Role of PORT Diminishes in Early-Stage NSCLC, as Novel Approaches Emerge for Unresectable Stage III Disease

Kristen Marrone, MD

The use of postoperative radiotherapy (PORT) appears to have diminished clinical relevance in the treatment of patients with early-stage non–small cell lung cancer (NSCLC), while immunotherapy and TKIs are changing the way disease control is discussed in those with unresectable stage III disease, according to Kristen Marrone, MD.

“[We have seen] so much evolving data regarding best [approaches] for each individual patient, particularly [with regard to] the use of radiation following surgery,” Marrone said. “The biggest excitement for us is that the use of immunotherapy with durvalumab [Imfinzi] has greatly improved OS for those patients who had unresectable lung cancer following chemotherapy and radiation.”

Although historically, PORT has been a standard approach in the setting of R1 or R2 resection, positive margins, surprise pN2 disease, and patients with pN1 disease who can’t receive adjuvant chemotherapy,¹ when examined in the phase 3 LungART trial (NCT00410683), this approach failed to significantly improve disease-free survival (DFS) vs no PORT.² The median DFS in the investigative and control arms was 30.5 months vs 22.8 months, respectively (HR, 0.58; 95% CI, 0.67-1.07; P = .16).

Additionally, data from the phase 3 PACIFIC trial (NCT02125461) supported the rationale to use checkpoint inhibitors after chemoradiation. Here, the use of durvalumab (Imfinzi) was found to improve median OS over placebo, at 47.5 months vs 29.1 months, respectively (HR, 0.71; 95% CI, 0.57-0.88).³

Now, investigators are examining the concurrent use of durvalumab and chemoradiation vs chemoradiation alone in patients with unresectable stage III NSCLC as part of the phase 3 PACIFIC-2 trial (NCT033519971), and the efficacy of osimertinib (Tagrisso) as maintenance therapy following chemoradiation in patients with stage III, unresectable EGFR-mutant disease, as part of the phase 3 LAURA trial (NCT03521154).

In an interview with OncLive® during a 2021 Institutional Perspectives in Cancer webinar on lung cancer, Marrone, the associate program director for the Hematology/Medical Oncology Fellowship Program, and an assistant professor of oncology at Johns Hopkins School of Medicine, discussed the evolving role of PORT in early-stage NSCLC and ongoing trials examining the use of immunotherapy and targeted agents in patients with unresectable stage III disease.

OncLive®: What are some of the key advances that have recently been made with regard to radiation in patients with NSCLC?

Marrone: For the stage I disease setting, surgery is the primary treatment of choice for patients, so getting them in quickly to see a surgeon and doing a proper workup with imaging, pulmonary function tests, and potentially a cardiac workup when needed, is important. In the stage II and III settings, the art of oncology comes into play. [That is where] we are thinking about how we can use systemic therapy with chemotherapy, either before or after surgery, of surgery is a good option for our patients. The use of radiation in that setting is reserved for [those who have] positive margins after the surgery. That has been a really big change in the past year, [the consideration of] radiation after surgery, and that is in the context of a recent [phase 3] study called LungART. That [research] is really going to change how we use radiation following surgery in the stage III setting in the coming years.

In the stage III setting, we break down into [subgroups of those with] stage IIIA, IIIB, and IIIC disease; [treatment] is really based on resectability, which often deals with nodal involvement and thinking about whether we can safely remove all the areas of cancer that we know about. The stage IIIA setting is the most complicated; [here] we can use chemotherapy then surgery, or surgery then chemotherapy, or even throw in some radiation—all of that really does [require] a multidisciplinary approach.

Unfortunately, in stage IIIB or IIIC lung cancer, we really cannot safely perform surgery, so then we are using concurrent chemotherapy and radiation, followed by 1 year of immune checkpoint inhibition with durvalumab, which is an anti–PD-L1 antibody. That was an exciting update [that we saw] this year; data showed that the survival benefit of doing that 1 year of immunotherapy remains even at 4 years. The median OS in that treatment setting is 47.5 months, so almost 4 years, and then the 4-year OS rate was 50%.

We love that for our patients, and we are excited to see those numbers [continue to] improve in other studies that are combining other drugs or [that are] moving the immunotherapy up with the chemotherapy and radiation.

For those with stage II disease, how do you determine whether to give chemotherapy neoadjuvantly or adjuvantly?

That is dependent on a lot of factors – both patient factors and cancer factors. A lot of the patient factors go into is whether this patient is a good surgical candidate in terms of thinking about will they retain function following a surgery such as that. In terms of neoadjuvant versus adjuvant chemotherapy, a lot of times that is based on nodal involvement and looking at where the cancer is, whether it is a big tumor with negative nodes, or whether the tumor has nodal involvement.

There are also best practices within each institution, because when you look at national guidelines, you see that those approaches are equally recommended. For a lot of academic institutions, we also want to try to offer our patients either a neoadjuvant or adjuvant clinical trial to see if we can improve outcomes in terms of decreasing risk of recurrence. In that setting we often will talk with them about those options, as well, and that often plays into whether we use chemotherapy before or after. In the stage II setting, as a whole, if patients are good surgical candidates, we usually will use the chemotherapy after, so in the adjuvant setting.

In terms of stage III disease, what is the role of surgery? Do you utilize different approaches with the goal of making patients more amenable to surgery?

When we consider N2 disease, so multiple lymph nodes involved or multiple station lymph node disease, we really do try to go with neoadjuvant systemic therapies, even potentially with concurrent radiation, in that setting. [We do that] to increase the likelihood of an R0 resection, which is the chance of getting all of the cancer out and having negative margins. We know that doing those 2 things ahead of time really can help with that. When I think about who we have considered surgery for first, we really have not thought about doing that; we usually use systemic therapy up front, and then go to surgery.

When we look back through our patient experience, many of our [patients with] stage IIIA disease ends up being those whom that was incidentally found at the time of surgery, so on PET scans. Mediastinal involvement and lymph nodal status were not the same pre-surgery as when they were taken to surgery. In that stage IIIA setting, where we have multi-station N2 disease at resection, those are the patients we then speak with about adjuvant therapy options.

Earlier you had mentioned the LungART trial. Could you elaborate on the preliminary data and the significance of this research?

Those data are impressive in that they really make us reconsider how we have used radiation in the stage III, N2 disease setting after surgery. We used to always offer radiation in that scenario because we thought it would help [provide] local control and prevent recurrence. The LUNG ART study showed that that was not the case.

No statistically significant difference in median DFS was observed [between those who received PORT and those who did not]. The control arm, [where patients did not receive PORT], experienced a median DFS of approximately 23 months, while it was about 30 months with the radiation. When you look at the 3-year DFS [rates], they were about 44% [in the control arm] versus 47% [in the PORT arm].

The mediastinal relapse rate was certainly lower with the radiation, but brain metastases were more common in the PORT group, while other metastases were about even [between the arms]. [These data] show us that [PORT] might help with mediastinal control, but when you look at the full patient experience, we are not really sure that the potential risks and the morbidity associated with the radiation are really going to give us that long-term control that we are looking for.

The phase 3 PACIFIC-2 trial (NCT03519971) is taking a closer look at sequencing. What insight might this research bring to the field?

PACIFIC-2 is currently ongoing and looks at using chemoradiation compared with immunotherapy plus chemoradiation. When you look at what that could offer us, it is going to be an interesting study. The issue is that for the patients who do not receive concurrent immunotherapy, they do not go on to immunotherapy afterward, so that is a confusing comparison since that is not our standard of care anymore.

I do worry about the generalizability of these results, but I do believe it prompts [us to question whether] we can improve outcome while we combine the immunotherapy with the chemoradiation. From a safety perspective, it is also really important for us to learn more about the ability to safely combine radiation with immunotherapy for these patients.

Is that also true of the phase 3 LAURA trial?

LAURA looks at [patients with] stage III lung cancer following chemoradiation and then randomizing them to osimertinib vs placebo. Technically we have durvalumab [for use] in this setting, but its FDA approval is not predicated on EGFR status. There certainly are data when you look at PACIFIC in a non-statistically rigorous way, for patients whose tumors had EGFR mutations, the benefit of durvalumab does not necessarily exist there. In LAURA, where you are comparing osimertinib with placebo, there is equipoise there, but it is going to be difficult. [It will be challenging to explain] these complicated results to patients, [especially] when it comes to durvalumab vs osimertinib and how we consider that question. It’s a really exciting trial and thinking about what we can offer patients in this stage III disease setting is important.

References

1. Marrone KA. Locally advanced non–small cell lung cancer. Presented at: 2021 Institutional Perspectives in Cancer webinar on lung cancer; February 9, 2021. Accessed April 6, 2021.
2. Pechoux CL, Pourel N, Barlesi F, et al. An international randomized trial, comparing post-operative conformal radiotherapy (PORT) to no PORT, in patients with completely resected non-small cell lung cancer (NSCLC) and mediastinal N2 involvement: primary end-point analysis of LungART (IFCT-0503, UK NCRI, SAKK) NCT00410683. Ann Oncol. 2020;31(suppl 4):S1178. doi:10.1016/j.annonc.2020.08.2280
3. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non–small cell lung cancer. N Engl J Med. 2017;377(20):1919-1929. doi:10.1056/NEJMoa1709937