Roundtable Discussion: Kim Assesses Stages of Treatment in NSCLC

Edward S. Kim, MD, MBA (Moderator)

Physician-in-Chief

City of Hope Orange County

Vice President-in-Chief

City of Hope National Medical Center

Newport Beach, CA

CASE SUMMARY

An 60-year-old White woman presented with a nonproductive cough. She had an ECOG performance status of 0, her lungs were clear to auscultation bilaterally, and laboratory results were within normal limits. She had never smoked, but a chest x-ray showed a 5.5-cm mass in the right upper lobe (RUL), and a chest/ abdomen CT scan showed a lobulated mass measuring 5.5 × 5.1 cm in the RUL. After a biopsy, she was diagnosed with adenocarcinoma, positive for TTF1 non–small cell lung cancer (NSCLC). PET imaging was negative for lymph nodes or distant metastasis, an MRI of the brain was negative for metastases, and pulmonary function test results were normal.

Treatment consisted of mediastinoscopy with negative lymph nodes on frozen section, followed by right upper lobectomy without complications. Her pathology showed a 5.5-cm tumor with negative margins, 0 nodes positive for malignancy (2R, 4R, 7, and 11R all negative), and confirmed stage IIB (pT3N0M0) lung adenocarcinoma. Her laboratory results were still within normal limits, and her current performance status is 1.

DISCUSSION QUESTION

• What are the surgical considerations for a patient like this?

SAFAR: In our institution, mediastinoscopy has not been done for a long time, probably for 5 to 6 years, because of EBUS [endobronchial ultrasound]. It probably depends on the competence and reliability of the interventionist at your institution. We have somebody who is capable [of using it], and they can sample all the nodes, so we have been relying on EBUS.

Determining the status of the nodes is essential, especially when the mass is this size of 5.5 cm. If there was node positivity in the mediastinum, I would consider chemoradiation before surgery and then maybe only limit surgery to those who are going to need either lobectomy or who have cleared the mediastinum, and these were the 2 subsets of the Intergroup [0139] trial [INT 0139/RTOG9309].

KIM: I think EBUS can do a lot of things. The key is for the thoracic surgeon to make sure they do an adequate dissection or detailed sampling during the surgery.

DISCUSSION QUESTIONS

• Do you routinely order molecular testing for early stage NSCLC?
• What are the challenges and barriers to testing?
• Who on the multidisciplinary team orders the molecular testing?
• What tests are ordered at your institution/practice?

OPPELT: We tend to test just about everybody. The few people who probably aren’t tested are maybe the ones who had such a small volume of disease that they may never make it to medical oncology because thoracic surgery just felt that a small, less-than-1-cm lesion doesn’t need our input.

ZOGHBI: One of the barriers [is insurers’ refusal to pay]. In fact, I saw a patient today whose insurance did not approve…his molecular testing. He came to me to discuss adjuvant therapy. He is stage I, so he will not need adjuvant treatment, but interestingly, he mentioned that the Tempus testing has been sent and [that] there is fighting with the insurance to pay [for] this testing.

RAJA: There aren’t many barriers for testing because we do have tissue when patients have surgery. In a multidisciplinary team, it’s typically a medical oncologist who makes the decision, based on whether the patient is a candidate for adjuvant therapy or not.

SUMOZA: The other thing is sometimes you get the biopsy but there is not enough tissue to perform the molecular testing. That’s when you can think about liquid biopsy and see if the patients are positive. The thing is that if it’s negative, you will still have to request…more tissue.

SAFAR: In the adjuvant setting the only reason to test, in my opinion, is for EGFR. Other than that, I’m not sure we have a rationale for why, other than knowing. The molecular testing interpretation requires some clarification. There are almost no rules, and I don’t know how people are really using it, so I would not be able to make a good case for the insurance company to pay unless it is for EGFR.

DISCUSSION QUESTIONS

• What is the role of adjuvant chemotherapy in your practice?
• What are the treatment goals?

SAFAR: I give it to those with lesions above 4 cm. I give it to all with node-positive disease, whether N1 or N2. For those with N2 disease, if we haven’t done any preoperative treatment and we just discovered postoperatively, I clearly offer them adjuvant therapy.

If we already knew they were N2, usually we would try to do preoperative chemoradiation and then consider surgery, but not for all of them necessarily. I don’t really use LVI [lymphovascular invasion] or poor differentiation as a reason to give chemotherapy myself. Also, those who are EGFR-positive, of course, all would be given [it] because the impact there is inarguable.

RAJA: I use platinum mostly. If they are EGFR-positive, then osimertinib [Tagrisso], and PD-L1–positive patients get atezolizumab [Tecentriq] for chemotherapy.

KIM: OK, does that sound reasonable to others?

SAFAR: Yes. With regards to the performance status and age, I would use the same argument that we always consider, that most of the patients needing adjuvant therapy will have relatively good performance statuses, so not a big problem.

Age is an issue. If somebody is quite old and has competing reasons for mortality, maybe the benefit of adjuvant therapy becomes a little harder to justify. We have that discussion that maybe the benefit that emerges 4 or 5 years down the road may not be as valuable, but it’s not a reason not to give it, for me.

KIM: As we start getting a little more sophisticated with precision medicine and other modalities, certainly people are starting to look at the overall value of adjuvant chemotherapy. It’s still the standard of care and something that we need to continue to think about. Do you still administer adjuvant radiotherapy at any of your sites?

MATTAR: Not typically. I think the role of radiation therapy data are limited, unless maybe if there’s positive margin or tumor left inside. For adjuvant chemotherapy, usually the patient must be fit to use a platinum-based kind of adjuvant therapy. If they’re not fit for cisplatin [Platinol]—not any platinum, it must be cisplatin, in my mind—then they should not get adjuvant therapy.

DISCUSSION QUESTIONS

• What recommendations does the NCCN (National Comprehensive Cancer Network) have on adjuvant treatment?
• What are your reactions to the ADAURA trial (NCT02511106) of osimertinib?

KIM: For stage IIB disease, which includes our patient who had T3 and N0 and negative margins, chemotherapy and atezolizumab or osimertinib are recommended if there is a mutation. The NCCN Guidelines define high-risk features for use of chemotherapy in stage IB or IIA disease. They include tumors greater than 4 cm, vascular invasion, visceral pleural involvement, and wedge resection.

The preferred and recommended regimens for neoadjuvant and adjuvant therapy are cisplatin-based. Again, this is where we can get a little sideways with the NCCN Guidelines. For regimens useful in certain circumstances, carboplatin [Paraplatin] gets put in there with some of these regimens, but some of the biologics come in later.¹

The ASCO [American Society of Clinical Oncology] recommendations are to give adjuvant cisplatin-based chemotherapy to all patients. If they have an EGFR mutation, then it is recommended to give adjuvant osimertinib after chemotherapy regardless of what the PD-L1 status is. Also, adjuvant atezolizumab is to be given to all patients with a PD-L1 of greater than or equal to 1% after cisplatin-based chemotherapy, and again this is excluding those patients who have a sensitizing EGFR mutation [From the Data²].

SAFAR: Can you [explain] why the erlotinib [Tarceva] studies were negative when [they] have such a big impact?

KIM: I think purely…because of the [population with] EGFR mutation. I think there wasn’t as much attention [paid] to that. We saw little hints and trends. I reported on a gefitinib [Iressa] study that went head-to-head with docetaxel and…showed noninferiority, [which was] good but it wasn’t a selected patient population. I think what we’re seeing is, as we choose the right population of folks, you can really get more bang out of your buck.

It’s possible if you did a study like this with some of the other drugs, you might see similar outcomes. What we know is this is a fourth-generation drug as opposed to a first or second. The adverse event profile is better, and we know that the distribution of the drug is better through the CNS [central nervous system].

SAFAR: The prior adjuvant trials had [patients with] EGFR mutations only, right?

KIM: They had some. They didn’t necessarily use them to direct the randomization, but they measured them. Even when we looked at trials like IPASS [NCT00322452] in the metastatic setting, it was an exploratory end point.

PODDAR: For osimertinib, [these patients with] EGFR mutations whom we are looking at are at stage IB. Isn’t that questionable when chemotherapy was also used? In this stage IB…who is benefiting the most? Is it those with pleural invasion or lesions of more than 4 cm? Who is benefiting?

KIM: It’s good to start asking these nuanced questions because you’re asking about…[whether] the patient having a high [or low] risk…is benefiting. As you say, the 4 cm come[s] out a little bit arbitrarily based on some of the prior adjuvant studies.… The staging we know is sort of grouping multiple types of eggs in the same basket, right? What we do know is that if you have a driver mutation, there is clearly going to be a high level of effectiveness in this.

PODDAR: Yeah, that too is true because the cytotoxic chemotherapy was approved based on that Italian trial where a subset analysis was done, and they found [that] patients with tumors of more than 4 cm were the ones who benefitted from chemotherapy. From there, we extrapolated the data, and trials were run for these drugs. What do you do in patients who are minimally focally, visceral pleural positive, and EGFR positive?

KIM: The general practice has always been, prior to any of these data, [that] whenever you saw pleural involvement— and these were discussions I had back when I was at [The University of Texas MD Anderson Cancer Center] with our surgeons—we always gave it a gentleman’s half stage up because pleural involvement made it more high-risk. I think whether it’s microscopic or macroscopic, it still did that and so it exhibits a characteristic of the tumor. I still don’t have the correct answer for you regarding if they have an EGFR mutation in that setting, whether just giving osimertinib is enough or chemotherapy should be added on top of that.

_REFERENCES

_{1. NCCN. Clinical Practice Guidelines in Oncology. Non–small cell lung cancer, version 5.2022. Accessed March 27, 2023. https://bit.ly/3LQ8BE9}

_{2. Pisters K, Kris MG, Gaspar LE, Ismaila N; Adjuvant Systemic Therapy and Adjuvant Radiation Therapy for Stage I to IIIA NSCLC Guideline Expert Panel. Adjuvant systemic therapy and adjuvant radiation therapy for stage I-IIIA completely resected non-small-cell lung cancer: ASCO guideline rapid recommendation update. J Clin Oncol. 2022;40(10):1127-1129. doi:10.1200/JCO.22.00051}