Suresh S. Ramalingam, MD(Professor of Hematology and Medical Oncology, Emory University, Atlanta, USA)

Development of targeted therapy inNSCLC

NSCLC has undergone major shifts in treatment paradigms in the past de⁃cade. In the 1990s, all patients were treated alike with systemic chemotherapy. In the present day, determination of the specific histological subtype is important for treatment selection. In addition, molecular testing is considered part of “standard of care” for certain mutations and gene re⁃arrangements. For patients with mutation in EGFR and rearrangement of ALK, specific targeted therapies are utilized with high response rate and improved PFS over chemotherapy.

A number of other less common“driver” mutations have also been observed in lung adenocarcinoma. Notable among them include the BRAF mutation, which is present in 1%~2% of patients. Arecent study that evaluated the combination of dabrafenib and trametinib demonstrated ORR of 68% . The combination was tolerable with fever, nausea, vomiting and diarrhea as the common adverse events. Mutation in exon 14 of MET gene has also been demonstrated to serve as anoncogenic driver that is potentially treat⁃able with MET inhibitor. Nearly 2%~3%of lung adenocarcinoma tumors harbor this mutation. Rearrangement of RET oncogene is also a treatable target observed in 1%~2% of the patients. Cabozantinib ,a RET inhibitor, has been noted to result in a response rate of nearly 40% for these patients. These recent developments have enabled the use of targeted therapies for an increasing proportion of patients with lung cancer.

However, nearly 2/3 of patients with lung adenocarcinoma do not have a targetable mutation. For these patients, systemic chemotherapy remains the main stay of treatment. The addition of targeted agentssuch as bevacizumab, ramucirumab and nintedanib have resulted in modest improvements in overall survival compared to chemotherapy alone. These anti-angiogenic agents have proven beneficial with either platinum-based combinations (bevacizumab) or docetaxel (ramucirulab and nintedanib). The BEYOND study conducted in China demonstrated a significant improvement in overall survival with the addition of bevacizumab to carboplatin and paclitaxel in patients with advanced non-squamous histology (24.3 m vs. 17.7m, P=0.0154).

Target therapy in SCC

In squamous cell carcinoma(SCC) of the lung, recent findings from the Cancer Genome Atlas Project has identified a number of targetable mutations. The ongoing S1400 study in the United States will evaluate a number of novel agents to target specific mutations in patients with squamous cell lung cancer. PARP inhibition appears to be another novel strategy to treat squamous cell lung cancer. When given in combination with platinum-based chemotherapy, veliparib, a PARP inhibitor has demonstrated improved efficacy without excessive toxicity in a randomized phase 2 study. This has resulted in a phase III study that is con⁃ducted for patients with advanced squamous cell carcinoma of lung.

New therapy in lung cancer

More recently, the advent of immune checkpoint inhibitors has provided for an entirely new treatment approach for lung cancer. Nivolumab has gained FDA approval for salvage therapy of advanced squmous cell lung cancer. Pembrolizumab, Atezolizumab and Durvalumab are allimmune checkpoint inhibitors with documented activity in lung cancer.

Conclusion

Taken together, the exciting developments in recent years have resulted in improved outlook for the treatment of lung cancer patients, either with or without driver mutations.