Sherwood Discusses Treatment Options for Unresectable Stage III Lung Adenocarcinoma

CASE SUMMARY

A 63-year-old man presented to his physician with intermittent cough and difficulty breathing on exertion. He had a history of hypothyroidism, which was managed on levothyroxine; and chronic obstructive pulmonary disease (COPD), which was managed on inhalers. He recently quit smoking and has a 40-pack-year history. His ECOG performance status was 1. Complete blood count, chemistries, and creatinine were within normal limits.

A chest CT scan showed a 3.1-cm spiculated left upper lobe (LUL) mass and 2 enlarged left mediastinal lymph nodes (stations 4L and 7), measuring 2.5 cm and 1.7 cm, as well as moderate emphysema. A PET scan confirmed lung lesion and mediastinal lymphadenopathy without evidence of distant metastases. His brain MRI was negative. Pulmonary function tests showed a forced expiratory volume of 1.2 and a diffusing capacity of the lungs for carbon monoxide of 35%.

Bronchoscopy with transbronchial lung biopsy of LUL mass and lymph node sampling via endobronchial ultrasound revealed adenocarcinoma at primary site, with positive nodes in stations 4L and 7. His cancer staging was T2aN2M0, stage IIIA.

DISCUSSION QUESTION

• What approach to biopsy is appropriate for a patient like this?

SHERWOOD: What do you think about the choice of biopsy? What would you do if this patient had no sufficient sampling from the lymph nodes at the time of bronchoscopy?

KRAUT: Because of the location of the lymph nodes, navigational bronchoscopy or endobronchial ultrasound [EBUS] are completely suitable. It’s been demonstrated by enough data that it is equal to a traditional mediastinoscopy. It’s a reasonable approach. We would refer to the pulmonary department for an EBUS, traditional bronchoscopy, or even a navigational one.

SHERWOOD: If you’re practicing in a situation where access to EBUS is limited or the primary care physician worked this up and did a CT-guided biopsy of the primary mass for lymph nodes that haven’t been pathologically confirmed to be malignant, what criteria do you use to decide when to go back and recommend another biopsy? Or in the interest of simplifying the patient’s evaluation, when to not send them back for another biopsy but just clinically stage them as stage III.

KRAUT: Mediastinoscopy is a great tool, and we still use it often. If they couldn’t get to it with bronchoscopy, then traditional mediastinoscopy is a useful tool to stage the patient.

SHERWOOD: What do you do in your practice if you happen upon a patient who you suspect has pathologic involvement of lymph nodes but that wasn’t proven with their biopsy?

BENDANDI: This would be discussed in the tumor board…and maybe a collegial decision would be made. Sometimes patients have different outcomes based on the feelings of the group.

BHANDARI: In our hospital, we have a multidisciplinary tumor board, and most of the EBUS and bronchoscopies are done by the thoracic surgeon, especially in such an area where it’s stage III or stage II. Our thoracic surgeon will decide. They’re pretty good with EBUS and bronchoscopy.

GILL: I work at Pardee Hospital in Hendersonville, [North Carolina], so we don’t have our own thoracic surgeon, but we will send patients to Greenville [Memorial Hospital in South Carolina]. Our pulmonologists are good, but if they can’t get to it, they will refer the patient. So by the time they come to me, we’ve already had this definitively handled. Even though we don’t have our own thoracic surgeon, there is usually cohesive and good communication.

SHERWOOD: Great, thanks for sharing. As medical oncologists…we [usually] want more tissue for biomarker testing.

DISCUSSION QUESTION

• What was your reasoning for the up-front option you would choose?

SHERWOOD: I selected concurrent chemotherapy with radiation. I am intrigued by some of the neoadjuvant chemoimmunotherapy data, and I believe they are going to be a paradigm-shifting option down the road. I want to see a little more of the [disease-free survival] and [overall survival] data mature. But as I work very closely with my surgical colleagues, I’ve learned that these cases do add an element of trickiness to them. Can someone who selected neoadjuvant chemoimmunotherapy be brave and talk us through the process?

BHANDARI: In the tumor board, it’s a decision between the medical oncologist, radiation oncologist, and the surgeon. The surgeon can say, “I’m comfortable taking it out,” or “I don’t think it’s resectable.” Then concurrent chemoradiation is given. But it is a discussion had by the multidisciplinary tumor board. I picked neoadjuvant chemotherapy and immunotherapy because I’m confident the thoracic surgeon will probably agree with my opinion.

BENDANDI: I reluctantly picked neoadjuvant chemotherapy with or without immunotherapy, followed by surgery. I would say [it should not be] followed by surgery because the patient is deemed not to be a good surgical candidate. [At my hospital], we don’t have [radiation therapy], so concurrent treatment is rarely feasible. As for sequential treatment, I hope that the future will be neoadjuvant chemotherapy plus immunotherapy, followed by surgery, [though] probably not in this case.

KUZMA: I don’t think this patient has macroscopic N2 disease. That’s usually not the ideal candidate for surgery. We identified that this patient, based on his pulmonary function, was never going to be a surgical candidate. For all those reasons, I chose concurrent chemoradiotherapy.

SHERWOOD: Those are all great points. N2 disease is a subgroup I’m going to be paying a lot of attention to when I’m looking at the CheckMate 816 study [NCT02998528]. There’s a whole host of neoadjuvant immunotherapy alone and chemoimmunotherapy studies, which are a lot for medical oncologists, surgeons, and radiation oncologists to sift through over the next few years.

KUZMA: I don’t think a patient like this would have been eligible for CheckMate 816.

SHERWOOD: You’re probably correct, based on those [pulmonary function tests]. I would imagine they would say that even if the patient had a complete response on imaging, that would be someone who would not do well with an operation. Dr Kraut, you’re the only one here with experience operating after neoadjuvant chemoimmunotherapy. What’s been your experience?

KRAUT: We’ve had good outcomes with our patients. It’s been a little more challenging in the interval from completion of treatment to surgery. Those patients have more desmoplastic changes, particularly around the lymph nodes, and the lymph nodes are around arteries and the bronchus. It’s a little more from a dissection standpoint, but it has not added a whole lot more time.

If you look at some of the data that are out there, [it can be] anywhere between 30 to 45 minutes more due to the surgical complexity, but we’ve not really found that. Most of our patients have done very well. We [perform] them robotically; I think we’ve done all but 8 or 9 robotically. It’s a little more complex because of the scarring and the desmoplastic changes, but overall, it’s not been anything like when we used to see patients who had chemoradiation to the hilum.

SHERWOOD: Great, thanks for sharing.

CASE UPDATE

• In this patient, the results of molecular testing show negative results for driver oncogenes in EGFR, ROS1, BRAF, ALK, RET, MET, ERBB2, NTRK, and KRAS. His PD-L1 expression level is 1%.

SHERWOOD: Does this change anyone’s thoughts about what they would do for this patient? Not so much for me. I probably would still be recommending concurrent chemoradiotherapy.

BENDANDI: I would switch to chemotherapy plus sequential radiotherapy, unless I can obtain it concomitantly. But the radiotherapy must be outside the VA [Veterans Affairs hospital].

SHERWOOD: Yes. I trained at a VA facility, and it was always a little problematic to refer someone outside the VA for radiation therapy, and to time concurrent chemotherapy with that, too. I recognize that conundrum.

CASE UPDATE

• Based on patient preference and extent of mediastinal disease plus symptomatic COPD, the patient’s cancer was deemed unresectable and he was referred for consideration of concurrent chemotherapy and radiation. He underwent therapy with cisplatin/ pemetrexed and concurrent thoracic radiotherapy to 66 Gy. He tolerated therapy relatively well, except grade 2 esophagitis, which was treated medically. A restaging CT scan showed a partial response with shrinkage of the primary and nodal lesions. No evidence of distant spread was observed.

SHERWOOD: In terms of timing of the restaging CT scan, for those of us who are working closely with the radiation oncologist, who owns that? Are they ordering it? Are you ordering it as the medical oncologist? Are you getting a CT chest, abdomen, or pelvis scan with contrast, or are you getting a CT chest scan without contrast?

PANDIT: Our interventional radiologist, medical oncologist, and I usually wait for [approximately] 4 to 6 weeks after the radiation is done. We do a CT scan with contrast.

GILL: I wait 4 weeks after and typically do a CT scan with contrast. If the radiation oncologist sees the patient, sometimes they’ll order the scan as well.

YUAN: In my practice, the medical oncologist orders CT chest with contrast. I [often] try to follow the protocol ordering within 3 to 4 weeks, but our radiation oncologist always say it’s too soon…. So in this kind of situation, I would love to hear from others [about] what their practice does. What is the best window to get the CT scan?

DISCUSSION QUESTION

• What is your next step after the last dose of radiation for patients receiving chemoradiation, assuming the restaging CT scan shows no evidence of progressive disease?

SHERWOOD: I talk to patients about durvalumab [Imfinzi] as they’re finishing concurrent chemoradiation. If I’m seeing them weekly, by their fifth or sixth week of treatment, they’re dealing with adverse effects [AEs], but I prepare them for the next step. I’ve always found it hard to know how to talk to a patient about the total duration of therapy.

If you meet someone like this patient at the beginning, do you tell them right up front that after their 8 weeks of concurrent chemoradiation, you’re going to recommend up to 1 year of adjuvant therapy or consolidation therapy?

I tend to not focus on that initially and just focus more on getting the patient to understand the stage, the diagnosis, and the rationale behind concurrent chemoradiotherapy. Then I focus more on the data for consolidation durvalumab, how immunotherapy is different, and why we think that it works well after concurrent chemoradiotherapy.

When are you mentioning durvalumab to your patients? Is it only after their scan is done and you see that they’re a candidate, or are you mentioning it before? Is that something you want the radiation oncologist to talk to them about, or is that something you feel is best handled by a medical oncologist?

BENDANDI: I mention it while they are receiving chemotherapy. Then, of course, a patient like this will ask me [whether] they have PD-L1 [expression greater than 1%], after they understand what PD-L1 is.

OSEI-BOATENG: While I do the discussion about concurrent chemoradiation, I also mention that we’re going to do a restaging scan [after]. If they have a good response, then we will do the maintenance phase with durvalumab. Like you, I don’t go into a lot of detail about it. I just mention it so it’s on their radar. After they come back with the scan, we go into a more detailed discussion about it.

PANDIT: I also mention the whole treatment package but go into detail at each step when the treatment is about to start or just before.

GILL: I’m doing something similar. I also try to focus on how this is very different from what they’re getting now, so that they know immunotherapy works in a different way. I focus on that more and tell them they have done the hardest part, so they don’t need to worry.

DISCUSSION QUESTION

• How long do you typically continue durvalumab?

SHERWOOD: Do you get patients through 12 whole months? I do try to push patients. There’s treatment fatigue. Patients get tired of coming to see me…. We do have patients who say, “I want to be done. I’ve done 9 months, do I have to keep going?” Is that something you deal with? Patients who are a year into treatment and they’ve got a few months left, but they don’t want to keep going.

BENDANDI: In my experience, the opposite happens. If I tell them that after 12 months…they don’t want to stop.

SHERWOOD: It does feel arbitrary to stop at 1 year, so you’re right.

BENDANDI: Also, what happens if the CT scan shows progression 3 or 6 months later? Would that happen if they stayed on medication? Of course we don’t know, but you don’t feel good if [that happens when] they weren’t on medication.

SHERWOOD: You’re right.

OSEI-BOATENG: Most of the time—maybe because we had discussed that it’s going to be a year—I haven’t had as many patients on maintenance durvalumab wanting to continue like in other diseases [such as] melanoma, or where they want to continue after they’ve been on it for a longer period of time. When I’ve had to stop it, it hasn’t typically been because they didn’t want to continue. It’s been because there’s been some AEs that have made us discontinue treatment. It doesn’t happen often, but I’ve stopped it on a couple occasions.

PANDIT: I’ve had a couple of patients with grade 3 or higher musculoskeletal AEs. They got tired after 9 to 10 months and said they couldn’t do it anymore and wanted to come off therapy. Otherwise, patients typically complete therapy.

SHERWOOD: For the subgroup analysis, durvalumab is favored in almost every single subgroup, apart from in patients with PD-L1 of less than 1% [From the Data¹]. The total number of patients in that group is small. I believe the European Union, at least for a time, did not approve durvalumab in that patient population, based on the unplanned subgroup analysis, which I think is interesting.²

My practice for the driver mutant–negative patients is generally to offer durvalumab. Is anyone not offering durvalumab based on PD-L1?

KUZMA: No, but I’d like to see a study that gets at that question.

_REFERENCES

_{1. Spigel DR, Faivre-Finn C, Gray JE, et al. Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. J Clin Oncol. 2022;40(12):1301-1311. doi:10.1200/JCO.21.01308}

_{2. European Commission approves Imfinzi for locally-advanced, unresectable NSCLC. News release. AstraZeneca. September 24, 2018. Accessed June 26, 2023. https://tinyurl.com/y56j5eby}