My career in lung cancer care started at a time when nihilism prevailed and the standard approach in advanced disease consisted of best supportive measures. No treatments were available in which the benefits outweighed the toxicity. The arrival of chemotherapy eventually rendered improvements in survival possible; in addition, this strategy allowed for symptom relief and increases in quality of life. Platinum-based chemotherapy became the first-line treatment of choice.
For at least a decade, chemotherapy doublets were compared across trials, but none gave rise to superior clinical outcomes as compared to another. Most notably, for patients with advanced disease, cure was still out of reach. It must be kept in mind, however, that all of these trials were performed before the era of molecular testing for driver mutations. Also, selection based on the histological subtype only took hold with the introduction of the VEGF inhibitor bevacizumab, which caused severe toxicity in patients with squamouscell tumours. Re-examination of previously conducted pemetrexed trials revealed significant beneficial effects of this chemotherapy in non-squamous disease, whereas the subgroup with squamous histology fared even worse with pemetrexed than with the comparator. This was the first example of qualitative interactions, as opposed to quantitative interactions, which describe the magnitude of benefits conveyed by different treatments.
Today, it is common knowledge that numerous molecular changes drive the development of lung cancer. Critical pathways have been identified, and targeted agents have become indispensable players in our armamentarium. Patients can now expect to derive survival benefits from first-line chemotherapy, second-line chemotherapy, and third-line molecularly targeted therapy.
In patients with EGFR-activating mutations, the first-line treatment of choice is not chemotherapy, but rather EGFR tyrosine kinase inhibitor therapy with erlotinib, gefitinib or afatinib. However, resistance invariably develops, frequently due to emergence of the T790M mutation. Research has found answers to this phenomenon, too; numerous drugs are being tested in the T790M-mutated setting, with promising results.
Nevertheless, the established druggable molecular targets are virtually restricted to adenocarcinoma, and frequently in cancers of lifetime non-smokers. For patients with squamouscell carcinoma, proven targeted therapies are lacking. The scientific community is called upon to rise to the occasion and identify both driver mutations and resistance mutations upfront, as retrospective analyses of samples are not appropriate any more.
Immunotherapy represents an exciting new option, particularly in patients with squamous cell cancer, and in prior or current smokers. In the CheckMate 017 trial, the PD-1 inhibitor nivolumab provided clinically meaningful and statistically significant overall survival benefit independent of PD-L1 expression in a population of previously treated patients with advanced squamous-cell lung cancer. Similar results have been reported in trials of another PD-1 inhibitor pembrolizumab and the PD-L1 inhibitor atezolizumab, but in these studies, benefit appeared to be limited to patients whose tumours expressed PD-L1.
The proof of usefulness of these new checkpoint inhibitors marked the beginning of a tremendous change in the therapeutic landscape. Currently immunotherapy is being evaluated in earlier lines of therapy and even in the adjuvant setting, where the goal will be to change the cure rate.
The development in the treatment of lung cancer over the last decades is certainly reason for optimism. Nihilism has given way to great advances. Early detection, enhanced selection of patients, and molecular targeting should contribute to turning the prospect of cure into a realistic option for many patients.
Frances A. Shepherd, MD, FRCPC, Scott Taylor Chair in Lung Cancer Research, Princess Margaret Cancer Centre, Professor of Medicine, University of Toronto, Toronto, Canada