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Ipilimumab with radiation may slow late-stage cancer tumor growth
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The combination of ipilimumab and stereotactic body radiotherapy delivered sequentially demonstrated promising response rates and survival in patients with solid tumors and metastatic lung or liver lesions, according to prospective phase 2 study results presented at the American Society for Radiation Oncology Annual Meeting.
“If you have someone with 10 or 20 sites of metastatic disease, you cannot irradiate them all,” James Welsh, MD, associate professor of radiation oncology at The University of Texas MD Anderson Cancer Center, said during a press conference. “So, this work is taking stereotactic body radiotherapy combined with immunotherapy and trying to get responses in other areas where we do not even add radiation.”
Welsh and colleagues evaluated a combination SBRT with ipilimumab (Yervoy, Bristol-Myers Squibb) — a CTLA-4 inhibitor — in 100 patients with metastatic disease refractory to standard therapy. Patients had at least one lung or liver lesion amenable to SBRT and at least one noncontiguous lesion.
The most common primary histologies included adenocarcinoma (n = 55) and squamous cell carcinomas (n = 13).
“These are heavily pretreated patients, many of whom progressed on prior PD-1 drugs,” Welsh said.
Patients received 3 mg/kg ipilimumab every 3 weeks for four cycles plus radiation given concurrently — starting on day 2 of cycle 1 — or sequentially, 1 week after the second ipilimumab dose.
Researchers assigned 20 patients each to one of five treatment cohorts:
- concurrent liver 50 Gy;
- concurrent lung 50 Gy;
- sequential liver 50 Gy;
- sequential lung 50 Gy; or
- sequential 60 Gy to lung or liver lesion, whichever was bigger.
Patients received 50 Gy radiotherapy in four fractions and 60 Gy in 10 fractions.
“We are trying to answer simple questions,” Welsh said. “What is the right dose of radiation to use? What is the right sequence — should it be immunotherapy first then radiation? What’s the better site — is it better to do the lung or the liver? So, we have five different arms to try to get some insight into these different questions.”
When researchers evaluated response rates to treatment in nonirradiated tumors, they observed the greatest benefit in the lung cohorts. In the concurrent lung cohort, 42% achieved stable disease and 58% achieved clinical benefit, meaning patients experienced tumor shrinkage or went 6 months without tumor growth. In the sequential lung cohort, 47% achieved stable disease, and 63% achieved clinical benefit.
In the concurrent liver cohort, 21% of patients achieved stable disease and 26% achieved clinical benefit. In the sequential liver cohort, 25% achieved stable disease and 31% achieved clinical benefit.
Fifty-two percent of patients in the sequential 60-Gy cohort showed clinical benefit.
Partial responses occurred in three patients in each of the lung arms, one patient in each of the liver arms and two patients in the 60-Gy arm.
In the overall population, 32% of patients had nonirradiated tumors that shrunk, and 47% achieved clinical benefit.
“This trial was in patients who do not respond to ipilimumab,” Welsh said. “That is clinically approved for melanoma, but there were no melanoma patients in this trial. This trial predominantly had patients with prostate, colorectal and lung cancer, which do not respond to ipilimumab.”
The low-dose scatter from the radiation is what helps the tumors respond, Welsh added.
“A small percentage of patients experienced a potential abscopal effect, where tumors that were not irradiated became smaller after we treated different sites with radiation,” Welsh said in a press release. “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.”
Median PFS for all patients was 5 months (95% CI, 2.7-7.2) and median OS was 12 months (95% CI, 9.3-14.6).
Sequential radiation to lung metastases over liver metastases appeared associated with improved 12-month PFS and OS, but no difference occurred between the concurrent groups.
No grade 4 to grade 5 treatment effects occurred. Twenty-seven patients experienced grade 3 toxicities related to ipilimumab, which included colitis (n = 8), diarrhea (n = 7), rash (n = 4), elevation of liver enzymes (n = 3), hypophysitis (n = 3), elevation of bilirubin (n = 1) and intestinal obstruction (n = 1). Grade 3 events attributed to combination therapy included liver enzyme increase and pneumonitis in one patient each.
“We found that the addition of SBRT for patients who are on immunotherapy to be safe and well tolerated, meaning that radiation oncologists can feel confident continuing immunotherapy for most patients when adding SBRT to lung or liver metastases,” Welsh said. “In fact, there may be additional benefit from combining the therapies in terms of improved disease control. Follow-up research in larger clinical trials is needed to determine which types of tumors and patients will respond best to this immunotherapy-radiation approach.” – by Alexandra Todak
Reference:
Welsh JW, at al. Abstract LBA-5. Presented at: American Society for Radiation Oncology Annual Meeting; Sept. 24-27, 2017; San Diego.
Disclosures: Welsh reports stock options or ownership in Healios, MolecularMatch, OncoResponse and Reflexion Medical. Please see the abstract for a list of all other authors’ relevant financial disclosures.
Perspective
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Joshua E. Meyer, MD
This study is significant as it represents a substantial prospective experience with the combination of high-dose radiation and immunotherapy. The combination appears safe, with a toxicity profile similar to that expected with ipilimumab alone. The stratification into groups of either concurrent or sequential therapy is relevant, as we are still learning about the optimal timing of immunotherapy and radiation. Additionally, this study provides fascinating data suggesting that there may be a difference in the immunological response of a metastasis in the lung vs. the liver. Additional analysis will be necessary to help 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.
Overall, this study represents a substantial step forward for the field. 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.
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Brian Czito, MD, FASTRO
Welsh and colleagues evaluated a group of very poor-prognosis patients with stage IV cancer who otherwise failed standard treatments. These patients were treated with a combination of high-dose radiation and the immunotherapy agent ipilimumab. The preliminary results suggest that treatment using both modalities can halt tumor growth in 30% to 60% of patients, with treatment that was generally very well tolerated. With a proposed mechanism of the irradiated tumor acting as a vaccine of sorts to stimulate the body’s own immune response, this cutting-edge strategy provides support for larger, future trials investigating this mechanism of action and novel approach.
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