Targeted Therapies: Past, Present and Future

Juhi Kunde, MA

Alice Shaw, MD, PhDAlice Shaw, MD, PhD, is a pioneer in the field of targeted therapies for lung cancer—treatments designed to target specific gene mutations that are present in the cells of some patients. Her work was instrumental in earning FDA approval for three targeted therapies for patients with the ALK mutation: crizotinib, ceritinib, and alectinib. She recently presented the results of a critical clinical trial that suggest alectinib could replace crizotinib as the initial treatment for ALK-positive patients. In addition to conducting groundbreaking research, Dr. Shaw is a celebrated thoracic oncologist at Massachusetts General Hospital and Harvard Medical School who primarily treats patients with lung cancer. Dr. Shaw recently spoke with LUNGevity about the changes in the field of targeted therapies and her advice for patients facing a lung cancer diagnosis.

LUNGevity Foundation: How has the field of targeted therapies changed over the past decade?

Alice Shaw: When I entered the field more than a decade ago, we only had one targeted therapy option and that was for patients with the EGFR mutation. Because this mutation is only found in 10%-15% of patients with lung cancer in this country, the vast majority of our patients only had chemotherapy as an option. But since then, numerous targeted therapies have been developed for patients with many different types of genetic alterations. This has resulted in many more options for our patients, and it has transformed the way we treat lung cancer. These targeted treatments are more effective and better tolerated than standard chemotherapy and, as a result, are improving the quality of life for patients.

LF: What is the greatest obstacle to successfully treating lung cancer with targeted therapies?

AS: The biggest issue is drug resistance. Targeted therapies typically work for a year or two, and then the cancer figures out a new way to grow. This is called drug resistance, and it is the most common reason a patient comes off a targeted therapy drug. There are numerous research groups, including mine, that are working on understanding drug resistance. Once we get a handle on how the cancer is developing resistance, we can work to find a drug or combination of drugs that can overcome that type of drug resistance.

LF: How do you anticipate the field of targeted therapies changing over the next decade?

AS: Over the next decade, we’re going to see more efforts focused on upfront treatment and preventing the development of resistance.  Right now, we are developing lines of drugs that are typically given sequentially—once the cancer becomes resistant to the first drug, the second one is given, and so on. The drugs that we are developing now are actually more effective and often safer for patients than the older generation of drugs.  We’ve already started moving these newer drugs into the front-line setting, including alectinib for ALK-positive lung cancer and osimertinib for EGFR-mutant lung cancer. In addition, combination approaches may also move into the front-line setting.  These combinations could include two targeted therapies, which may be more effective than a single targeted therapy, or multimodality strategies that incorporate highly potent targeted therapies to maximally reduce tumor burden and focused radiation to eradicate any residual sites of disease. These residual sites of disease may harbor the seeds of resistance, so targeting these sites may be particularly effective in preventing the development of resistance. Finally, over the next decade, I think we will be using more and more liquid biopsies, the sampling of circulating DNA shed from cancers. These liquid biopsies may help detect the first signs of resistance and may help us better tailor our targeted therapies to each patient.

LF: What advice do you have for patients who are newly diagnosed with advanced-stage lung cancer?

AS: I recommend that all patients with newly diagnosed advanced-stage lung cancer undergo multiplex molecular testing and PDL1 testing.  While EGFR, ALK, and ROS1 are the best studied of the molecular targets, there are many other important targets for which we have highly active targeted therapies—for example, BRAF, MET, RET, and NTRK1.  I would also recommend that all patients consider participating in a clinical trial because it is the only way we have to bring new discoveries to patients and it is a great way for patients to access the latest cutting-edge treatments. Finally, I would also suggest that patients get involved with advocacy and research organizations such as LUNGevity Foundation.  LUNGevity is an amazing resource for patients and their families and also helps fund critical research into new treatments for lung cancer.  Many patients and oncologists participate in LUNGevity’s Breathe Deep walks and other events, which are so important to raising awareness and helping to connect all of us fighting against lung cancer.

(Dr. Shaw is a member of LUNGevity Foundation’s Scientific Advisory Board. She is also Director of the Center for Thoracic Cancers at Massachusetts General Hospital and an Associate Professor of Medicine at Harvard Medical School.)

Juhi Kunde, MA, is a science writer for LUNGevity. Juhi Kunde

Blog category: 
-> Treatment


I am happy for the targeted therapies that are available. But saddened there is nothing for Kras.

Hi Ceilann,

Thank you for your comment. Considerable progress has been made our knowledge and understanding of KRAS, and some drugs have shown promise in the preclinical space. We are hoping to see some of these drugs enter clinical trials soon.



What is the best approach for a long term Crizotinib patient (3 years).... stay on Crizotinib until there is progression and potentially brain tumours or switch to Alectinib as it crosses the BBB more effectively?

Dear Di Darcey:

Thank you for reaching out. Several factors, such as the age and health status of the patient, would decide what would be the best course of action. Both options - stay on crizotinib or switch to alectinib - may be possible. The ultimate decision should be made through shared-decision between the patient and the doctor.



Hi,what about patient with ros1 who fell from crizotinib after 7 month,what is the next treatment?

Good morning, Orly. Thank you for reaching out. If a patient has ROS1-positive lung cancer and has progressed on crizotinib after 7 months, please talk to your doctors about clinical trials.  I would also recommend you check out ROS1ders website on the latest research in ROS1-positive cancer. ​


After a patient progresses on a second TKI do you recommend re-biopsy also in your opinion can a blood biopsy be done instead of a regular biopsy?

Hi Sharon,

Thank you for reaching out. The decision to do a liquid biopsy would depend on the type of mutation and the health status of the patient and should be made by the patient and the oncologist together.  Certain types of mutations can definitely be tested through a blood test but if the test is negative, then a re-biopsy is recommended. 

I am somewhat newly diagnosed with Stage IV NSCLC with MET Exon Skipping mutation. I just started Crizotinib and I do not know what to expect.

Really lucky to get a chance to read real life stories of lung cancer patients and cases of their targeted therapies. And nice to meet here Alice Shaw, an innovator in the field of targeted therapies for lung cancer.


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