IMMUNOTHERAPY-RT COMBINATION

Among heavily pretreated cancer patients with solid tumors and metastases to either the lung or liver, the novel combination of the immunotherapy ipilimumab (Yervoy, Bristol-Myers Squibb) and radiation therapy provided rates of clinical benefit ranging from approximately 30% to 60%, according to phase 2 trial results.

Clinical benefit was defined as the sum of the rates of partial responses and stable disease; there were no complete responses, and most of the benefit was found in patients with stable disease.

This new combination approach differs from the more familiar strategy of "hitting a limited number of individual metastatic tumor sites for the sake of local control," explained lead author James Welsh, MD, of the University of Texas MD Anderson Cancer Center in Houston.

"If you have someone who has 10 sites of metastatic disease or 20 sites, we can't irradiate them all. So what we are trying to do...is taking stereotactic radiotherapy combined with immuno[therapy] and...trying to get responses in areas where we don't even add radiation," Dr Welsh commented.

He was speaking at a press briefing here at the American Society for Radiation Oncology (ASTRO) 2017 Annual Meeting, where study results were presented.

The study is "very different than what you will see at most presentations at ASTRO," he summarized.

The five-arm trial investigated a variety of schedules (concurrent and sequential radiation in combination with immunotherapy), as well as two doses of stereotactic ablative radiation therapy (50 and 60 Gy) and two disease sites (liver and lung) in an attempt to identify the most effective and least toxic method.

The trial used the first-ever approved immunotherapy, ipilimumab. However, another similar trial is now underway using the more efficacious nivolumab (Opdivo, Bristol-Myers Squibb).

In the current trial, which involved 100 patients, median progression-free survival was 5 months, and median overall survival was 12 months.

Clinical benefit was observed for 63% of the patients in the sequential 50-Gy lung cohort, 58% of the concurrent lung group, 26% of the concurrent liver group, and 31% of the sequential 50-Gy liver group. Also, in the larger-lesion sequential group, which included patients with lesions that were too big for stereotactic radiation therapy alone, higher-dose radiation (60 Gy) yielded a clinical benefit in 52% of patients.

Most of the benefit was in patients with stable disease; only a minority of patients achieved partial responses.

"We were surprised that a large percentage of patients achieved stable disease several months after treatment ― meaning that while their tumors didn't shrink, they did stop growing," said Dr Welch in a press statement. "Longer follow-up is needed to determine if this benefit of stable disease will endure over time."

Dr Welch also observed that in a small percentage of patients, a potential "abscopal effect" was observed. In these patients, tumors that were not irradiated became smaller after radiation therapy was administered at other sites. "For example, one patient with anaplastic thyroid cancer ― one of the deadliest types of cancer ― experienced a reduction in the primary tumor after we irradiated a lung metastasis. This patient had controlled disease for more than 13 months."

Overall, follow-up research in larger clinical trials is needed to determine which types of tumors and patients will respond best to an immunotherapy-radiation approach, said Dr Welch.

"The new results represent a substantial step forward for the field," said Joshua Meyer, MD, of Fox Chase Cancer Center in Philadelphia, Pennsylvania, who attended the meeting.

The new results represent a substantial step forward for the field. Dr Joshua Meyer

"The disease stability and response rates appear encouraging. However, in a nonrandomized study, it is difficult to quantify how much the radiation treatment is adding to the active immunotherapy of ipilimumab," he said.

The effect of the combination may be best in patients whose disease has spread to the lungs, suggested Marka Crittenden, MD, PhD, of the Oregon Clinic in Portland. "Radiation of lung lesions with ipilimumab appears to look more favorable than liver," said Dr Chittenden, who acted as the study's discussant at the meeting; she was referring to the superior rates of clinical benefit in the patients with lung cancer.

Fox Chase's Dr Meyer said the lung outcomes are "fascinating" because they suggest that "there may be a difference in the immunological response of a metastasis in the lung vs the liver." More study is needed to "understand whether this difference is really due to the site of metastasis or other factors predisposing patients to one or the other site of disease," he said.

Discussant Dr Crittenden observed that toxicity was "manageable" with hypofractioned radiation therapy plus ipilimumab in these patients.

Dr Welsh was more enthusiastic, saying the combinations were "very well tolerated" and calling the safety data "a very nice surprise."

No patients experienced grade 4 or 5 treatment-related side effects. Twenty-seven of the 100 participants experienced grade 3 toxicities related to immunotherapy. Two patients experienced grade 3 toxicities related to combination therapy, including one patient who experienced an increase in liver enzymes and one patient who developed pneumonitis.

The nonrandomized study had 20 patients in each of the five arms of the trial.

Eligible patients included those with metastatic disease that was resistant to standard therapies, with one or more lesions (in the liver or lung) and one or more additional metastases not touching the lung or liver lesion. The majority of patients (55%) had adenocarcinomas; 13% had squamous cell carcinomas; and 32% had tumors of other histologies.

All patients received four cycles of ipilimumab (3 mg/kg every 3 weeks) and stereotactic body radiation therapy to the site or sites of metastasis in either the liver or the lungs.

Concurrent radiation therapy began on day 2 of the first immunotherapy cycle to a total radiation dose of 50 Gy delivered in four fractions. Sequential radiation was administered 1 week after the second immunotherapy cycle to a total dose of 50 Gy delivered in four fractions, or 60 Gy in 10 fractions for larger lung or liver metastases.

Multiple study authors have financial ties with industry, but none are with Bristol-Myers Squibb, the makers of ipilimumab. Dr Meyer has disclosed no relevant financial relationships. Dr Crittenden has financial ties with multiple pharmaceutical companies, including Bristol-Myers Squibb, the makers of ipilimulab. 

American Society for Radiation Oncology (ASTRO) 2017 Annual Meeting. Abstract LBA-5, presented September 24, 2017.

Follow Medscape senior journalist Nick Mulcahy on Twitter: @MulcahyNick