Roundtable Discussion: How to Treat a Patient With Non–Small Lung Cancer and When to Use the PACIFIC Regimen

Jessica Donnington, MD, professor of Surgery and chief, of the Section of Thoracic Surgery at the University of Chicago Medicine, led a discussion with a group of peers regarding treatment of non–small cell lung cancer during a virtual Targeted Oncology Case-Based Roundtable event.

Participant 1: In this case, with [the patient] having enlarged [lymph nodes] and having some positivity on the PET scan, I would tend to send him for an EBUS.

DONINGTON: Would anyone send this patient directly to treatment without a mediastinal biopsy?

Participant 2: Probably not. If possible, it would be nice to get [one].

DONINGTON: When I started my career out in Palo Alto, California, one of my very first patients was a 40-year-old woman who was sent to me [with symptoms very similar to] this. They were going to start her on chemoradiation, and someone sent her in from the Central Valley to see me. We got the mediastinoscopy and immediately found granulomas, then we resected her stage I cancer and she was cured. She has done great, and her dad [was] one of the largest asparagus farmers in the state of California, so he sent me crates of asparagus every Easter for the next 10 years. Every April, I am reminded of the value of verifying mediastinal nodal positivity before moving on.

I think EBUS has made this very easy for most of us, but would anyone do a mediastinoscopy [rather than] EBUS?

Participant 3: EBUS, absolutely.

DONINGTON: Yes, patients greatly prefer [EBUS]. I think we’ve all made this transition where we have EBUS available.

Participant 3: It’s safer [and] easier on the patient.

Participant 2: It’s harder to diagnose the benign disease [with EBUS].

DONINGTON: For lung cancer, I think [EBUS] is a better way to start. I think most of us have made that change.

Participant 1: For restaging of the mediastinum, how often are we to do an EBUS versus mediastinoscopy after neoadjuvant treatment?

DONINGTON: That’s a good question. I think EBUS after neoadjuvant therapy is challenging in terms of accurate diagnostic yield. I’ve never been a person who used pathologic verification of nodal disease or clearance of nodal disease to determine whether I took someone under resection or not. But [regarding] physicians who do, I think most of them prefer to start with EBUS and follow with mediastinoscopy. Do you feel the same?

Participant 1: Yes. That’s been our practice. We start with EBUS, and the restaging is typically done with mediastinoscopy on the same day with the plan to proceed. It has to be overtly positive for me to stop with the mediastinoscopy. Our pathologists have to see viable tumor cells for me to stop.

Participant 2: What do medical oncologists think about EBUS versus mediastinoscopy?

Participant 4: I definitely think EBUS is the first step….The tricky part has been when we do an EBUS and we have a high suspicion. We get a good sample, there [are] lymphocytes, but it doesn’t come back positive for cancer, and you [think], “That has to be positive.” Ultimately, we might go to mediastinoscopy on that to confirm [cancer]. Honestly, I think it’s been a toss-up— sometimes [patients] have these reactive inflammatory lymph nodes versus [being] truly involved surgery on the table, but I don’t think [this patient is] a surgical candidate at all. That’s [because of] the comorbidities in him. I share the opinion that I do not like doing pneumonectomies in the stage III setting.

DONINGTON: If you feel as though a pneumonectomy is on the table, would you defer a patient to definitive chemoradiation instead of putting them down a neoadjuvant route?

Participant 3: Not always, but in this patient for sure. His FEV1 was 35%.

DONINGTON: If you had an otherwise healthy patient, would you feel OK treating them with neoadjuvant and then doing a pneumonectomy?

Participant 3: Yes, I would be OK with that, although I would [try to convince] the radiation oncologist not to radiate that patient. I would want to give chemotherapy only.

DONINGTON: Are you ever put into a situation where you’re asked to do an extensive resection in someone who already has had neoadjuvant chemotherapy and radiation?

Participant 3: Not very often, fortunately, but I really don’t like the idea of doing a pneumonectomy after chemoradiation. My preference would be, if I had any say in the matter, [to] offer a patient neoadjuvant chemotherapy….If their performance status was good and they had a physiologic reserve to tolerate it, I would still consider [resection].

Participant 5: Many times, these patients are presented at a tumor board as a [case]. It’s important, at least in my mind, that the surgeon have the opportunity to speak directly to and examine the patient as compared with sitting in a tumor board and hearing their discussion, because many times you’ll find that patient is an operable or resectable candidate, whereas sitting in that room, the direction may swing away from resecting that lesion.

I’ve seen a patient or 2 [who received] a diagnosis on EBUS of metastatic carcinoma because they had lymphocytes in the specimen. They were told their disease was not resectable [after the physician had] gone through the lymph node with their needle and biopsied the lung lesion, but then decided, on the basis of that, that the patient was not resectable when in fact the patient was resectable.

DONINGTON: It [shows] the importance of either having confidence in knowing your interventional pulmonary team well or doing those procedures yourself, because I have also seen that. It does happen, especially with central lesions.

Participant 4: We are going through our second surge [of COVID-19 in my area], and it has been worse than the first, but we have not modified our treatment plans. It may be that we are seeing [fewer] patients [because] patients have delayed coming in. But once they come in and they are going to get chemoradiation, we’ve been able to deliver therapy. We have continued to try to get the optimal chemoradiation for this clinical scenario and been able to do it.

DONINGTON: We have, too, and it has not really changed how we do this. I think in the beginning we were scared that we were making them too immune suppressed, but the lung cancer is still a bigger enemy here.

NGS for the locally advanced population [is something that] we definitely order on all of our patients. Patients such as those who had a biopsy as an outpatient would have an NGS. We collect that on everyone, along with PD-L1 testing.

Participant 4: I think we still struggle with not getting enough tissue because a lot of these patients are still getting fine needle aspirations. That’s not enough to do genomics. It’s definitely not enough to do PD-L1 testing. I would prioritize doing genomics in this kind of situation because the PD-L1 expression isn’t going to change my management. In the United States, you’re going to give durvalumab [Imfinzi] independent of PD-L1 expression, but NGS may change how you think about consolidation therapy. I think the bigger struggle in testing is still getting insufficient tissue.

DONINGTON: Our recommendation for durvalumab is based on the PACIFIC trial [NCT02125461].¹ [Patients] were randomized to durvalumab for 12 months versus placebo after the completion of chemoradiation. The patients had to finish their chemoradiation and do well, and then they were randomized [in PACIFIC]. Similar to the ADAURA data [NCT02511106], there were really impressive survival curves—more impressive than we are used to seeing in lung cancer.

The investigators have now shown the overall survival [OS] data at 4 years, [and there] was an impressive bump in OS in a population that has been challenging to cure before this.2 [There was approximately a] 50% overall survival at 4 years, which is, I think, stellar for an unresectable stage IIIA population. These patients were all unresectable, although most of this was done outside of the United States and most of these patients weren’t seen by a surgeon. I think that always makes some [individuals] question it, but they are still impressive data.

The subset analysis looked at which population really benefited, and it was impressive that the overwhelming majority of the subsets saw a survival benefit. The 1 population that clearly crosses the 1.00 line and crosses significantly are patients who are EGFR-mutation positive. So, this would be a population that you might not put on that therapy.

This is a medicine that is fairly well tolerated. We are talking about treating for a year, which is a pretty long time. I think the safety data [that were] most worried about [dealt with] pneumonitis. We have [patients] who are given radiation and then you’re firing up their immune system, but [pneumonitis] hasn’t been a significant problem. Some of that fear was dispelled through this trial.

Durvalumab has become the recommendation through most of our governing agencies.3 Then there are even recommendations to remove extra cycles of maintenance therapy in patients and move directly to durvalumab, which seems to make perfect sense. I think this is a game changer in the unresectable setting.

DONINGTON: As a surgeon, do you get a lot of questions about PACIFIC?

Participant 3: I don’t get a lot of questions, but I must say I have had an increasing sense at our tumor board that many of our medical oncologists have extrapolated from these data to say that patients with IIIA disease that is resectable should go down this treatment pathway. I think we’re in danger in surgery that we’re going to see fewer of these patients because the data [are] so impressive, compared with what we’ve been able to generate, that an extrapolation of it is “Well, if you have IIIA disease and even if your tumor is resectable, you may end up going down this pathway.”

DONINGTON: I share your fear. Recently in the clinic, I sat with a 42-year-old woman with a 1.2-cm right middle lobe lesion and micrometastatic disease [in her] 4R lymph node, and she worked her way through chemoradiation. Then [she is in the clinic asking me], “Should I get surgery or should I get durvalumab?” [But] the PACIFIC trial didn’t include her. So, I think that is happening.

Participant 3: I think we’re going to see fewer of these patients because they will get siphoned off. We’ll never see them. I don’t know if that’s necessarily a horrible thing, but I think it’s coming.

Participant 4: I do think that is a horrible thing because that is an extrapolation that doesn’t necessarily pan out to be the right thing to do for patients. The message is that patients need to have a multidisciplinary approach. We will get the answers for the adjuvant immunotherapy after resection; we just don’t know yet. It makes sense that it would be beneficial to do resections followed by chemoimmunotherapy, I think, but the clinical trials are still ongoing. I think there’s a lot of enthusiasm for the positive durvalumab data, but I don’t think [durvalumab treatment is for] the patients [who] need to have a surgery followed by appropriate adjuvant therapy.

We need to continue to educate [providers and patients] on the right thing to do as these results come out, because occasionally it doesn’t pan out. Bevacizumab [Avastin] in the metastatic setting works. When we used it in the adjuvant setting, it didn’t. So sometimes the trials don’t pan out the way we envisioned [they would,] and we have to get the answers.

DONINGTON: Yes, I agree. I think the real question will be, when you take those patients, [is whether] a regimen such as this or a team regimen makes more sense in this population…. When we look at the OS, I think it’s going to be hands down in favor of induction immunotherapy with chemotherapy followed by resection.

_References

_{1. Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. N Engl J Med. 2017;377(20):1919- 1929. doi:10.1056/NEJMoa1709937}

_{2. Faivre-Finn C, Vicente D, Kurata T, et al. Durvalumab after chemoradiotherapy in stage III NSCLC: 4-year survival update from the phase III PACIFIC trial. Ann Oncol. 2020;31(suppl 4):S1178-S1179. doi:10.1016/j.annonc.2020.08.2281}

_{3. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 8.2020. Accessed February 4, 2021. bit.ly/30sRU9e}