Day 10 – CHEMOTHERAPY vs. IMMUNOTHERAPY vs. TARGETED THERAPY AND LUNG CANCER
There are 3 main types of systemic pharmaceutical treatment for cancer:
- Chemotherapy – The most widely-used and effective systemic treatment for cancer, it works by targeted fast-dividing cells in the body. While this includes “bad” cancer cells, it also includes other “good” cells like hair, nails, digestive track and bone marrow. This causes hair loss, nail breakage, nausea, digestive problems, weak immune systems and a variety of other side-effects. Multiple types of chemotherapy are available for NSCLC and SCLC, though carboplatin and cisplatin remain predominant. However, given the multitude of advanced treatments appearing for NSCLC, some researchers are beginning to see chemo as a thing of the past for that disease. It remains the standard of care for first and second line treatment for SCLC.
- Immunotherapy – This category of drugs has recently come onto the cancer scene, with the first FDA approval awarded to Yervoy in 2011 and the 2018 Nobel Prize in Medicine going to James Allison and Tasuku Honjo for their advances in the field. Immunotherapy works in an almost opposite way to chemotherapy by programming the body’s natural immune system to target cancer cells. However, this sometimes causes the immune system to hyper-react and attack healthy cells, such as those of the joints or digestive system. Though generally better-tolerated by patients than chemotherapy, immunotherapy seems to produce a wider and more random array of side-effects, and, given its relative newness, the full set of side-effects and long-term ones are not very well understood.
- Targeted therapy – Targeted therapy refers to treatment with drugs that have been developed to target cells that deviate from normal cells in some specific ways. For example, cancer cells exhibit different variants of proteins or lack/abundance of certain kinds of proteins. Targeted therapies will attack cells exhibiting these differences. For example, the cell growth signaling protein BRAF is present in an altered form (known as BRAF V600E) in many melanomas. Vemurafenib (Zelboraf®) targets this mutant form of the BRAF protein and is approved to treat patients with inoperable or metastatic melanoma that contains this altered BRAF protein. Because they only attack deviant cells, targeted therapies generally produce the fewest side-effects.
NSCLC, particularly adenocarcinoma, has been one of the most promising cancer battlegrounds for targeted and immunotherapy, with a consistent flow of advances both in terms of new drugs targeted toward specific mutations as well as additional indications for existing drugs. Unfortunately, one of the difficulties of SCLC is that is has very few treatment options available, unlike NSCLC. Platinum-based Chemotherapy (typically carboplatin or cisplatin combined with etoposide) remains after decades the standard of care. However, these chemotherapies often produce significant side effects, and though initially highly-effective (estimates ranging from 60-90%), these treatments are often confounded by a resistant relapsed disease.
Targeted therapies have been approved for NSCLC, including Bevacizumab (Avastin) and Ramucirumab (Cyramza), with clinical trials ongoing for new drugs and expansions of existing drugs to include an NSCLC indication. Unlike with NSCLC, targeted therapies have produced disappointing results in trials for SCLC, and none are currently approved as a treatment. There are some promising signs lately, such as PARP inhibitors combined with thoracic radiation, but trials are in very early stages.
Immunotherapy is now accepted as an important component of lung cancer treatment, with FDA approval for a number of drugs and indications. Even for SCLC, there have been some very hopeful clinical trials showing significant efficacy of Opdivo, Keytruda and Tecentriq. In fact, the FDA broke new ground by approving Opdivo as a third-line treatment for SCLC in August 2018.
However, the difficulty has been finding biomarkers which would indicate immunotherapy efficacy for SCLC. For instance, with NSCLC and other cancers, genetic tests showing certain mutations (PD-L1 often seen as the most significant) indicate the use of certain immunotherapies. With SCLC, there have been mixed signals about what biomarkers indicate immunotherapy efficacy, probably due to the fact that SCLC tends to have a very high concentration of mutations, meaning the cancer grows and spreads through multiple pathways. This topic is currently the subject of ongoing research, but many leading researchers currently believe high tumor mutation burden (TMB) and Microsatellite Instability (MSI) are useful indicators, with some disagreement over the significance of PD-L1 in SCLC. Expect more advances in the coming years, with a flurry of hopeful findings coming in the last half of 2018 alone.
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