Combined Modality Approach May Benefit Select Patients With Oligometastatic NSCLC

Daniel Gomez, MD

Researchers’ understanding of the biology of oligometastatic non—small cell lung cancer (NSCLC) continues to evolve, and there is now a basis for more aggressively treating a specific subset of patients with combined modalities, said Daniel Gomez, MD.

“There are ongoing attempts to identify who exactly those patient subsets are,” said Gomez. “[The questions are], ‘can we determine upon diagnosis or at the beginning of therapy who should be treated aggressively and who should receive standard systemic therapy, whether that be chemotherapy, immunotherapy, targeted therapy, etc.?’”

An area of particular interest in the space has been exploring the potential benefit of combining immunotherapy with radiation therapy, based on the proven synergy between the 2 modalities. Although early data look promising, longer-term data are needed to understand the proportion of patients with oligometastatic disease that will derive benefit from this approach, Gomez explained.

Specifically, stereotactic body radiation therapy (SBRT) in combination with immunotherapy is under investigation in several prospective clinical trials.

“The questions will be, ‘how much do we have to gain by adding immunotherapy to SBRT in early-stage disease and how much do we have to gain by adding SBRT to immunotherapy in advanced-stage disease?’” said Gomez.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Gomez, director of Thoracic Oncology, chief of Radiation Oncology, Manhattan Service, Memorial Sloan Kettering Cancer Center, provided insight on the different treatment approaches under exploration for those with oligometastatic disease.

OncLive: How has treatment of patients with oligometastatic NSCLC shifted in recent years?

Gomez: We have seen somewhat of a shift over the past 5 years or so due to this potential for an oligometastatic state, biologically, and because of emerging data—first retrospective, then prospective, and then most recently, some actual randomized data—there is more of a basis for treating aggressively in a selective subset of patients.

What we're seeing is an evolution from the historic paradigm of patients being treated with systemic therapy, failing, and then [receiving] more and more systemic therapy, to attempting to define which patients benefit from a combined modality approach, which includes systemic therapy, radiation therapy, and even surgery.

How is radiation therapy being combined with immunotherapy in an attempt to improve outcomes?

Right now, immunotherapy is being used in several metastatic settings in NSCLC. The role [of this approach], specifically in oligometastases, is being defined. There’s a potential advantage to combining immunotherapy with radiation therapy in this scenario through the synergy between the two modalities. There have been some studies that have already been published looking at this and have provided preliminary data.

However, in the next 2 to 3 years, we'll start to find out more about the true proportion of patients who derive this synergistic effect—meaning, [identifying] which patients do better with immunotherapy plus radiation therapy or surgery than either modality alone. That’s through primarily the abscopal effect with radiation therapy. Are we eliciting some host response that's then allowing us to control disease and provide long-term survival in a greater proportion of patients? I believe that right now, [immunotherapy is] primarily being limited to the polymetastatic setting, but a lot of work is being put into determining which patients would benefit from combining that [approach] with radiation therapy to provide longer-term [disease] control.

How is pembrolizumab (Keytruda) being explored in combination with locally ablative therapies?

There's at least one single-arm prospective study that has been published combining the two treatments in NSCLC that came out of the University of Pennsylvania, I believe. I know that [this approach is] being studied in other prospective trials as well, but given how much of a benefit we've seen in the metastatic setting overall, this is a very ripe area to continue to study within the context of radiation therapy as well.

Could you speak to the promise of SBRT in this space? Are there any safety concerns with this approach?

SBRT in itself is pretty well tolerated. There are certainly more complex cases that have a higher chance of significant toxicity. Those [cases include] centralized tumors, particularly those that involve the bronchus or even those that are adjacent to the mediastinum, larger tumors, or those involving the chest wall where you have a greater risk of chest wall toxicity or pneumonitis. However, in general, SBRT has an acceptable toxicity profile.

It remains to be seen how this [approach] will play out in the setting of immunotherapy. With studies that combine SBRT and either induction concurrent or adjuvant immunotherapy, we may see a slight bump in some of these toxicities. However, overall, because the current rate is relatively low, I don't anticipate that this will be something that [will prohibit us from] combining the two [treatments].

What research is being done to address these questions?

There are at least 3 prospective studies being done in the setting of SBRT and immunotherapy that [have already been] initiated or are close to being initiated. One is by Merck, one is a SWOG study, and then there is PACIFIC-4, which is the follow-up to PACIFIC-2, which is looking at the role of immunotherapy in early-stage disease.

There are also several studies that are looking at SBRT plus immunotherapy. A couple have been published with nivolumab (Opdivo) and ipilimumab (Yervoy). There are also studies with pembrolizumab and with a variety of immunotherapy agents that are looking at which patients who have more advanced disease and are being treated with immunotherapy should be selected for SBRT.

What advances have been made with targeted therapies?

That poses a whole separate question, because often those patients, even in the metastatic setting, do quite well [with this approach]. They can have progression-free survival (PFS) rates that are among the magnitude of 1 year—even more. Therefore, it's a higher bar in terms of the benefit of local consolidative therapy.

In the study that we did at The University of Texas MD Anderson Cancer Center, there was a percentage of patients who had EGFR or ALK alterations that were randomized to either continue systemic therapy or radiation therapy plus systemic therapy. The numbers were too small to actually make a comparison, but all of those patients did quite well.

Now there are several ongoing studies that are randomizing patients specifically with EGFR mutations and are looking at the benefit of local therapy versus continued TKIs in that scenario. Those [data] will be very interesting, again, because those treatments are quite effective for those patients with molecularly targetable lesions. It will be interesting to see how much impact the addition of aggressive therapy with radiation therapy or surgery [will have on outcomes].

What research needs to be conducted in order to move the needle forward?

There are several questions that still need to be answered. We have some preliminary, small phase II data that shows that there's a benefit in PFS and potentially overall survival in this patient cohort, but many of these trials are limited and they're not well selected.

The first thing that needs to happen is that there need to be larger, randomized studies that assess these questions in phase III fashions. Second, studies need to incorporate more novel systemic agents. The studies that have been published in the randomized setting have been pre-immunotherapy. Incorporating immunotherapy [into these trials] will make them more contemporary and applicable. Third, the assessment of specific subsets of patients who have varying levels of immunotherapy markers or molecular alterations, such as EGFR or ALK, and determining how [effective] local consolidative therapy is in those subsets [is needed]. That’s the other focus of many of these studies.

Two other additional areas of interest are the correlative studies that we mentioned—defining the biologic state and then determining if patients with oligometastatic disease at presentation behave similarly to those with oligoprogressive disease. Those are cases in which patients have more metastases at presentation but then only have progression in a small number of lesions. Biologically, it can be inferred that those [cases] may be different in that one has initial limited disease and one has widespread disease with progression in a small number of lesions. However, the data are a little mixed on how different, if at all, they are. Therefore, studies that focus on each of the subgroups of patients and compare results will allow us to better classify patients.