As discussed in previous blog posts, lung cancer is a devastating diagnosis for a person. Especially when the disease is far advanced, patients have little time to live left. For decades, we have seen few advances in lung cancer research and only for small subgroups of patients with specific oncogenic drivers despite very hard work. Other than that there was fine-tuning of chemotherapy and radiotherapy. To be fair new more efficacious and less toxic chemotherapeutics were developed …. but no ground breaking innovation really.
What is missing? What needs to be done to help these patients? Why is lung cancer treatment so tricky to improve and why is lung cancer always outsmarting the smartest scientists and clinicians?
Sorry we won’t find the answer today. It really is complicated. But let’s think about it for a bit and write down some hypotheses that have been presented at the latest congresses.
The specific oncogenic drivers mentioned above are for example mutations in genes like EGFR, ALK and ROS1. Tumors that depended on these mutations to grow in an uncontrolled manner are targetable with small molecule inhibitors designed to bind receptors like EGF-R, Alk and Ros1. These inhibitors induce a high response rate and tumor shrinkage for around one year in selected patients with a better toxicity profile than chemotherapy. One year is the average time a tumor needs to exhibit resistance in almost all patients. Mechanisms of acquired resistance include new mutations in the same target or activation of additional molecular pathways bypassing the pathway used by cancer cells prior to therapy. Consequently new inhibitors have been designed with great success. The new inhibitors are capable of binding to the new situation.
Here the research community achieved very impressive break throughs in the recent past. The beauty about these achievements is that not only industry and academia worked closely together but also chemists, clinicians, molecular biologists, ….. attacking urgent needs in very efficient cross-functional team work.
Interestingly the newer generation inhibitors have additional characteristics like higher potency and better brain penetration. So now the difficult task is to figure out the best sequence for those first, second and third generation inhibitors to get the longest survival time for patients until their MDs run again out of options.
Much better situation compared to a few years ago and all this hard work provided more time for some patients but again still no cure or chronic disease option for lung cancer patients in general and for specific histologic types of lung cancer like small cell lung cancer (see prior blog post) and mesothelioma (which is strictly speaking not a lung cancer but thoracic cancer) in particular.
In July, I wrote about immunotherapy/immuno-oncology (IO) as an option for many different types of cancer including lung cancer. Several agents are now approved for non-small cell lung cancer and there may be hope for small cell lung cancer and mesothelioma as well. It is a highly innovate approach for a significant percentage of patients but unfortunately not every patient shows a positive response. It is not fully understood yet how to select patients. IO has great potential for many patients because it is a different type of targeted therapy compared to the inhibitors described above. It targets the many players of the immune system and not only one single target.
However, monotherapy did not show efficacy in all patient groups and combinations may be the answer as one hypothesis. Combining what? There are many possibilities: combining two or three immunotherapeutics, IO + radiation, IO + targeted therapy (small molecule inhibitor) IO + chemotherapy and more. Or two or three different types of inhibitors? There are more targets for small molecule inhibitors in addition to EGF-R, Alk and Ros1 like FGF-R, PI3-kinase, DDR2, cell cycle checkpoint inhibitors and VEGF-R as Gerber recently reviewed in squamous, small cell and rare lung cancers. Will these different types of drugs synergize? Do they have overlapping toxicities? What are the right biomarkers to select patients?
All this needs to be tested in preclinical and clinical well thought-through trials to find the right dose, schedule, sequence …. A seemingless endless task …… It will take a long time (decades) and many research studies to collect all the necessary data. Does this sound negative? It should not. Studies mean opportunities for patients to participate in the research that might help them and future patients to one day make advanced lung cancer a chronic or curable disease.
These are very exciting times shifting paradigms that require changes of traditional mind sets in the presence and more to come in the future for sure.
Gerber D. E. et al. (2015) Beyond Adenocarcinoma: Current Treatments and Future Directions for Squamous, Small Cell, and Rare Lung Cancer Histologies. ASCO Educational Book