Roundtable Discussion: Dowlati Debates the Role of Osimertinib in Adjuvant Treatment of NSCLC

Afshin Dowlati, MD (Moderator)

Professor of Medicine, Case Western Reserve University

Director, Thoracic Oncology and Phase I Programs

University Hospitals Seidman Cancer Center

Cleveland, OH

DOWLATI: The National Comprehensive Cancer Network [NCCN] recommendations for NSCLC are that [frontline testing for NSCLCs should include] molecular testing, including for EGFR, ALK, ROS1, BRAF, NTRK1/2/3, MET exon 14 skipping, RET, and KRAS tumor mutations.¹

The NCCN [guidelines recommend] that this [testing] should be conducted as part of broad molecular testing, along with PD-L1, which requires using next-generation sequencing [NGS] as opposed to selective testing using fluorescence in situ hybridization. Sequentially, [the guidelines] suggest that a broad panel should be used up front, to minimize tissue use and potential wastage, and to identify rare driver mutations that you otherwise wouldn’t see. It is thought that doing [all tests in one setting may] improve patient care.

The NCCN guidelines [also recommend] that if there’s insufficient tissue for all [tests], we should either do a repeat biopsy [or, in select cases], use plasma testing. However, in patients with more advanced-stage disease, the chances of finding a plasma-positive test for early-stage disease is extremely low. So, plasma testing would not apply to patients with advanced disease.

FEAGIN: Some of the health maintenance organizations [HMOs] aren’t interested in paying for NGS [for patients with early-stage disease]. They want to [limit NGS testing to patients] with advanced disease. So, [to address this], I order the tests individually, and some of them pass through, and some of them don’t.

DOWLATI: Do any HMOs [do this]?

FEAGIN: I’ve had a lot of [pushback on NGS testing from the Medicare HMOs.

DOWLATI: Does anybody else have any problems in terms of reimbursement [for NGS testing]?

ASHRAF: Yes, Blue Cross Blue Shield Alabama has been difficult to deal with in terms of NGS [testing].

DOWLATI: [Has this been for] early-stage disease?

ASHRAF: Early-stage disease and sometimes also later-stage disease.

ASHRAF: Typically, it’s up to the oncologist to order the testing.

DOWLATI: Does everyone agree with that?

HAMMOUD: Yes, I agree. Oncology usually orders the NGS.

FEAGIN: Oncology typically orders it, and that causes a delay in initiating treatment, unless the patient is seen as an inpatient.

DOWLATI: We initially had that process, as well, but we ended up making NGS reflex testing. So, at our institution, any [patient with NSCLC] who has surgery automatically gets NGS and by doing this, the oncologist and the surgeon have been taken out of the picture, and it’s the pathologist who orders [NGS testing]. That way, by the time [the patient is seen] in our office [after surgery], we already have all the NGS data. We implemented this system about a year ago, and it’s been extremely helpful for us. Does anybody in this group [work at an institution] where another member of the team orders NGS testing?

GALLAGHER: Sometimes the pathology team will [order NGS testing] on our behalf, and that’s very helpful because by the time I see a new patient, it’s possible that the NGS results will already be there.

DOWLATI: Well, we’re extremely spoiled because we have a fantastic in-house NGS program that gives us our results in 5 days. Since NGS testing is reflex, it’s made our lives easy when we meet the patient for the first time.

DOWLATI: In your practice, how you do you approach explaining adjuvant therapy to the patient?

ALBERTI: Typically, I will talk to [patients about adjuvant therapy once] they have had their lesion surgically resected. If the [patient has] early-stage disease, we will talk about a plan with curative intent. So, we’ll go through the toxicities of adjuvant therapy, [and discuss how this therapy may help] to potentially cure them, although that may not happen.

DOWLATI: I have had discussions with my colleagues [on how best to present the curative potential of] adjuvant therapy. [Should we] use the absolute improvement in survival at 5 years? [Should we] use the percentage of improvement, meaning the odds ratio, like a lot of the breast cancer doctors do? [Or should] we use the numbers needed to treat, like we do in internal medicine all the time? I find that discussion fascinating. Does anyone have any comments on how they [discuss this issue with patients]?

STOREY: For me, having this [discussion about the potential benefits of adjuvant therapy] is one of the biggest challenges of our job as oncologists. It’s a very nuanced conversation, and I find that it’s a lot of information to get across [to the patient] in a single visit. For what it’s worth, I tend to explain the absolute numbers, [such as the] number needed to treat. I shy away from discussing relative numbers because I don’t think that it’s too helpful for the patients. A lot of the time, [I approach the discussion by framing it around] what I would call a regret conversation. What decision would we make today that you, as a patient, wouldn’t regret later, depending on how things turn out?

CHARBONNET: For adenocarcinoma, we use cisplatin plus pemetrexed [Alimita] for 4 cycles. For squamous [cell carcinomas], if the [patient does not have] diabetes, we use carboplatin plus paclitaxel [Taxol], but if the patient does have diabetes, sometimes we’ll use gemcitabine [Gemzar] plus carboplatin.

DOWLATI: For squamous cell carcinoma, it seems like you gravitate toward carboplatin, and for adenocarcinomas, you gravitate toward cisplatin.

CHARBONNET: Yes, we [don’t combine cisplatin] with taxanes. It’s a little bit easier on the patient to combine carboplatin with gemcitabine than cisplatin with gemcitabine.

DOWLATI: For patients who can’t tolerate [some treatments], we tend to use carboplatin plus pemetrexed if we can’t use cisplatin. In squamous cell carcinoma, I have a lot of experience using cisplatin plus paclitaxel, a regimen [that I find is] tolerable in many patients. [For patients to whom] I can’t give cisplatin plus paclitaxel, I think carboplatin plus paclitaxel is a reasonable regimen, and I’ve used this as well.

HAMMOUD: I’ve noticed that cisplatin plus docetaxel [Taxotere] is a little bit more toxic for my patient population. So, for nonsquamous cell carcinoma, we’ve been using cisplatin plus gemcitabine if they can tolerate cisplatin.

GALLAGHER: I consider the performance status of the patient [when deciding whether to use adjuvant therapy]. The patient’s age doesn’t matter as much as how active they are and what their activities of daily living are. Performance status is a lot more important than chronological age, so everybody’s different.

DOWLATI: For a patient, [such as our case patient with] stage IIB disease, and negative margins, the NCCN guidelines recommend giving chemotherapy and considering osimertinib [Tagrisso] if the lesion is EGFR positive. However, [NCCN guidelines are somewhat vague] for patients with node-negative disease [who have certain high-risk prognostic factors]. In these patients, NCCN guidelines have assigned a lower category of evidence for adjuvant therapy and recommend observing and considering chemotherapy. Factors that the NCCN considers to be high risk are tumors that are greater than 4 cm, that have vascular invasions, are poorly differentiated, or have visceral pleural involvement. Other high-risk factors are having a wedge resection as opposed to a standard lobectomy or having an unknown lymph node status because the surgeon could not find the lymph nodes.

So, our case patient had stage IIA, T3, N0, disease, but also had a large 5.5-cm tumor, which would be considered a poor prognostic factor. In this setting, one should consider using adjuvant therapy, after discussion with the patient. What parameters would you use to decide to send a patient, such as our case patient, for adjuvant radiation therapy after chemotherapy?

HAMMOUD: Well, if a patient had a positive margin, I would refer them for evaluation for another resection. If the patient did not get another resection, I would refer them for evaluation for adjuvant radiation therapy after chemotherapy. I would also refer patients with N2 disease.

DOWLATI: It sounds like [N2 disease and positive margin] are the 2 common reasons to send patients to the radiation oncologist for adjuvant radiation. I think that’s what I would do as well but if the patient has gross residual disease and the surgeon removes only 25% of the tumor and says, “I can’t do it, it’s an R1 resection,” then one would probably also treat the patient with radiation because the tumor is locally advanced at that point.

FARAG: I think the disease-free survival [DFS] data are practice-changing [for patients with early-stage disease], but I would say that what are missing are the clinical implications of the trial’s overall survival [OS] data. I was wondering what the next line of therapy, other than chemotherapy, should be for patients who progress on osimertinib.

BAGHIAN: Osimertinib is now included in the NCCN NSCLC guidelines, based on the DFS data from ADAURA, and I agree that this is practice-changing. However, [the question for me is], Do we need to give chemotherapy to these patients? A lot of the patients in the ADAURA trial did receive adjuvant chemotherapy, right?²

DOWLATI: I don’t know if anyone’s going to do that study, but it’s an important question. What is the value of chemotherapy in patients who are getting such a great benefit from an EGFR inhibitor? We have a little bit of insight into that from a Chinese study that randomly assigned patients to receive gefitinib [Iressa] or chemotherapy.³ Although [the EGFR inhibitor] was gefitinib and the patient population was different, the trial showed that patients with EGFR-mutated tumors who did not get chemotherapy [had very different outcomes compared with other patient groups]. That study raised concerns that perhaps patients also need chemotherapy.

One of the reasons for this finding, which I’ve heard from my colleagues in the thoracic oncology world, is that patients with EGFR mutation–positive lung cancer have higher response rates to chemotherapy [compared with other patient groups]. So, does this mean that the patients also benefit from the chemotherapy? It’s a fantastic question.

STOREY: The plots in the New England Journal of Medicine article suggest that all patient subgroups benefited from osimertinib therapy, including [both patients] who [did and did not] receive adjuvant chemotherapy.² I would have loved to see Kaplan-Meier plots stratified based on who received adjuvant chemotherapy and who didn’t. It seems like a lot of information [on this question from the ADAURA trial] wasn’t made totally clear in this article.

DOWLATI: Patients who received adjuvant chemotherapy had slightly better DFS than those who didn’t. The hazard ratio [HR] was 0.16 for [patients who received adjuvant] chemotherapy and 0.23 for those who didn’t. So, that’s about a 7% difference [in DFS]. [This difference wasn’t] statistically significant because it was from a subgroup analysis, but still there seemed to be a potential benefit to adjuvant chemotherapy.

GALLAGHER: [I think that] patients who are not eligible for the platinum or the platinum doublet could be offered the EGFR inhibitor osimertinib.

STOREY: I guess I’m old-fashioned, but I feel that an evaluation of an adjuvant therapy trial should be based on OS. I guess [that the results of the ADAURA trial are] practice-changing just because there was such a significant response in DFS. But we’ve been surprised so many times before when we use DFS to evaluate the effect of therapy in an adjuvant setting. I must admit that the NCCN guidelines kind of push you in the direction of osimertinib, but I’m not sure that you can offer it to somebody today.

DOWLATI: I’m old-fashioned, too, and I think we all want to see the data on OS. However, the FDA considers DFS an appropriate end point [in the adjuvant setting]. If not, they would have never approved osimertinib.⁴ Nevertheless, especially for lung cancer, we would all be more comfortable evaluating the effect of adjuvant therapy based on OS. However, I can refer you to a meta-analysis published a couple years ago evaluating whether DFS in the adjuvant setting in lung cancer is predictive of OS, and it is.

FEAGIN: I think that, eventually, having a large number of patients with lung cancer [who are receiving long-term adjuvant osimertinib] will clog up your practice. You’ve got to regularly check in with these patients, particularly regarding pulmonary toxicity, and you can’t just put them on a 3-month follow-up [plan] as you might with a patient who’s been resected.

DOWLATI: Yes, that’s what it’s done to my practice, which is primarily for patients with thoracic disease. I have many patients who are living with immunotherapy, and now I have to treat them using an adjuvant EGFR inhibitor. I see [these patients] monthly, or every other month, and it’s clogged up my practice. I like the term that you used—clogged it up—because it’s become very difficult to get new patients in, given all the follow-up appointments that we have.

CHARBONNET: The HR [for osimertinib] was 0.12 for stage IIIA disease, and 0.39 for stage IB disease. That’s a big disparity, although any time a HR is less than 0.5, I’m very happy, so I would be strongly pushing my patients with stage IIIA disease to get the osimertinib after chemotherapy. However, in patients with stage IB disease, if they didn’t want it, that’s fine, but I think you could make the argument that stage IB patients aren’t given a whole lot of adjuvant chemotherapy, [which I use more in] patients with stage II or III disease.

Maybe osimertinib could be used instead of chemotherapy for patients with stage IB disease. [Now, in my view], osimertinib should be given to patients with stage II or III disease. I’m hesitant regarding patients with stage IB disease because, although there’s a clinical benefit, you also have to look at the cost of taking an expensive medicine for many years.

_REFERENCES

_{1. NCCN. Clinical Practice Guidelines in Oncology. Non–small cell lung cancer, version 1.2022. Accessed January 17, 2021. https://bit.ly/33KCBNr}

_{2. Wu Y-L, 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):1711-1723. doi:10.1056/NEJMoa2027071}

_{3. Wu Y-L, Chu D-T, Han B, et al. Phase III, randomized, open-label, first-line study in Asia of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer: evaluation of patients recruited from mainland China. Asia Pac J Clin Oncol. 2012;8(3):232-243. doi:10.1111/j.1743-7563.2012.01518.x}

_{4. FDA approves osimertinib as adjuvant therapy for non-small cell lung cancer with EGFR mutations. FDA. December 18, 2020. Accessed January 14, 2022. https://bit.ly/3frqrfe}