Do you offer consolidative thoracic radiation for oligometastatic NSCLC following upfront immunotherapy?

Yes, I do offer consolidation in patients with oligometastatic lung cancer after immunotherapy. Like @Dr. First Last, often these patients are referred to me at "oligoprogression," when one lesion progresses (often the primary or largest site), but most minor lesions appear to be under control. The medical oncologist doesn't want to switch from a well-tolerated antibody to more toxic chemotherapy when only one lesion among 3 or 4 is growing. In that sense, this XRT isn't true consolidation, but in general, it is better to gain control early rather than too late. If immunotherapy is like all other known anti-cancer agents, it will probably work best when the overall burden of disease is low.

My practice is an extrapolation from the trial by Iyengar P, et al, a small randomized phase 2 study at UT Southwestern that showed consolidative radiation after chemo-RT nearly tripled the duration of progression-free survival. From their abstract: "The trial was stopped to accrual early after an interim analysis found a significant improvement in PFS in the SAbR-plus-maintenance chemotherapy arm of 9.7 months vs 3.5 months in the maintenance chemotherapy-alone arm (P = .01)." Reference:

1.Is it safe to give immunotherapy after prior radiation?
Yes. We know from patients treated at UCLA with pembrolizumab after chemo-radiation for non-small cell lung cancer, that giving immunotherapy later did not increase the risk of pneumonitis, when compared to those who never received lung radiation. Patients who received prior radiation generally outlived those who did not, by double: 10.7 months with prior radiation versus 5.3 months without (Shaverdian N, Lisberg AE, Bornazyan K, et al, Lancet Oncol, 2017).

We also know from the PACIFIC Trial, which gave durvalumab immunotherapy after chemo-RT to stage IIIB non-small cell lung cancer patients, that safety is similar between those who did or did not receive radiation and immunotherapy. Notably, the median time to death or distant metastases was 59% longer with chemo-RT plus immunotherapy (23.2 months) than with chemo-RT alone (14.6 months). (Antonia SJ, Villegas A, Daniel D, et al; NEJM, 2017)

2. Is it safe to give radiation and immunotherapy at the same time?

Short answer: signs point to yes. We know from melanoma, where not just one but two immune checkpoint drugs are given together (ipilimumab+nivolumab) that adding radiation does not significantly increase local immune side effects. For example, radiating the abdomen does not increase the risk of colitis or hepatitis (of course, you still need to meet your SBRT dose constraints). This comes from the work of Dr. Jonathan Schoenfeld, Dr. F. Stephen Hodi, and others in Boston who looked at side effects among patients who received PD-1 blockade, anti-CTLA-4, or both within 2 weeks of radiation therapy. The highest risk of any immune side effect was seen among those receiving both PD-1 and CTLA-4 inhibitors together, which is well known from studies without radiation, but radiation didn't specifically appear to worsen local side effects like pneumonitis.

Reference: Bang A, Whilhite TJ, Pike LRG, et al; Multicenter evaluation of the tolerability of combined treatment with PD-1 and CTLA-4 immune checkpoint inhibitors and palliative radiation therapy. Int J Rad Oncol Biol Phys, 2017. They also had a good poster on this at the Society for Immunotherapy of Cancer meeting in 2016.

The question of how to combine immunotherapy and radiation has also been evaluated in a prospective randomized trial at MD Anderson that gave radiosurgery to lung or liver metastases during ipilimumab immunotherapy. This study was presented ASTRO meeting in 2017, by James Welsh, MD. His group showed combination ipilimumab plus radiosurgery to the liver or lung was safe and well tolerated with no severe (grade 4 or 5) toxicity.

Of note, most combinations of PD-1 blockade seem to result only in the ADscopal effect (local, on-target synergy with concurrent XRT), whereas adding CTLA-4 blockade seems necessary but not always sufficient for a broader immune response (ABscopal). Giving both drugs before and also during radiation is probably necessary for the best chance of a favorable interaction. At least that seems to be the case with many of the melanoma and now renal cell case reports, e.g. LaPlant Q, Deselm C, Lockney N, et al, Potential abscopal response to dual checkpoint blockade in renal cell carcinoma. Practical Radiation Oncology 2017 7:396-399.

Its important to point out that these patients can be enrolled on the NRG LU-002, which has recently been amended to include metastatic NSCLC patients who get immunotherapy as first-line therapy and have limited sites of disease afterwards.  The trial randomizes to consolidative RT or not, and I think this highlights what a good question this is.

I do offer RT to selected patients in this situation.  When you look at patients who respond to immunotherapy, there appears to be a subset who have 1 or 2 or 3 sites of disease that either don't respond as well, or begin to progress.  Its not clear whether these have evolved focal resistance, or in some way escaped immune surveillance entirely.  In my experience, after local therapy these patients frequently continue to respond to immune therapy afterwards at other sites.

I don't offer RT to all patients with measurable disease after immune therapy, unless there is reasonably good evidence that those sites are progressing or otherwise "active".  I guess I'm making the distinction between using RT as consolidation therapy, and treating oligoprogressive areas.  I think this is a great area for investigation.