Part 2: Barriers and Sequencing for Osimertinib in EGFR+ NSCLC

Matthew A. Gubens, MD, MS (Moderator)

Thoracic Oncologist

UCSF Thoracic Surgery and Oncology Clinic

Helen Diller Family Comprehensive Cancer Center

UCSF Health

San Francisco, CA

DISCUSSION QUESTIONS

• What are your thoughts on the ADAURA data (NCT02511106) of osimertinib (Tagrisso)?¹ Do you consider the results to be practice-changing?
• What are the advantages and disadvantages of this strategy for adjuvant therapy?

MATTHEW GUBENS, MD, MS: Most think that ADAURA is practice changing to some extent, but I am curious, are there any nuances that people want to draw out?

MICHAEL HARRIS, MD: A subset analysis might be helpful in that the [Kaplan-Meier] overall survival [OS] curves seem to be coming together or approaching each other. It would be interesting to note if that that was because of the patients that did not receive chemotherapy in addition to osimertinib, or if it makes any difference? I would like to have that kind of subset analysis to help guide me in the future.

GUBENS: I think that is going to be some important work over time as they [evaluate] the data. Who got chemotherapy and what was the differential effect? I think that is an important point.

RICHARD KOSIEROWSKI, MD, CCHP: Cost…It is a lot of money.

GUBENS: That is for sure. This is not a cheap drug, and it is also not a nontoxic drug. We have a subset of patients in this setting who will get pneumonitis. They were included on the safety analysis. It is a different risk-benefit ratio as adjuvant [treatment] than in the metastatic setting. It can affect patient adherence to a regimen we might suggest for them.

ANA VELÁZQUEZ MAÑANA, MD: I think there is also a question on whether we are curing patients or delaying progression. [Is it] EGFR-positive disease that will progress as soon as you remove osimertinib in this setting?

GUBENS: That is an important point because it is great if you cure a patient and they never fail after that disease-free survival curve or that OS curve. But what if you are just forestalling their progression? What do you do at that progression point?

If you progress during the 3 years, then you have to go to chemotherapy presumably or other targeted trials. Are you actually improving their OS? I think that is where Dr Harris also makes his points about these curves converging. Is it just that we are doing a really good job of suppressing their micrometastatic disease for longer, but eventually it shows itself? Maybe we will learn more about as these data mature.

HARRIS: That does not worry me as much though, because I think when patients look at the benefits of a chemotherapy or tyrosine kinase inhibitor therapy, they are looking more at a disease-free survival because that is symptomatic for them. So whether they live the same amount or not, are they going to be suffering with the disease during that interim period? I think that outweighs the cost factor for me.

GUBENS: It is an important point, the patient perspective. A lot of the focus at our conferences was on if a patient sees those differences in curves, which I think that the rhetorical point made is which curve do you want to be on? I think as long as you have a thorough conversation about the risks of adverse events and the financial toxicity; the patient has a stake in this, too.

RACHNA ANAND, DO: I think ADAURA is definitely practice changing because osimertinib is relatively much better tolerated than chemotherapy, especially in the patients with IIIA disease. I would be interested in a subset analysis to see if patients who got a specific chemotherapy benefited more than others.

TIMUR MITIN, MD, PHD: [Osimertinib gives] central nervous system [CNS] disease control without radiation therapy.

GUBENS: That is an important contrast as you are trying to look at historical data when the earlier adjuvant trials were with first-generation agents where we did not have as much CNS penetration. The patient does not want disease to progress in the brain.

GUBENS: I think, even in this cure vs non-cure context, I am always thinking about if this is metastatic disease, post-surgery, that we do not recognize yet, and that there is maybe some benefit to suppressing these clones early.

Patients who present with lower burden of metastatic disease tend to have longer disease-free or progression-free survival. I think that maybe your point emphasizes that.

The primary end point of the ADAURA trial was for stage II and above. The FDA approval has no reference at all to stage.² You have to do with that what you will in clinic because technically you can do this for an early-stage IA case.

Based on this discussion, how do you predict you will use adjuvant osimertinib for EGFR-positive NSCLC?

DIANA SUPERFIN, MD: It is going to be quite interesting with the atezolizumab [Tecentriq] approval for PD-L1 for stage II and III. So if insurance denies use of the next generation for the patients, unless it is stage IV—the people who have ALK or EGFR do not respond to PD-L1 therapies as well so we try to avoid it in some of the regards. We will probably be pushing insurance to clear this hurdle for these patients, even in the adjuvant setting.

GUBENS: You bring up an important point. In the IMpower010 data [NCT02486718] that came out in Lancet and was approved by the FDA, these were patients [with EGFR mutations] who would not have had access to adjuvant EGFR therapy.³

RIZVI: What about sequencing in terms of EGFR inhibitor after immunotherapy?

GUBENS: That is important, too, because there is definitely a toxicity if you go from immunotherapy into osimertinib. I think that we have to be thoughtful about that and have the EGFR data in our hand, at the very least for the demographically appropriate patients. But I would argue we should probably have it globally exactly for the reason that you could potentially do harm with immunotherapy, and then do harm by switching over in an early setting.

Adjuvant chemotherapy was optional on this trial. About 60% of patients chose to get it.¹ Some of that was probably stage-based, but some of it might have been alternative-possibilities based. Would you be more willing to recommend foregoing a platinum-based chemotherapy in otherwise eligible patients before you do osimertinib?

ANAND: I think it would be on a case-by-case basis. But if a patient was eligible, I would offer them chemotherapy followed by osimertinib.

SUPERFIN: That is a case when I do not know if insurance covered the DetermaRx in [limited] stage, because they will say who has a high chance of responding to chemotherapy vs a low chance. So you can push the patients toward the data….Maybe that is going be an additional role for DetermaRx, to persuade or dissuade patients to get chemotherapy.

GUBENS: I think it is going to be good to be able to do a better dollar-risk assessment than purely [based on] stage. That is one of the ways we hope to do it.

But to Dr Anand’s point, this is a curative situation. So even if that marginal benefit is not huge, you have to talk to the patient about it. Do we want to grab every [match], especially if the demographics of this patient population tends to be younger and fitter? I am not as afraid of 4 cycles of chemotherapy if it potentially improves their chances. Though I think there is more to learn with the subgroups as these data mature.

_References:

_{1. Wu YL, Tsuboi M, He J, et al. Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2020;383(18):1711-1723. doi:10.1056/NEJMoa2027071}

_{2. FDA approves osimertinib for first-line treatment of metastatic NSCLC with most common EGFR mutations. FDA. Updated April 19, 2018. Accessed March 8, 2022. https://bit.ly/3CoxLD5}

_{3. Felip E, Altorki N, Zhou C, et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet. 2021;398(10308):1344-1357. doi:10.1016/S0140-6736(21)02098-5}