Driving Innovative Cancer Science to Patient Care was the name of this year’s April meeting of the American Association for Cancer Research (AACR) in Chicago, and it was fitting―there were lots of exciting advances in targeted therapies, immunotherapy, and more that I am pleased to share with you in this blog.
Progress in targeted therapies is continuing in two areas.
Understanding how to overcome EGFR and ALK mutations
Currently, patients whose tumors have an EGFR or ALK mutation are treated with drugs called tyrosine kinase inhibitors (TKIs). Although these drugs work really well initially, the cancer inevitably comes back by developing resistance to them. When a patient progresses on a first- or second-generation EGFR TKI, they are typically prescribed a third-generation TKI called osimertinib (Tagrisso®). This drug works by blocking a mutation called T790M, which cancer cells develop to outsmart the initial EGFR TKI(s) used. However, cancer cells have now developed mechanisms to resist osimertinib as well. Work from LUNGevity SAB member Dr. John Heymach’s laboratory shows that EGFR-positive lung cancer cells develop resistance to osimertinib via additional mutations in the EGFR gene—such as C797S or L792H—or they may lose the T790M mutation that makes them sensitive to osimertinib. This research is setting the foundation for answering What’s next? for patients whose cancer comes back after osimertinib treatment.
Patients whose tumors are positive for the ALK gene rearrangement also relapse after treatment with ALK TKIs because their lung tumors develop additional mutations in the ALK gene. LUNGevity SAB member Dr. Alice Shaw’s laboratory showed that such patients may respond to a third-generation ALK TKI, lorlatinib. Again, great news―lorlatinib has the potential to become an option for ALK-positive lung cancer patients in the not-too-distant future; the FDA has given it priority review status.
Targeting mutations such as KRAS—previously considered untargetable—and other, rare mutations
Progress is being made in targeting genes such as KRAS, long considered “undruggable.” Scientists have already developed drugs that block G12C, a specific mutation in the KRAS gene, the most common mutation in lung cancer. These drugs have shown immense promise in preclinical studies, and we hope to see them move into clinical trials by the end of the year. In addition, scientists have started developing drugs for other types of KRAS mutations and testing these in preclinical studies.
We may soon have drugs that block the RET mutation, found in only 1%-2% of non-small cell lung cancer (NSCLC) patients. Data from a phase 1 trial with a RET-blocking drug show that the drugs worked in 50% of the patients enrolled in the clinical trial. Although the trial included only a small number of patients, the data are promising and will lead to phase 2/3 trials soon.
Immunotherapy, specifically “rational immunotherapy combinations,” might have made the biggest splash at this year’s AACR. Scientists are learning how to combine and sequence immunotherapy drugs with other immunotherapies or with conventional treatments such as chemotherapy. Data from a phase 3 combination trial using an immune checkpoint inhibitor called pembrolizumab (Keytruda®) in combination with chemotherapy (pemetrexed-platinum compound) showed that the combination was far superior to chemotherapy alone in the first-line setting for advanced-stage non-squamous NSCLC, a subset of NSCLC. The most interesting piece of the data was that this effect was seen independent of PD-L1 protein expression. PD-L1 is a biomarker often used to identify which patients may respond to immunotherapy. In addition, another trial studying a combination of two immune checkpoint inhibitors, ipilimumab (Yervoy®) and nivolumab (Opdivo®), showed that the combination was more effective than chemotherapy alone in the first-line setting for patients with advanced-stage NSCLC. Additional data from this trial are awaited. Immunotherapy is also showing promise in patients with early-stage lung NSCLC. LUNGevity Career Development Awardee Dr. Patrick Forde’s work showed that immunotherapy given to patients with early-stage NSCLC before surgery (also known as neoadjuvant immunotherapy) may prevent the cancer from recurring after surgery. This trial has laid the groundwork for several neoadjuvant immunotherapy trials for patients with early-stage NSCLC.
Small Cell Lung Cancer
Research in small cell lung cancer (SCLC), which has not yet seen the same progress as treatments for NSCLC, has definitely taken off. The small-cell session chaired by LUNGevity awardee Dr. Julien Sage focused on the latest research on understanding how SCLC lung cancer cells become resistant to chemotherapy and whether combination treatment approaches for SCLC are effective. DLL3, a protein produced in excess by SCLC cells, continues to progress through clinical development, not just as a therapeutic target, but also as a possible imaging target for SCLC. LUNGevity’s Scientific Advisory Board chair, Dr. Charlie Rudin, presented promising data on how SCLC evades the effects of chemotherapy by stopping the production of a protein called SLFN11. Combining chemotherapy with drugs that restore the production of SLFN11 makes SCLC sensitive to chemotherapy in preclinical studies. Clinical trials testing these combinations are expected to start soon. LUNGevity Career Development Awardee Dr. Lauren Byers’ team showed that SLFN11 may also be a biomarker for response to PARP-blocking drugs. PARP inhibitors are currently in clinical trials for SCLC, and SLFN11 may serve as a potential biomarker to predict which patients will derive benefit from these drugs. Her team also presented data that showed that combining immunotherapy with drugs that block a protein called CHK1 may work better in SCLC cells than immunotherapy alone.
No cancer conference is now complete without sessions on liquid biopsies. Although liquid biopsies are not quite ready for prime time, considerable progress has been made in the new technology that relies on testing blood from lung cancer patients. Circulating tumors cells, or CTCs, are cancer cells shed by certain types of tumors into the blood. Detection of CTCs in the blood of early-stage cancer patients suggests a more aggressive cancer. Scientists are refining CTC-based technologies to better identify patients with early-stage NSCLC who will have a higher chance of recurrence after surgery. CTC-based technology is also being developed for SCLC, to classify which patients with late-stage SCLC will not respond to chemotherapy and so may need to be monitored more vigilantly.
Patient Advocacy Groups
In her opening plenary presentation, Dr. Margaret Foti, the Chief Executive Office of the AACR, recognized the importance of patient advocacy groups in increasing awareness about cancer, helping raise funds for research, and partnering with researchers to develop drugs and execute clinical trials. A perfect example is the work of the ROS1ders, a group of passionate ROS1-positive lung cancer survivors and their caregivers, which was presented at a poster session. This group is building a global community to accelerate ROS1 research and turn ROS1+ cancer into a manageable chronic disease.
This AACR meeting was just one of the important annual meetings where lung cancer research is presented. Next up, in June, is the American Society of Clinical Oncology (ASCO) conference. I’ll have more progress to report to you then.
Dr. Basu Roy is LUNGevity's Director of Translational Research Programs/Director of Patient FoRCe.