People with limited-stage small cell lung cancer may benefit from adding immunotherapy to chemoradiation, but not if both treatments are given at the same time, new research finds. The results suggest that the timing of immunotherapy plays a key role in its ability to extend survival. Findings from the multi-institutional phase III trial, which also found that twice-daily radiation treatments offered greater survival benefits than once-daily treatment, will be presented today at the American Society of Radiation Oncology (ASTRO) annual meeting.
The research comes on the heels of a recent study showing that immunotherapy given after completion of radiation and chemotherapy can increase overall survival for people with limited-stage small cell lung cancer. Researchers in this new study, the NRG Oncology/Alliance LU005 trial, wanted to test whether there would be a similar benefit when the treatments were given at the same time.
The introduction of immunotherapy marked the first breakthrough in the treatment of small cell lung cancer in decades. Now, we’re seeing that if you give immunotherapy at the same time as chemoradiation, it doesn’t have the same survival benefit as when we add it after standard treatment.”
Kristin Higgins, MD, principal investigator of the trial and radiation oncologist, professor and chief clinical officer, City of Hope Cancer Center, Atlanta
“This seemingly small difference in the timing of drug administration has a very significant impact on outcomes. At the same time, we found that changing the way you deliver radiation—giving it twice a day—improved survival rates compared to the once-daily approach ».
Lung cancer is the leading cause of cancer death for both women and men in the U.S. Small cell lung cancer, a particularly aggressive form of the disease, accounts for 10% to 15% of all lung cancers. Standard treatment for patients with limited-stage disease, which has not spread outside the chest and is potentially curable, includes concurrent radiation therapy and chemotherapy. While treatments may be effective initially -? the five-year overall survival rate is 30% -? cancer often recurs and options for additional treatment have historically been limited.
Earlier this year, the landmark phase III ADRIATIC trial found that adding a similar immunotherapy agent (durvalumab) six weeks after completing chemoradiation reduced patients’ risk of death by 27%. The ADRIATIC trials and similar trials that showed a survival benefit from this new class of drugs were “the first therapeutic improvements for this ‘forgotten cancer’ in decades,” Dr. Higgins said. NRG Oncology/LU005 adds to this progress by shedding light on the importance of when treatment is delivered.
For the study, Dr. Higgins and colleagues randomized 544 patients at centers in the US (n=500) and Japan (n=44) to receive standard chemoradiation with or without atezolizumab immunotherapy. All patients received radiotherapy either twice daily to a total dose of 45 Gy (47.2% of participants) or once daily to a dose of 66 Gy, as well as four cycles of concurrent chemotherapy. For patients in the experimental arm, atezolizumab was also given every three weeks starting at the start of radiation, for a maximum of one year. Prophylactic cranial radiation was prescribed at the discretion of the investigator for patients with a complete or near-complete response to chemoradiation. The median follow-up for this second planned interim analysis was 21 months.
Contrary to expectations, concurrent treatment with atezolizumab and chemoradiation did not improve survival rates compared with standard care. After one year, overall survival for patients who received chemoradiation alone was 82.6%, compared with 80.2% with concurrent chemoradiation and atezolizumab. At two years after treatment, the rates were 62.9% and 58.6%, respectively, and at three years, 50.3% and 44.7%. Median overall survival for patients in the standard treatment arm was 39.5 months, compared with 33.1 months for those also receiving immunotherapy (HR=1.1, 95% CI: 11.3-18.2) .
The lack of survival benefit when immunotherapy is given along with chemoradiation, rather than after radiation is completed, suggests that the activity of this type of immunotherapy is reduced when given concurrently with chest radiation, likely due to the inherent immunosuppressive effects of radiation, Dr. Higgins said.
“We know that radiation suppresses the immune system to some degree in a direct sense, and immunotherapy relies on the immune system to be effective,” he explained. “Adding these drugs after radiation can make the immunotherapy more powerful, but you have to let the immune system recover to really see the two work well together.”
Adding concurrent immunotherapy to chemoradiation also did not improve progression-free survival (median 11.5 months with atezolizumab vs. 12.0 months without) or distant metastasis-free survival (13.2 vs. 16.8 months, respectively).
“Sometimes if you give too much treatment at once, it actually has worse results,” Dr. Higgins said. “And this trial showed that. But at the same time, we saw that changing the way you give radiation can help.”
There was a benefit of twice-daily radiation over once-daily radiation, regardless of study arm. In both groups, patients treated twice a day lived longer on average. Median overall survival for those treated twice daily was 35.4 months, compared with 28.3 months for those treated once daily (HR=1.44, 95% CI: 1.10- 1.89).
Most radiation oncologists in the U.S. prefer the once-a-day approach because it presents fewer logistical challenges in delivering treatment, Dr. Higgins said, but these data suggest a possible need to reevaluate current practices.
“Although this was not the primary endpoint of the study, we clearly see that patients receiving radiation for small cell lung cancer do better when you treat them twice a day,” he explained. “Many physicians and patients may find twice-daily radiation more cumbersome, but these data show that delivering radiation in a more compact manner is beneficial for survival.”
