Eric Ko on Combining Radiation Therapy With Immunotherapy to Treat Non–Small-Cell Lung Cancer

Oncology (Williston Park). 32(9):460-2.

Eric Ko, MD, PhD

ONCOLOGY spoke with Eric Ko, MD, PhD, a radiation oncologist at New York–Presbyterian Weill Cornell Medical Center in New York City, who recently published a review article[1] with his colleagues on strategies for combining radiation therapy with immunotherapy for the treatment of non–small-cell lung cancer (NSCLC).

1.Could you give us an overview of how radiotherapy is generally used in treating NSCLC? Is radiotherapy used more predominantly in earlier-stage disease?

DR. KO: Based on current practice guidelines, radiotherapy may be utilized across all stages of NSCLC, with different treatment intents. In early-stage disease, stereotactic body radiation therapy (SBRT) or stereotactic ablative radiation therapy allows the delivery of short-course, high-dose-per-fraction radiation treatments to lung cancer with curative intent. This is a very effective local treatment, often used for patients who are considered medically inoperable. It may also be used in patients who are surgical candidates.

In more advanced cases, such as large or central lesions not amenable to SBRT or any node-positive disease, conventionally fractionated radiation therapy is typically used, often with concurrent chemo, given the level 1 evidence to support this approach.

Patients with resectable, locally advanced disease may potentially receive radiation therapy along with chemotherapy in neoadjuvant or adjuvant settings.

Lastly, for metastatic disease, radiotherapy has traditionally been used in the palliative and sometimes consolidative settings, with the primary goals of addressing symptoms and stabilizing radiographically evident disease.

2.What is the accumulating preclinical evidence that there might be a synergistic systemic effect when local radiotherapy is combined with systemic immunotherapy?

DR. KO: There is convincing preclinical evidence that combining local radiotherapy with systemic immunotherapy, such as immune checkpoint inhibitors, can result in significant tumor regression at sites not targeted with radiation. This effect has been shown to mostly depend on the generation of tumor-specific immune responses.

What’s important in many of these experiments is that you lose the ability to control tumor growth at distant nonirradiated sites if you test the same strategy in an immunodeficient mouse, or selectively deplete effector cells such as CD8+ T cells, or if you use a different tumor type, presumably one without significant shared antigens.

In addition, this effect is rarely observed in the absence of immune checkpoint inhibitors. It should be noted that this so-called abscopal effect is not a phenomenon that is necessarily restricted to NSCLC, but may be observed across other tumor types as well.

3. Is there clinical evidence accumulating for this combination approach in lung cancer?

DR. KO: The strategy of combining SBRT or SBRT-like approaches with immunotherapy is still fairly new and has not made its way to broad clinical use yet. However, multiple early-phase trials have established a good safety record for this strategy, as well as displaying some promising signals in tumor control.

One good example is the PEMBRO-RT trial, which was presented at the ASCO [American Society of Clinical Oncology] Annual Meeting in June.[2] In this study, investigators from the Netherlands Cancer Institute showed that for metastatic NSCLC patients who have progressed past first-line therapy, a strategy that adds SBRT to one metastatic site, to a systemic regimen of the anti–programmed death 1 (anti–PD-1) antibody pembrolizumab, was effective in doubling the overall response rate-to greater than 40%. It should be noted that some of the observed differences could be due to differences in tumor programmed death ligand 1 (PD-L1) expression between groups. Regardless, these are exciting new data that will lead the way to additional strategies combining SBRT and immunotherapy.

We should also note the remarkably positive results of the PACIFIC trial in patients with unresectable stage III NSCLC,[3] in which there was a significant benefit in progression-free survival (PFS) when the anti–PD-L1 antibody durvalumab was given to patients who did not progress after definitive chemoradiation. However, this is utilizing conventionally fractionated radiation and also includes chemotherapy, so it is difficult to attribute the beneficial effects specifically to the combination of radiation with immunotherapy.

In addition, there was a recent post-hoc analysis of KEYNOTE-001[4] showing that patients who received radiation prior to pembrolizumab had increased PFS and overall survival. Although it is difficult to attribute the differences in survival outcomes specifically to the effects of radiation in this setting, these findings do provide supporting evidence for a beneficial effect in combining radiotherapy with immune checkpoint inhibitors.

4. So you are saying that patients are not yet being treated with this combination outside of a clinical trial?

DR. KO: There are some uses of radiotherapy-immunotherapy combinations in standard practice as well as in clinical trials. However, the majority of the patients being treated with the combination are being treated in the setting of a clinical trial.

Based on the PACIFIC trial discussed earlier, patients are now able to receive durvalumab after chemoradiation for unresectable stage III NSCLC.

In the metastatic setting, patients are frequently receiving immunotherapy and occasionally radiotherapy as well. However, when both are used, it is typically the case that treatment decisions are based on clinical indications for each modality rather than an attempt to optimize the immunologic response. Most, if not all, of the other radiation and immunotherapy combinations are still being given in the setting of ongoing clinical trials, which we summarized in the table in our recent Clinical Cancer Research paper.[1]

5. Of those trials, are there ongoing ones that you could highlight that combine radiation and chemotherapy?

DR. KO: There are many interesting ongoing trials, the vast majority of which are still early-phase. Along the lines of SBRT or SBRT-like combinatorial approaches, there is still a lack of consensus within the field as to the optimal dose-fractionation schedule to use when combining with immune checkpoint inhibitors.

Other questions include: Who are the ideal patients for this strategy? Should we focus on early-stage disease, locally advanced but nonmetastatic disease, or metastatic disease? Now that immune checkpoint inhibitors have made their way to mainstream clinical use and are indicated for a significant number of metastatic NSCLC patients in the first-line setting, does this present more of an opportunity to offer targeted radiation in at least some of these patients?

A large proportion of the ongoing trials are looking into SBRT and immune checkpoint inhibitors in the metastatic NSCLC population. This is the basis of one of our institutional trials, which combines radiation to a metastatic lesion with dual immune checkpoint blockade utilizing ipilimumab and nivolumab.

There is also increased interest in combining SBRT and immune checkpoint inhibitors for early-stage NSCLC, in some cases even in those patients deemed to be surgically resectable. Neoadjuvant radiation and immunotherapy trials, such as PembroX at the University of California, San Francisco, and our institutional trial of neoadjuvant durvalumab and SBRT, have the distinct advantage of allowing pathologic tissue assessment to follow, which will provide correlative data to help us better understand the underlying immunologic mechanisms. These trial endpoints are very important, as they will provide a rational basis for the design of future clinical trials.

Financial Disclosure:The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. Ko EC, Raben D, Formenti SC. The integration of radiotherapy with immunotherapy for the treatment of non-small cell lung cancer. Clin Cancer Res. 2018 Jun 26. [Epub ahead of print]

2. Theelen W, Peulen H, Lalezari F, et al. Randomized phase II study of pembrolizumab after stereotactic body radiotherapy (SBRT) versus pembrolizumab alone in patients with advanced non-small cell lung cancer: the PEMBRO-RT study. J Clin Oncol. 2018;36(suppl):abstr 9023.

3. Antonia SJ, Villegas A, Vicente D, et al. Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. N Engl J Med. 2017;377:1919-29.

4. Shaverdian N, Lisberg AE, Bornazyan K, et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol. 2017;18:895-903.