Decker Details Key Updates in Radiation for Advanced NSCLC

Although local ablative stereotactic body radiotherapy (SBRT) and chemoradiation (CRT) have added great value to the advanced non–small cell lung cancer (NSCLC) treatment paradigm, ongoing research is exploring whether local ablative therapy has other applications in practice, such as single-site recurrence, and its utility in combination with other therapies, according to Roy Decker, MD, PhD.

“There is a lot to be learned about which patients will benefit from this and what is the right way to do it,” said Decker, vice chair for clinical research of the Department of Therapeutic Radiology and director of the Clinical Trials Office at Yale Cancer Center. “Similarly, after decades of stasis in the treatment of locally advanced NSCLC, all of a sudden, a lot of exciting trials are being conducted on the backbone of concurrent chemoradiation. Right now, the standard of care is completely up in the air—at least in the next 5 years. I am really excited to see the results of those trials and where we go next.”

In an interview with OncLive^®, Decker, who is also the Yale Cancer Center’s associate director of clinical sciences, discussed the utility of interventional radiology and SBRT in patients with oligometastatic disease and detailed ongoing clinical trials for NSCLC as they relate to radiation therapy.

OncLive^®: You were involved with a phase 1 trial (NCT02621398) of pembrolizumab plus concurrent chemoradiotherapy in patients with locally advanced NSCLC. What were the key points of this research?

Decker: This was a trial that I was very excited to participate in, [along with first author] Salma K. Jabbour, MD, of Rutgers Cancer Institute of New Jersey. [It] was a very innovative design. The standard of care for inoperable, locally advanced NSCLC has been CRT followed by a checkpoint inhibitor, durvalumab [Imfinzi], which has been the standard since the phase 3 PACIFIC trial [NCT02125461] was published.

In this study, a checkpoint inhibitor was added incrementally earlier and earlier in the treatment course. It was a phase 1 study and, in the final cohort, patients received weekly paclitaxel and carboplatin with concurrent radiation and started full-dose pembrolizumab on the first day. They received it concurrently with chemoradiation and then as an adjuvant treatment [following] chemoradiation. It was really among the first studies to demonstrate that it was feasible to move that checkpoint inhibitor earlier on in therapy, where it potentially could have an even greater benefit.

What are the future plans for that research?

This trial, along with others, shows that this approach is feasible. Prior to conducting this study, there were some concerns about toxicity, but [the approach] was very well tolerated. Now a number of studies, both cooperative group studies and industry-sponsored studies, are adding various checkpoint inhibitors concurrently with radiation. We are going to have an answer to this question soon about whether it is better to add these agents on the first day of therapy or to wait until later.

You were a senior author on a multi-institutional analysis that examined SBRT in patients with operable, early-stage NSCLC. What was the significance of this research?

SBRT was initially developed for patients who were medically inoperable—either too old or too ill from a comorbid medical illness to undergo surgery. In those early studies, we learned that SBRT was a superior way to treat these [patients] compared with older techniques, such as fractionated radiation.

What has happened in the intervening decade or longer is that, increasingly, patients eligible for surgery are opting for SBRT instead. This is kind of a natural progression. We think that on a population basis, this is a good thing, because some of these high-risk surgical patients are selecting themselves out of that surgical pool. What our research showed was that the long-term outcomes for those patients seem to be excellent [and] that SBRT still does work when the patients are younger and healthier and tend to survive longer.

This has informed ongoing research with the addition of other adjuvant systemic therapy into this population. These patients are living long enough after SBRT.

What recent developments have practice-changing potential regarding local ablative therapies in oligometastatic or oligoprogressive disease?

As a radiation oncologist, [I find that] the treatments of oligometastatic, oligoprogressive, and oligorecurrent disease are exploding. Thus far, we have good data [supporting] the addition of locally ablative therapies, such as interventional radiology or SBRT, [which] are a valuable part of therapy for patients with metastatic disease in a few settings.

The phase 3 SABR-COMET-3 trial [NCT03862911] was a large, randomized trial involving multiple tumor types. A large proportion of [patients with] NSCLC showed that the addition of SBRT to systemic therapy improves survival.

Similarly, 2 studies have shown that for patients who completed first-line chemotherapy, the addition of SBRT to their residual sites of disease after completing their initial 4 cycles of therapy improved their survival. It delays the time to progression and can improve overall survival.

Now the question is “In what other clinical situations is it appropriate to do some [type] of local therapy?” One of the most common situations that is not covered by these trials is a patient who may have been responding to therapy but recurs in a single site. It is very tempting to treat that patient with surgery, radiation, or radiofrequency ablation. [We can watch to] see if they continue to respond to that systemic therapy longer or [determine] whether the next line of therapy can be delayed. For the most part, we do not know the answer to that question.

How do you optimally manage your patients with NSCLC who have developed brain metastases?

Historically, we have always been very aggressive about treating [patients with] NSCLC [who have developed] brain metastases, with either surgery or radiation. It used to be that whole-brain radiation was our only approach. With newer technologies, we can treat numerous metastases conveniently and get patients on to further systemic treatments as quickly as possible with minimal risk.

What has been interesting over the past several years is that we are increasingly learning that the modern systemic treatments, newer-generation targeted therapies, and checkpoint inhibitors can affect brain metastases. Similarly, we have learned that the newer EGFR or ALK [inhibitors] can penetrate the blood–brain barrier and can control brain metastases.

For patients in whom we think we have an active [central nervous system lesion], we are increasingly comfortable with close observation. If we see a patient with a new diagnosis, we will carefully review the scans and examine them with a multidisciplinary team. We will often treat metastatic lesions that we feel are threatening, behaving aggressively, or causing symptoms.

[However], for patients with numerous metastases, we are often comfortable just repeating scans at interval and deferring treatment as long as possible. What’s unknown is whether it is better to treat those patients up front or to defer treatment. Radiosurgery is a wonderful technique for brain metastases, and it has very minimal risk, but some risks are associated with it. [Therefore], certainly delaying avoiding or deferring that as long as possible is beneficial to the patients.

What efficacy has radiosurgery demonstrated in patients with small cell lung cancer (SCLC) who have developed brain metastases?

SCLC is a disease with a real predilection for recurring and spreading in the brain. We know that patients who have initially localized disease, or metastatic disease without brain metastases, have a very high risk of [brain metastases developing]. Again, historically, we have often treated these patients with whole-brain radiation therapy.

Whole-brain radiation is very effective, but it does have significant short- and long-term morbidities. Most significantly, it can result in significant fatigue and worsening of performance status. What is a concern for these patients in particular is [that] they may not be eligible to receive chemotherapy or immunotherapy if they are still recovering from whole-brain radiation. This can be very consequential.

We reviewed our experience in treating a relatively small number of patients with radiosurgery for SCLC brain metastases. These were patients who had never had whole-brain radiation of any kind. We were avoiding whole-brain radiation. We are not the first to publish a series like this, and our findings were very much consistent with what other people have shown, in that it is very effective in treating brain metastases.

For the most part, if they do recur, they can be successfully salvaged or treated again with radiosurgery later. They did not have an excess risk of dying and neurologic death. Most importantly, we were able to successfully avoid giving them whole-brain radiation for a long period of time.

These patients have a very high risk of relapse; SCLC has a very high mortality rate. Avoiding the neurocognitive toxicity of whole-brain radiation is critical for both continuing their systemic therapy and ensuring that they really have optimal quality of life.

What research efforts at your institution in these areas would you like to highlight?

The phase 3 SWOG S1827/MAVERICK trial [NCT04155034] is a study in patients with SCLC with either limited or extensive disease. These are patients who have finished their first-line systemic therapy, and this trial is randomizing them to either prophylactic cranial radiation or MRI surveillance. This is a large international randomized trial seeking to answer whether we can safely defer prophylactic cranial irradiation in these patients. It has a number of end points, including survival as well as neurocognition. [The goal is to] capture whether we are preventing adverse effects by limiting the risk of brain relapse or whether we’re avoiding neurocognitive problems by [deferring] the prophylactic cranial irradiation. It is a very exciting trial.

The other study is the randomized phase 3 S1914 [NCT04214262] trial, which is attempting to answer the question of whether neoadjuvant and adjuvant treatment can prevent recurrence in patients getting SBRT for early-stage lung cancer.

Patients will receive either standard SBRT or atezolizumab [Tecentriq] before, during, and after surgery. It is a wonderful trial. Atezolizumab is given for 6 months, so it is a shorter duration of therapy. This is something that could really improve outcomes in patients [receiving] SBRT, which is a growing population.

What other radiotherapeutic innovations are on the horizon for NSCLC?

Some exciting technology is specifically designed to address this, and one is the RefleXion unit of PET-directed therapy, which is well designed to treat multiple metastatic lesions.