Chemotherapy refers to a class of drugs that are usually given intravenously to travel through the bloodstream and reach all (or most) parts of the body to slow or halt the growth of any rapidly dividing cells. Because chemotherapy drugs are not as targeted as the Tyrosine Kinase Inhibitors (TKIs), they are often (but not always) associated with more difficult side effects such as nausea, fatigue and sometimes hair loss.

Usually these drugs are given in combinations of two, although for people who might not tolerate combination chemotherapy well - such as those in poor overall health or those with intolerable side effects - sometimes a single chemotherapy agent may be given.

The systemic chemotherapy agents most commonly used for non-small cell lung cancer (NSCLC) include Carboplatin or Cisplatin (the platinum-based agents), plus Pemetrexed (Alimta). Docetaxel (Taxotere), Paclitaxel (Taxol), Gemcitabine (Gemzar), Vinorelbine (Navelbine) or Etoposide (VP-16) are also sometimes used as second- or third-line agents.

Immunotherapy refers to a group of treatments that help a person’s own immune system eliminate or control their cancer. This includes the ‘Immune Checkpoint Inhibitor’ (ICI) or ‘Immunomodulator’ class of drugs, as well as several other investigational treatments such as vaccines, cytokines, monoclonal antibodies and cellular Car-T cell therapies, all of which are currently being researched for more effective applications.

The first PD-1/PD-L1 ICIs, Nivolumab (Opdivo) and Pembrolizumab (Keytruda), were FDA-approved for NSCLC in 2015. Subsequent FDA ICI approvals include Durvalumab (Imfinzi) (2018), Atezolizumab (Tecentriq) (2020) and Cemiplimab (Libtayo) (2021). These drugs have shown survival benefits over second-line chemotherapy when looking at all patients with advanced NSCLC who have higher PD-L1 expression and higher tumor mutation burden (TMB).

Unfortunately however, subsequent analysis revealed that, overall, a majority of NSCLC patients with specific driver mutations such as EGFR, ALK or RET had little survival benefit with this class of drugs(1,2). Therefore, patients with actionable driver mutations like RET should receive targeted therapies and chemotherapy before considering immunotherapy as a single agent(2.)

This does not mean that a response to this class of drugs is impossible for someone with RET-positive NSCLC - only that it may not be likely. Given the relatively low side effect profile of these immunotherapy agents, however, many centers add Pembrolizumab, Atezolizumab or one of the other checkpoint inhibitors alongside first-line platinum-based chemotherapy, or alongside first-line chemotherapy once progression has occurred with a TKI.