Immunotherapy Has Shifted Every Cornerstone of Lung Cancer Treatment

Non-small cell lung cancer treatment can be considered under four main categories according to disease extent. Existing strategies developed through hundreds of well-designed randomized trials over more than 50 years, each becoming a cornerstone through international consensus over time.

1. In early disease (stages 1 – 3A), surgery is followed, if recurrence risk is high, by adjuvant (preventive) chemotherapy.
2. In locally advanced disease (stage 3B), surgery is unsuitable, and chemotherapy with concurrent radiation (chemoradiotherapy) is preferred.
3. Metastatic , or fourth-stage, non-small cell lung cancer patients who are unsuitable for targeted drugs receive first-line platinum-based chemotherapy combinations.
4. Patients progressing after first-line metastatic treatment continue with second-line single-agent chemotherapy.

Until the past few years, these four approaches were cornerstones of standard non-small cell lung cancer treatment. Immunotherapies began challenging chemotherapy-based strategies when tested in lung cancer:

• First, second-line chemotherapy in metastatic patients gave way to immunotherapies.
• Next came the goal of replacing first-line chemotherapy, achieved only in selected patients withPD-L1 levels of %50 or above. 
• The third step combined immunotherapy with first-line chemotherapy without PD-L1 selection, succeeding in nonsquamous non-small cell lung cancer. 
• In another difficult group, inoperable locally advanced disease (3B), continuing immunotherapy after concurrent chemoradiotherapy improved survival.

First Immunotherapy Results in Early Lung Cancer

Evidence for another change came in April 2018 in New England Journal of Medicinefrom a pilot study in very early-stage (1 – 3A) non-small cell lung cancer, using neoadjuvant (preoperative tumor-reducing) 2 cycles of immunotherapy nivolumab (Opdivo).

The Study Found; 

• Among 21 evaluable early-stage non-small cell lung cancer patients, no intolerable effects beyond conventional immunotherapy effects occurred. No adverse consequences from treatment-related preoperative delays were detected.
• Preoperative CT scans showed significant radiological regression in 2 patients, stable findings in 18 and increased tumor size in 1. 
• Postoperative pathological staging showed significant immunotherapy response relative to initial stage in %45 of patients. 
• 3 patients achieved pathological complete response , considered remarkable after two immunotherapy doses.
• Genomic analyses assessed tumor mutational burden and found higher responses in patients with greater burden.
• Responses occurred in both PD-L1-positive and negative groups.

Although small, this study provided important information opening the way to larger trials. Seeing that even brief preoperative immunotherapy might benefit early non-small cell lung cancer was encouraging to us all.

Before treatment, tumor mutational burden was examined in 12 patients' pathology specimens and correlated with response. Predicting who may benefit before recommending expensive treatments such as immunotherapy is among the most important aims of modern medicine and precision oncology . Evidence that pretreatment mutational burden may predict response also opened a door toward selecting the right treatment for the right patient.

Commentary

These data undoubtedly challenge the last cornerstone of lung cancer treatment strategy. However, they are insufficient to recommend routine preoperative immunotherapy in early lung cancer. We will follow planned and ongoing studies and share their results.

Related Topic:

- Innovations in Lung Cancer Treatment — 2017 and 2018