Preface ASCO 2021
Martin Reck, MD, PhD
Department of Thoracic Oncology
Airway Research Center North,
German Center of Lung Research
Lung Clinic Grosshansdorf
Grosshansdorf, Germany
Dear Colleagues,
As in 2020, the 2021 Annual Meeting of the American Society of Clinical Oncology (ASCO) was held online, with both the scientific and education programs taking place on June 4-8. Among more than 2,500 abstracts presented, findings in the area of lung cancer made for exiting news. Immune checkpoint inhibition has been moving forward in the continuum of care across the treatment lines and is now defining new standards in early-stage lung cancer. In patients who underwent complete resection, the IMpower010 trial established PD-L1 inhibition as a new adjuvant option in stage II-IIIA, PD-L1–expressing NSCLC. Previously, based on the PACIFIC study, another PD-L1 inhibitor has already transformed the treatment of patients with unresectable stage III tumors responding to chemoradiation. Here, the updated results have revealed lasting benefits.
Important data have also been obtained for targeted therapy that involves not only individualized tailoring of treatment but also the handling of resistance that emerges with it. Various mechanisms of resistance depending on the type of the administered agent have been identified for EGFR-mutant lung cancer. The answer can be targeting of alternative aberrations such as HER3 or the use of regimens that inhibit both likely resistance mechanisms and the primary target. Inactivating somatic mutations such as STK11 and KEAP1 can also have a predictive effect regarding the activity of KRAS inhibition from the outset, according to exploratory analyses of the CodeBreaK100 trial. Immunotherapy and targeted treatment may intertwine, which applies particularly to the KRAS-mutated setting as demonstrated by various analyses reported at ASCO 2021. Sequencing can play an important role in terms of use of checkpoint inhibitors and targeted tyrosine kinase inhibitors but also antiangiogenic agents, with a view to creating an immunosupportive tumor microenvironment.
Moreover, small-cell lung cancer is being increasingly characterized at the molecular level, with differential expression of genes and biomarkers possibly informing therapeutic vulnerabilities in the future. For the time being, innovative strategies such as bispecific T-cell engager therapies are tested in patients with relapsed SCLC who have a high unmet medical need. While the armamentarium is being refined to improve efficacy and tolerability at the individual patient level, we hope to meet again at future conferences to hear about breakthroughs that will further advance daily patient care.
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Opening up new vistas for patients with SCLC
Concurrent chemo-radiation with a platinum-etoposide backbone constitutes the standard of care in limited-stage small-cell lung cancer (LS-SCLC). Here, cisplatin is traditionally the preferred platinum agent. However, data on the comparative efficacy of the less toxic carboplatin in this setting are lacking. To fill this gap, Azar et al. conducted a retrospective study based on the National VA Cancer Cube database.
Enhancing immunosupportive mechanisms via anti-angiogenesis
Treatment with anti-angiogenic agents offers potential in the management of patients progressing on immune checkpoint inhibitors as it has been shown that excessive VEGF production can create an immunosuppressive tumor microenvironment by modulation of immune cell function and reduction of immune cell access [1-3]. This might contribute to checkpoint inhibitor resistance and prime the tumor for anti-angiogenic therapy.
How does checkpoint inhibition perform in the setting of oncogene-driven lung cancer?
Retrospective analyses have demonstrated limited activity of immune checkpoint inhibitors (CPIs) in patients with actionable oncogenic driver mutations. In similar vein, the randomized controlled IMpower150 and IMpower130 studies revealed no survival benefit of adding CPIs to platinum doublets in patients who harbored EGFR and ALK aberrations.
Immunotherapy: from predictive factors to antibiotics
Based on the randomized, phase III CheckMate 9LA study, the first-line regimen of nivolumab plus ipilimumab and two cycles of chemotherapy has been approved in the indication of metastatic NSCLC without EGFR or ALK aberrations in many countries. CheckMate 9LA included approximately 360 patients with stage IV or recurrent disease in each arm and demonstrated significant OS, PFS, and ORR improvements with the immunotherapy-based regimen compared to four cycles of standard chemotherapy.
KRAS, MET, ROS1, HER2: current perspectives
Approximately 13 % of patients with adenocarcinoma of the lung harbor the KRASG12C mutation. To date, no agent targeting this oncogenic driver has been licensed, although there is a need to improve outcomes in this population after progression on first-line treatment encompassing immune checkpoint inhibitors. The first-in-class, irreversible, selective KRASG12C inhibitor sotorasib has demonstrated durable clinical benefit in pretreated patients with KRASG12C-mutated, locally advanced or metastatic NSCLC in the single-arm phase II CodeBreaK100 trial.
EGFR-mutant disease: strategies against sensitizing and resistance-mediating mutations
EGFR tyrosine kinase inhibitors (TKIs) are the established first-line option in patients with EGFR-mutated NSCLC, although resistance inevitably develops in the long run. A wide variety of genomic alterations has been identified in the context of EGFR TKI resistance. HER3, which is expressed in 83 % of NSCLC tumors, is not known to confer resistance to EGFR TKI therapy in EGFR-mutant disease.
