Ablative Radiotherapy Controls Resistant Non-Small Cell Lung Cancer in Clinical Trial

Patient receiving stereotactic body radiation therapy at Memorial Sloan Kettering Cancer Center.

Stereotactic body radiation therapy, which uses extremely precise, intense doses of radiation, proved to be effective at controlling lung cancer that had spread to a small number of sites.

Non-small cell lung cancer (NSCLC), the most common form of lung cancer, is often diagnosed at an advanced stage. About half the time, it has already spread around the body and has reached stage 4. The standard treatment for most patients with metastatic NSCLC is systemic therapy (drugs that spread throughout the body) such as chemotherapytargeted therapy, or immunotherapy.

Systemic therapy, however, can become less effective against metastatic cancer over time. In some people, the treatment is still controlling the cancer in most places, but a small number of areas have begun to grow. This is called oligoprogressive disease. For these patients, the critical question becomes: Can radiation treatment stop cancer growth at this handful of sites so that systemic treatment can keep doing its job everywhere else?

Now a Memorial Sloan Kettering Cancer Center (MSK) team has shown that a highly focused radiation therapy called stereotactic body radiotherapy (SBRT) can keep oligoprogressive lung cancer under control more than four times longer than when patients receive standard care alone.

First Trial To Demonstrate Benefit of Radiation Treatment for Oligoprogressive Cancer

The phase 2 clinical trial (research study) published in The Lancet is the first to demonstrate the benefit of radiation treatment on oligoprogressive cancer. It suggests SBRT should be used on more patients with oligoprogressive NSCLC to stop the cancer from growing.

Daniel D’Amico was the first patient, and one of 106, to participate in the study. The father of five was diagnosed with stage 4 NSCLC at age 48. Now, nearly five years after his last SBRT treatment, his disease remains stable.

“I’m grateful to have been able to participate in this clinical trial,” Daniel says. “I knew it was my only hope — I felt I could try this, or do nothing and die. This gave me a chance.”

The research was led by MSK radiation oncologist C. Jillian Tsai, MD, PhD, and supervised by Simon Powell, MD, PhD, Chair of MSK’s Department of Radiation Oncology.

“This could provide a huge benefit for many people with lung cancer whose disease starts to progress after the first line of treatment,” Dr. Powell says. “When we identify oligoprogressive sites where cancer has become resistant, we can treat them with this focused, ablative therapy and achieve good long-term results for the patient.”

Clinical Trial Results Showing Effectiveness of SBRT for Lung Cancer

SBRT delivers extremely precise, intense doses of radiation while minimizing damage to healthy tissue. It uses sophisticated image guidance that pinpoints the exact three-dimensional location of a tumor.

In the clinical trial, called CURB (Consolidative Use of Radiotherapy to Block Oligoprogression), 106 patients with either non-small cell lung cancer or breast cancer were randomly split into two groups:

  • One group received standard therapy (chemotherapy, immunotherapy, or targeted drugs).
  • The other group received standard therapy plus SBRT.

The patients were then monitored for up to a year with imaging scans to measure disease progression:

  • For the lung cancer patients, there was a striking difference in outcomes. Median progression-free survival was 10 months for those receiving the added SBRT, compared with 2.2 months in the group receiving only the standard of care. (“Progression-free survival” is the time the cancer remains under control without getting worse.)
  • In the breast cancer patients, there was no significant difference in disease control between the two groups.

Dr. Powell says the researchers are investigating why there was more benefit for lung cancer patients than breast cancer patients after adding SBRT to standard therapy. He suspects the main reason may be that breast cancer has more effective systemic therapies that are available if the first one fails. Therefore, adding SBRT has less impact over time in breast cancer. However, there could be additional biological reasons, including differences in the immune response to SBRT, which are under investigation.

This could provide a huge benefit for many people with lung cancer whose disease starts to progress after the first line of treatment.
Simon N. Powell Chair, Department of Radiation Oncology; Enid A. Haupt Chair in Radiation Oncology

Previous studies have shown that SBRT could be effective if used when metastatic disease was first found at a few sites (oligometastasis). The CURB trial applies to existing metastatic disease that had started to progress (oligoprogression).

“The CURB study is the first randomized trial to do a direct comparison between the new approach and using standard of care alone,” Dr. Powell says.

Getting Radiation Oncologists Involved Earlier for Metastatic Cancer Patients

The researchers say the findings from CURB and similar studies highlight the critical need to involve radiation oncologists early in the care of people with metastatic cancer.

“Previously, radiation therapy for these patients was used mainly to relieve symptoms,” says Dr. Tsai, who is now at Princess Margaret Cancer Centre in Toronto. “Now the availability of advanced, targeted, high-dose techniques offers the chance to extend survival.”

Using Blood Tests to Measure Treatment Effectiveness

In addition to imaging scans, the researchers measured cancer progression by analyzing circulating tumor DNA in blood samples from the patients. This proved to be a useful predictor of whether the cancer was being controlled.

“This blood test is the tool we need for metastatic disease — to know if we’re getting a good treatment effect or not,” Dr. Powell says. “Although we used it in just an analytic way, in the future we could use it to guide treatment decisions.”

He says researchers are planning a phase 3 trial to test the approach in a larger patient group of lung cancer to validate the findings. The phase 3 trial is expected to open for accrual in 2024.

SBRT Prolongs Effectiveness of Systemic Treatment for Daniel

When Daniel was diagnosed with stage 4 lung cancer in 2018, he received systemic therapy under the care of MSK medical oncologist Juliana Eng, MD, at MSK Commack on Long Island. He took pills that targeted a mutation in his tumor called BRAF.

For the first year, the cancer was controlled well. But then a scan showed metastatic cancer growing near his heart, windpipe, and esophagus. Given its location, surgery was considered far too risky. Even though Daniel had no symptoms, the mass had to be treated without delay before it grew and pressed on surrounding organs.

“In the past, we likely would have switched Daniel’s treatment to chemotherapy and immunotherapy, hoping it would slow the oligoprogressive disease,” Dr. Eng says. “But they might not even have worked for as long as the initial targeted drugs. Plus, every new treatment carries its own side effects and risks.”

She proposed Daniel consider SBRT treatment as part of the CURB trial. Daniel did not hesitate to join.

“I had nothing to lose, given my situation,” he says.

In February 2019, he began receiving SBRT under the care of MSK radiation oncologist Narek Shaverdian, MD.

“Usually, I would be using SBRT on someone like Daniel only if he had symptoms, but the trial allowed us to see if targeting this one area with radiation would allow him to continue on the same drug combination that had been working,” Dr. Shaverdian says. “The disease was in a very tricky spot, where even radiation was risky, but we have the expertise to target the metastases with very high precision.”

Daniel had 15 doses over three weeks at MSK Commack, a short trip — often made on his motorcycle — from his home. There were no significant side effects, and Daniel was able to stay active and continue working full-time as an internet technology director.

Continuing an Active Life

Today, nearly five years after his radiation treatment, Daniel’s cancer continues to be under control. He has CT (computed tomography) scans every three months to watch for growth and continues his systemic treatment. He adopted a Mediterranean diet and eliminated alcohol, but his life has otherwise not changed much since the diagnosis. Still working full-time, Daniel enjoys relaxing with his wife, riding his motorcycle, and playing guitar.

He says he’s grateful to have been able to join an MSK clinical trial studying a new approach. Daniel knows someone with late-stage lung cancer whose doctors chose a more conventional treatment — and it didn’t work.

“You have this thought of ‘Why didn’t they try this or that on him?’ ” says Daniel. “I realize I’m lucky in that I reacted very well to the drugs and the radiation, but also that I had the chance to be on the trial in the first place. You just wish everybody could have this opportunity.”

Additional Authors, Funding, and Disclosures

Additional authors include Jonathan T. Yang and Erin F. Gillespie, formerly at MSK and now at the University of Washington; Juber Patel, Annemarie F. Shepherd, David Guttmann, Randy Yeh, Daphna Y. Gelblum, Azadeh Namakydoust, Isabel Preeshagul, Shanu Modi, Andrew Seidman, Tiffany Traina, Pamela Drullinsky, Jessica Flynn, Zhigang Zhang, Andreas Rimner, Daniel R Gomez, Nancy Y. Lee, Michael Berger, Mark E. Robson, Jorge S. Reis-Filho, Nadeem Riaz, and Charles M. Rudin.

The study was funded by the National Cancer Institute Cancer Center Support Grant P30 CA008748. Dr. Powell receives funding support from the Breast Cancer Research Foundation and the National Cancer Institute P50 CA247749 grant.

Dr. Tsai is on the Advisory Board of Nanobiotix and Varian Medical and received consultation fees and honorarium support from Varian Medical. Dr. Rimner received grants from Varian Medical, AstraZeneca, Merck, Boehringer Ingelheim, Pfizer, and the National Cancer Institute at the National Institutes of Health. Dr. Lee is on the Advisory Board of Merck, Merck EMD, Nanobiotix, and Galera Therapeutics, and received consulting fees from Shanghai JoAnn Medical Technology, Yingming Consulting, and Varian Medical. Dr. Riaz received research support from Invitae. All other authors declare no competing interests.