Based on what I learned at the 17th Annual Targeted Therapies of the Treatment of Lung Cancer conference in February in Santa Monica, California, 2017 is going to be an important year for progress in targeted therapies. The conference brings together doctors and scientists from all over the globe to discuss the advances that will result in the best care for lung cancer patients.
As usual, LUNGevity was well represented: 12 members of our Scientific Advisory Board and 15 past and current awardees presented and discussed latest research findings at the conference.
While other cancer conferences such as ASCO and World Lung are spread over four days, this conference is unique in that there are more than 200 short presentations packed into just two and a half days! Coffee was my best friend for those two and a half days while I learned how the field is evolving. I took away three big themes from these meetings.
Doctors are learning more about the WHY and the WHEN for combination therapies.
An important theme that resonated with me was the idea of “rational” combination therapies. We have made a lot of progress in understanding how to combine different treatments – which ones to combine and in what sequence – so that the combination is very effective with minimal side effects.
For example, a combination that is being tested in trials is immunotherapy with chemotherapy. Cancers cells escape from the immune system by wearing an invisibility cloak. Current immunotherapy drugs (called checkpoint inhibitors) work by uncloaking cancer cells. Combining chemotherapy with immunotherapy seems to make this uncloaking process extremely efficient. When patients receive the immuno-chemo combination, they respond faster than with immunotherapy alone. Also, preliminary results from clinical trials suggest that the sequence of giving the two treatments matters. There may be more benefit when immunotherapy is given after initial chemotherapy. We are waiting for the final readout of these trials.
We are learning about existing targetable mutations and adding new mutations to our list: the pie has more slices!
I still remember the year 2004, when I was a graduate student in cancer biology. It was the year that the first mutation in non-small cell lung cancer (NSCLC) – in the EGFR gene – was discovered. Soon, pie charts that showed that around 10%-35% of NSCLC patients have a mutation in the EGFR gene surfaced in textbooks. This discovery led to the development of tyrosine kinase inhibitors (TKIs), which block the growth-promoting effects of EGFR mutations. We have come a long way since then. Now at least 10 driver mutations (mutations that promote the growth of cancer cells) in lung adenocarcinoma (a type of NSCLC) have been identified (alterations in the EGFR, ALK, ROS1, RET, ERB2/HER2, MET, TRK, BRAF, and KRAS genes). TKIs that block the effect of some of these driver mutations already exist or are in clinical development. However, lung cancer cells are shrewd – despite an initial response to TKIs, they learn to outwit the effects of these drugs. So scientists are hard at work! They are developing TKIs that block the effects of these mutations, and are staying a step ahead, studying how cancer cells become resistant to the effects of TKIs. Their ultimate goal is to make sure that doctors have more than one tool in their toolkit, so that drug B is ready when cancer cells become resistant to drug A. This has been made possible because of the remarkable progress we have made in understanding the biology of lung cancer.
The best example of progress in this area has occurred in the EGFR space. Patients whose lung cancers test positive for an EGFR mutation are treated with first- or second-generation TKIs. When their cancer become resistant to these TKIs due to another mutation in the EGFR gene (often the T790M mutation), doctors prescribe a third-generation TKI such as osimertinib. Now clinical trials with osimertinib in the first-line setting are showing promise, and the drug may soon be approved for first-line treatment. Scientists are working on the next piece of the puzzle – learning how cancer cells outwit osimertinib.
Progress in the field of ALK TKIs has also been rapid. Now, patients whose cancer has progressed on first-generation ALK TKIs are prescribed second-generation drugs. Scientists are working on third-generation ALK TKIs (such as lorlatinib) that would provide options to patients whose cancers have developed resistance to second-generation drugs. Drug development for ROS1 is fast catching up. In 2016, the FDA approved crizotinib in the first-line setting for ROS1-positive lung cancers. New ROS1 TKIs are already in clinical development.
Other promising areas of clinical development are with TKIs that target mutations in the MET gene and in the BRAF gene. I am really excited to see these drugs move closer to the clinic.
We are making progress in treatment options for other lung cancer subtypes, such as small cell (SCLC) and squamous cell lung cancer
Currently, targeted agents are available for a subset of adenocarcinoma patients, whose tumors test positive for an actionable mutation. With the rapid progress we have made in understanding the biology of lung cancer, treatment options for other subtypes such as squamous cell lung cancer and SCLC are now being tested in clinical trials.
Chemotherapy was the mainstay of treatment for squamous cell lung cancer. However, that has changed with the approval of immunotherapy in the first-line setting for a subset of squamous patients. Also, targeted agents for squamous patients are being tested in biomarker-driven clinical trials such as Lung-MAP.
We are also seeing incredible progress in the area of SCLC. RovaT – a drug that targets a protein called Delta-like 3 (DLL3) – is continuing to show promise in clinical trials. In some SCLC patients, large quantities of DLL3 are produced. RovaT seeks out SCLC cells that make DLL3 and delivers an effective toxic drug to those cells. It may be the first biomarker-driven treatment showing promise in small cell. Another promising class of drugs is PARP inhibitors. These drugs work by making SCLC cells unable to repair themselves after they have been treated with chemotherapy. I am eager to see the final readout of the chemotherapy-PARP inhibitor combination trials.
I am sure you are surprised that I didn’t mention immunotherapy as a separate theme. In fact, the field of immunotherapy is exploding – with research on how to select patients who may benefit, how best to combine immunotherapy with other treatment options, and use of immunotherapy in early-stage lung cancer. LUNGevity SAB member Dr. Julie Brahmer beautifully summed up the progress so far in immunotherapy in her keynote presentation at the conference, “With immunotherapy, we have already gone to the moon. Now, let’s go to Mars!”
Next stop, the annual AACR meeting in Washington, DC. Stay tuned!
Dr. Basu Roy is LUNGevity's Director of Science Communications and Programs. 