Husain and Participants Discuss Lead-Up to Systemic Therapies for Patients With Lung Cancer

Hatim Husain, MD (MODERATOR)

Medical Oncologist

Associate Professor of Medicine

Moores Cancer Center at UC San Diego Health

San Diego, CA

Case Summary:

A White woman aged 60 years presented with a nonproductive cough. She was a former smoker with 15 pack-years and quit 20 years ago, and her ECOG performance status was 0. Her pulmonary function test results were normal and laboratory values were within normal limits. A CT scan of the chest and abdomen showed a lobulated mass in right upper lobe (5.5 cm × 5.0 cm), no mediastinal lymph nodes, and no distant metastases. Her brain MRI results were negative.

DISCUSSION QUESTION:

What are the surgical considerations for this patient with lung adenocarcinoma?

HUSAIN: In particular, [the considerations are] timing of the mediastinoscopy, lymph node involvement, pathological reports, criteria for surgery, surgical assessment. When I reflect on this, an important takeaway is the engagement of the multidisciplinary team. [It is vital to get] good lymph node staging to assess stage, important biomarkers, molecular, PD-L1. We started the discussion with the consideration about what is the right substrate to use, the biopsy material. From a staging perspective, as well as an examination perspective, the minimum criteria for surgery included PFTs [pulmonary function tests], PET scan, trying to understand the distant metastatic spread.¹ Anything else that you would think of that we would want to know early and up front?

YANAGIHARA: If this patient did have a staging EBUS [endobronchial ultrasound], I would not typically expect her to go to mediastinoscopy.

HUSAIN: I agree with that. With EBUS, especially if there is a good lymph node sampling, that wouldn’t necessarily be indicated. I think that the devil in the details is, how adequate is the lymph node sampling? A lot of lymph node sampling may not contain lymph nodes from contralateral sites. Pushing our pulmonologists to make sure that we have well-documented lymph node staging is important.

DISCUSSION QUESTION:

How eager are surgeons in your area to perform surgery on these patients?

YANAGIHARA: I have done neoadjuvant therapy infrequently—mainly because, in a clear-cut case like this, as soon as the surgeon sees the patient, they will take them straight to surgery. It is difficult to persuade them not to do surgery up front.

HUSAIN: I have seen in our practice that it is evolving. Whereas neoadjuvant treatment, when it was just chemotherapy, we would not have discussions about that; it would just truly be if the patient were borderline, or the patient wanted to drive that decision. I am seeing a change, though, among the thoracic surgeons. I think as thoracic surgeons are learning more about the systemic agents that there is a little bit more openness. But I would love to hear if others have different thoughts. How are the thoracic surgeons in other practices approaching this? Does anyone feel that they are more abrasive?

DEKKER: Maybe Los Angeles is an exception, but my cardiothoracic surgeons are more than willing for me to give neoadjuvant therapy. It is much easier for them. They get to schedule more patients in advance. The patient has a better evaluation, and if the patient responds, [it is easier to do] surgery, whereas if the patient progresses, that is fewer bad cases on their record.

HUSAIN: It is great to hear that. It sounds like it is very collaborative. The surgeons are viewing the positives here. I think a negative that one may hear about is if one doesn’t offer the surgery early and up front, will that patient go to a different surgeon and get the surgery done there? That is something that we sometimes hear about.

DEKKER: Most of my patients have HMO [health maintenance organization] insurance, so they cannot easily just jump ship and go to UCLA.

CASE UPDATE:

The patient underwent right upper lobectomy with no lymph nodes positive for malignancy (2R, 4R, 7, and 11R were all negative) and without complications. Her pathology showed the tumor was 5.3 cm with negative margins and confirmed stage IIB (pT3N0M0) lung adenocarcinoma. Her laboratory values after surgery were within normal limits and she now has an ECOG performance status of 1.

DISCUSSION QUESTION:

What are some reasons that eligible patients don’t receive adjuvant systemic therapy?

ONYSHCHENKO: There is often a fraction of patients who just don’t want any chemotherapy [due to] age and comorbidities. CHARU: These patients do not want to take it.

HUSAIN: Yes, I think the decision-making here is important and really speaks to the fact that, even in a setting where one is talking about curative intent, the magnitude of the curative intent is one that comes up in terms of how patients view the risk and the benefit. Also, there is a perception around chemotherapy and the toxicities that a lot of people walk in the room concerned about.

Do you feel that now with some of these newer agents, whether it be immune therapy or targeted therapy with EGFR inhibition—do you feel that sentiment is changing, that the perceptions are changing? Or do you feel like it is still a difficult decision to talk about adjuvant treatment?

ONYSHCHENKO: I think it is changing. Often patients don’t want to hear the word “chemotherapy.” Simple as that.

HUSAIN: I agree with you. In my practice it is similar. May I ask, in your practice, is cisplatin used routinely? Are there considerations for using carboplatin? How often is carboplatin being considered?

[In my opinion], the NCCN [National Comprehensive Cancer Network] guidelines do allow carboplatin for those patients who are not eligible to receive cisplatin.² I think what is also a curious finding is a lot of that data about cisplatin vs carboplatin predated some of these other agents that we are now using, such as targeted therapy or immune therapy. I’d be curious to see if the other agents that we use make the type of chemotherapy more or less important in that setting.

ONYSHCHENKO: I think there is a lot of consideration about whether it is squamous or nonsquamous. I think the squamous has more efficacy with chemoradiation.

HUSAIN: Yes, I think it’s important to think through some of these factors, such as histology, and the performance status with kidney function, and other clinical parameters—you must take these things into consideration. Patients can have adverse events [AEs] from the chemotherapy. We tend not to be overly excited about dose reductions, at least in our practice, because of the curative intent around adjuvant therapy. Patients may need growth factors, or other types of things, to get them through the treatments.

DISCUSSION QUESTION:

Which parameters are important when deciding on whether to use adjuvant systemic therapy post resection?

HUSAIN: One thing to consider is the type of chemotherapy, or whether to even consider chemotherapy. Are there clinical factors that speak to this? We heard about histology, nodal status, visceral pleural invasion; considering chemotherapy might be [appropriate] under those circumstances. I’ll just interject: There have been patients who, because of the visceral pleural invasions, get up-staged to meet the criteria to get the adjuvant therapy. Those patients would be eligible to get adjuvant therapy as well.

On the top [of the list of recommended therapies] we see considerations for combination therapy, including PD-1 and chemotherapy.² Again, that’s based around the trial CheckMate 816 [NCT02998528].³ Part of the NCCN guidelines do recommend testing for PD-L1, EGFR, and ALK rearrangements, and having that test available is part of the NCCN guidelines. For patients who are not candidates for immune checkpoint inhibitors, the chemotherapy regimens are also listed.

So, for perioperative systemic therapy, again, also for adjuvant treatment, the NCCN is very clearly asking for biomarkers: PD-L1, EGFR, and ALK.² Preferred regimens are cisplatin and pemetrexed for nonsquamous, and for squamous, cisplatinbased, gemcitabine or docetaxel are recommended. Listed as “useful under certain circumstances” are carboplatin and other cisplatin regimens. Importantly, the NCCN highlights use of systemic therapy following adjuvant chemotherapy for EGFR-mutant patients, osimertinib [Tagrisso].² Atezolizumab [Tecentriq] is also listed in this version of the NCCN guidelines.

DISCUSSION QUESTION:

What are your thoughts about the ADAURA trial?

HUSAIN: It would be great to hear your reactions to the data from the ADAURA [NCT02511106] clinical trial.4 What do you think about those HRs? Has ADAURA changed your thinking, or is this new information for you?

HSU: You said in the study patient population there was a “yes” and “no” to chemotherapy—so what was the number, again? There was a percentage of patients who never had chemotherapy and just went straight to osimertinib?

HUSAIN: Yes—60% of patients got adjuvant chemotherapy, and 40% did not receive adjuvant chemotherapy.

HSU: That was surprising to me. I thought it would be much smaller. I’m more familiar with the other parts of the [study]. I had never recalled that part. I was feeling bad about not doing chemotherapy in an [older] woman who is against chemotherapy and she’s EGFR positive, so I took her straight to the osimertinib.

HUSAIN: One of the lessons here is that patients were included who had not received chemotherapy as well; patients who refused the chemotherapy were still allowed on trial to receive it, and they had recruitment in disease-free survival with the osimertinib alone, so that is an important point.

HSU: My other thought is, not for this study, maybe for a future study—I’m sure the 3 years is arbitrary, but it’s a very tricky situation to get patients through 3 years of [treatment]—I wonder, maybe more is better, or less is more.

HUSAIN: That’s an excellent point, and 3 years was the criterion of the study, and I think some of the considerations are, is it better or not?⁴ Or, what is the optimal amount? I think future trials may even look at that to provide some clues.

LASHKARI: Also, in this study, patients who did not receive adjuvant chemotherapy also demonstrated significant benefit, making the argument: Do all patients with stage I through III disease need adjuvant chemotherapy? Can they avoid chemotherapy and move on to osimertinib alone? I don’t think this study answers that question, but it does raise the question.

HUSAIN: That’s an important point, Dr Lashkari. I think most of the academic oncologists who reflect on this point will continue to tout the importance of adjuvant chemotherapy, partly because adjuvant chemotherapy has had a survival benefit. That survival benefit is not to be completely dismissed, even in this setting.

I think because of that, most people will still recommend adjuvant chemotherapy followed by osimertinib. What has been noted before, many times here, is a lot of patients do refuse chemotherapy. So the question is, if a patient refuses chemotherapy, do they not get anything, or should they at least be allowed to get osimertinib?

ONYSHCHENKO: I think the difference in overall survival doesn’t look as good as disease-free survival, but that was expected from the prior second-generation EGFR inhibitor.^5,6 I think specifically for osimertinib, it still makes sense to use it, because of the central nervous system activity. Because of progression in the brain, that we know from progression from restarting the therapy, it will work during that period. For that reason, overall survival is likely positive, and that will be my main reason to offer it.

HUSAIN: That’s an excellent point, and I think a good addition to this trial was understanding how protective the medicine in the brain is, even in this early stage.

YANAGIHARA: One unexpected thing I found is that I’ve never had a patient with stage IV disease ask to stop osimertinib, but I’ve at least a half-dozen patients who have been unwilling to continue adjuvant osimertinib for more than 3 or 4 months, citing toxicity.

HUSAIN: What type of toxicity?

YANAGIHARA: Very nonspecific: asthenia, weight loss, malaise. But they felt different after starting adjuvant osimertinib and refused to continue.

CHARU: I have a patient with metastatic disease on osimertinib. Every time she starts, she develops a signifi cant rash, even if I give her methylprednisolone or doxycycline. She stops it for a few days, and she starts it again and she develops the rash again. I even decreased the dose, but she’s willing to take it because she’s responding right now. Is rash a major [problem] for your patients?

HUSAIN: Yes, rash is one of the most common AEs that can happen with osimertinib. What we typically recommend for patients in the first line is doxycycline and some antihistamine, as well as topical corticosteroids. We do escalate to steroids, but we usually also try to solicit dermatology recommendations as well.

One key point is early intervention, and with early intervention there can be improvement. Paronychia is the other AE that we counsel patients on a lot. Our practice is to use water and vinegar solutions, and that can help to clean the nail beds, whether it be the fingers or the toes in that way, to try to mitigate some of that. But this also highlights that even in a drug that is well tolerated, early intervention when the toxicities happen can hopefully mitigate [them].

REFERENCES

1. Lim W, Ridge CA, Nicholson AG, Mirsadraee S. The 8th lung cancer TNM classification and clinical staging system: review of the changes and clinical implications. Quant Imaging Med Surg. 2018;8(7):709-718. doi:10.21037/ qims.2018.08.02

2. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 3.2023. Accessed February 16, 2023. https://bit.ly/3ppx5uW

3. Forde PM, Spicer J, Lu S, et al; CheckMate 816 Investigators. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med. 2022;386(21):1973-1985. doi:10.1056/NEJMoa2202170

4. Wu YL, Tsuboi M, He J, et al; ADAURA Investigators. Osimertinib in resected EGFR-mutated non–small cell lung cancer. N Engl J Med. 2020;383(18):17111723. doi:10.1056/NEJMoa2027071

5. Tsuboi M, Wu YL, C. GroheC, et al. Osimertinib as adjuvant therapy in patients (pts) with resected EGFR-mutated (EGFRm) stage IB-IIIA non–small cell lung cancer (NSCLC): updated results from ADAURA. Ann Oncol. 2022;33(suppl 7):S1413-S1414. doi:10.1016/j.annonc.2022.08.047

6. Herbst RS, Tsuboi M, John T, et al. Osimertinib as adjuvant therapy in patients (pts) with stage IB-IIIA EGFR mutation positive (EGFRm) NSCLC after complete tumor resection: ADAURA. J Clin Oncol. 2020;38(suppl 18):LBA5. doi:10.1200/ JCO.2020.38.18_suppl.LBA5