhibitors.
Another important milestone was the discovery that rearrangement of the anaplastic lymphoma kinase (ALK) was an oncogenic driver for certain patients with lung cancer in the year 2007; this was followed rapidly by the evaluation of ALK inhibitors that provided dramatic benefits to patients. Six different ALK inhibitors have demonstrated robust efficacy for this patient subset with advanced-stage disease, for whom the median survival is more than 5 years.
More recently, promising results have been observed with direct targeting of the KRAS G12C oncogene, once thought of as an undruggable target, with novel agents inducing a response rate of approximately 32%. An antibody-drug conjugate has demonstrated a response rate of more than 60% in patients with HER2-mutated NSCLC, in early reports from an ongoing study. Taken together, the number of oncogenic targets for precision therapies will soon reach double digits, bringing to the forefront our long-held aspirations of individualizing treatments.
Latest Steps to Personalized Therapy: Immune Checkpoint Inhibitors
The advent of immune checkpoint inhibitors represents yet another major landmark in the journey of progress against lung cancer. Five immune checkpoint inhibitors are now used in routine clinical practice.
For patients with high PD-L1 expression, who represent approximately 30% of patients with metastatic NSCLC, the 5-year survival rate with pembrolizumab as monotherapy is 32%. Here again, biomarker-based treatment selection allows for maximizing the benefit of immunotherapy by using it alone or in combination with chemotherapy, dependent on the level of PD-L1 expression. The combination of ipilimumab and nivolumab has now been approved as the first nonchemotherapy combination approach in the context of immune checkpoint inhibition. It is hoped that many more such combination approaches will become available in the future to overcome resistance and to extend the benefits of immunotherapy.
“The number of oncogenic targets for precision therapies will soon reach double digits, bringing to the forefront our long-held aspirations of individualizing treatments.”— Suresh S. Ramalingam, MD, FACP, FASCO
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Immunotherapy has also been successfully integrated into the treatment of patients with surgically unresectable stage III NSCLC, representing the first major success achieved in 2 decades for this patient population, resulting in a 4-year survival rate of approximately 47% with chemoradiotherapy followed by durvalumab. Results from randomized trials that have evaluated checkpoint inhibitors as adjuvant therapy following surgery are eagerly awaited.
The Decade Ahead: Challenges and Opportunities
As we celebrate the progress made, we should not forget the hard work and dedication of researchers and clinicians who persisted despite increasing regulatory burden in their work, decline in research funding, and the increasing shift of authority toward administrators and insurance companies. Equally important, we owe this success to the patients and the community of advocates, who have worked to change the nihilistic mindset toward lung cancer.
The challenges and opportunities for the decade ahead of us are clear. Among them are the following:
1. Risk reduction by advocating for effective tobacco control policies, particularly against the alarming rise in the use of electronic nicotine delivery products among teenagers;
2. Early detection of lung cancer by increasing the adoption of CT screening in routine settings for individuals at risk and improve it from the current dismal screening rate of less than 5% among eligible subjects;
3. Development of novel treatment approaches to overcome inherent and acquired resistance to targeted therapies and immune checkpoint inhibitors;
4. Utilization of liquid biopsy platforms to detect and treat minimal residual disease;
5. Understand and address racial and other disparities in the management of lung cancer;
6. Increase accrual to clinical trials to accelerate the movement of promising discoveries to routine practice.
I strongly believe the lung cancer community is up for this challenge. Our patients are counting on us.
Dr. Ramalingam is the Roberto C. Goizueta Chair in Cancer Research at Emory University School of Medicine, Winship Cancer Institute, Atlanta.
Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO or The ASCO Post.
DISCLOSURE: Dr. Ramalingam has been a consultant/advisor for AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Genentech/Roche, Merck, and Takeda; has received institutional research funding from AbbVie, Advaxis, Amgen, AstraZeneca/MedImmune, Bristol Myers Squibb, EMD Serono, Genmab, Merck, Pfizer, Takeda, and Vertex; and has been reimbursed for travel or other expenses by AstraZeneca.
1. Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92-98, 2002.
2. Howlader N, Forjaz G, Mooradian MJ, et al: The effect of advances in lung-cancer treatment on population mortality. N Engl J Med 383:640-649, 2020.
3. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129-2139, 2004.