Optimizing Immunotherapy in Advanced Non-Small Cell Lung Cancer

Arjun V. Balar, MD

This year’s American Association for Cancer Research (AACR) Annual Meeting was the backdrop for pivotal data that may significantly change the standard of care in advanced lung cancer, the deadliest cancer worldwide and responsible for an estimated quarter of all cancer-related deaths in the United States.¹Antibodies that target the PD-1 checkpoint pathway have revolutionized cancer care; whether the best first-line treatment for any individual patient is chemotherapy or immunotherapy, or possibly both, remains unknown.

KEYNOTE-189 was poised to answer such a question and randomized 616 previously untreated patients with advanced nonsquamous non—small cell lung cancer (NSCLC) without EGFR or ALK alterations to either standard chemotherapy (platinum-pemetrexed) alone or in combination with pembrolizumab (Keytruda).²Presented at a plenary session at the 2018 AACR Annual Meeting, the trial demonstrated a significant benefit in overall survival (OS) for chemotherapy plus pembrolizumab, with an estimated 12-month OS rate of 69.2% versus 49.4% for chemotherapy alone (HR, 0.49; 95% CI, 0.38-0.64; P <.001). A benefit in OS was observed for chemotherapy plus pembrolizumab irrespective of PD-L1 status, including those with absent PD-L1 expression (<1% as measured by the immunohistochemistry 22C3 pharmDx assay on tumor cells; HR, 0.59; 95% CI, 0.38-0.92). The patients who derived the most benefit, not surprisingly, were those with the highest PD-L1 expression levels (>50%), however, it is not clear if the addition of chemotherapy for these patients offers an advantage over pembrolizumab alone.

Without the benefit of a randomized study focused on these patients, the authors concluded that patients and physicians need to have individualized discussions regarding the best approach to treatment. Nonetheless, this trial addressed a significant concern shared by many oncologists: the potential missed opportunity to provide cancer control in a patient who is treated with frontline immunotherapy alone but does not respond. Immunotherapy responses take time, and the treatment modality is generally less effective in patients with cancers that are progressing quickly. The efficacy observed with combination chemotherapy and immunotherapy in KEYNOTE-189 suggests synergy between these 2 seemingly diametrically opposed treatment modalities that may have broad-reaching implications, including in other cancers with similar disease biology, such as head and neck and urothelial bladder cancers. Similar, potentially practice-changing data from the IMpower150, a 3-arm phase III study evaluating carboplatin-paclitaxel with atezolizumab (Tecentriq) or bevacizumab (Avastin), or both, as first-line treatment in advanced nonsquamous NSCLC further support the notion of synergy between chemotherapy and immunotherapy.

However, there is clearly a subset of patients whose disease can be successfully treated with immunotherapy alone, leading to durable responses.³Part 1 of CheckMate 227 validated previous data supporting high mutational burden as a clinically meaningful predictive biomarker of immunotherapy efficacy and could have immediate implications in the clinic, especially for patients who are poor candidates for, or who are refusing, chemotherapy.⁴Taken together, the data from these 3 pivotal studies (see pages 31-33) firmly establish immunotherapy as a critical backbone of any treatment regimen for a significant proportion of patients with advanced NSCLC. I invite you to read more about these practice-changing data and other exciting research presented at the 2018 AACR Annual Meeting in this month&rsquo;s edition of Targeted Therapies in Oncology&trade;.

References:

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30. doi: 10.3322/caac.21442.
2. Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer [published online April 16, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1801005.
3. Reck M, Rodriguez-Abreu D, Robinson AG, et al; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823-1833. doi: 10.1056/NEJMoa1606774.
4. Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden [published online April 16, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1801946.