Part 2: Considerations for Using Adjuvant Chemotherapy and Osimertinib in NSCLC

Aaron E. Lisberg, MD (Moderator)

Assistant Clinical Professor, Medicine

UCLA David Geffen School of Medicine

Los Angeles, CA

CASE SUMMARY

An otherwise healthy White woman, age 60 years, presented with a nonproductive cough. She was a former smoker who quit 8 years ago (13 pack-years). She had an ECOG performance score of 0, blood pressure 120/93, heart rate of 75, body mass index of 22, and lungs were clear to auscultation bilaterally. All laboratory results were within normal limits. A chest x-ray revealed a 5.5-cm right mass in the right upper lobe of the lung, and a CT chest/abdomen scan showed a lobulated 5.5 × 5.1-cm mass in the right upper lobe.

A biopsy of the right upper lobe revealed thyroid transcription factor-1–positive adenocarcinoma consistent with non–small cell lung cancer (NSCLC). Positron emission tomography results were negative for any spread to lymph nodes or distant metastasis. A brain MRI result was negative and pulmonary function tests were normal.

The patient underwent a right upper lobectomy without complications. Pathology showed she had a 5.5-cm tumor with negative margins, node negative, and a pathologic stage IIB* (pT3N0M0) lung adenocarcinoma. Her ECOG performance status was now 1.

DISCUSSION QUESTIONS:

• What is the role of adjuvant chemotherapy in your practice? What are the treatment goals?​
• Which regimen(s) do you typically employ?​
• Which parameters are important when deciding whether to use adjuvant systemic therapy post resection? Do you consider tumor size, number of metastatic nodes, or histological poor-risk features?

MERIN STEPHEN, MD: I just go to the NCCN [National Comprehensive Cancer Network] guidelines and run through the most recent data, [considering] the typical goals of adjuvant therapy. If it is after their chemoradiation, if they’re willing to accept the toxicities of additional chemotherapy, then we go down that path. I offer it to whoever’s eligible and willing.

The node-positive disease is what I’ve seen more as an indication for typical patients who require adjuvant therapy, so it’s what I’m used to. I’d have to look back at patients with larger tumors [as to] who exactly qualifies.

AARON E. LISBERG, MD: Which regimens do you typically use for adjuvant chemotherapy?

STEPHEN: It depends on adenocarcinoma versus squamous cell carcinoma [histology]. I haven’t been using any targeted treatment yet, so it’s been more immunotherapy and chemotherapy.

NIHAL ABDULLA, MD: I do follow NCCN guidelines, so I try to do adjuvant chemotherapy to those who qualify for it, those with stage IB [disease] and above.¹ The treatment goal is to get them through their recommended treatments and improve their overall survival.

I try to incorporate mostly cisplatin, compared with carboplatin, when I’m using treatment. Then maybe I’ll consider pemetrexed [Alimta]. Or, with a patient with squamous cell carcinoma, I would consider a taxane-based combination treatment. And I have recently been trying to do mutation testing for patients in the adjuvant setting and ordering next-generation sequencing myself.

LISBERG: If you’re deciding for or against adjuvant chemotherapy, which factors are most important when making those decisions?

ABDULLA: The No. 1 factor is the lymph node status. We do have confusion on the tumor size; if it is less than 4 cm, then I’m trying to [consider] these high-risk features, like pleural invasion, lymphovascular invasion. Whenever we have a patient who doesn’t meet the criteria, the best thing is to discuss their cases with the tumor board and our pathologist. Sometimes we learn that there are now more features, which will guide our treatment. I have learned a lot discussing these cases, especially the borderline cases, in a tumor board meeting.

LISBERG: Do you discuss most of your patients with early-stage NSCLC in the tumor board, or just the ones where you’re on the fence?

ABDULLA: In our practice, we try to do all of them.

LISBERG: I always find that the discussion about adjuvant therapy can go in different directions, depending on the patients. How do you typically approach that discussion?

ABDULLA: Whenever I have a patient, or when I’m discussing adjuvant treatment, I show them graphs available online to show the risk of recurrence, which is high. Even in those patients whose disease [is treated with] resection, [the risk rate comes] up to be 50% to 60%.² Most of the patients are recurring. That’s a major driver.

I try to show them graphs [and say], “You still would have a chance of recurrence, but at least you would decrease the chances.” For some of the patients, I have had issues going into too much in detail.

LISBERG: Dr Sam Yeh, what are your thoughts about this?

SAM YEH, MD: All factors are important: tumor size, node [status] is very important—Hilar node positive versus node negative. I think about other high-risk features if they’re node negative. They’re all important: age, performance status, and potential toxicity. If you add multiple factors together then they become more important.

I think the case that’s controversial is tumor size of 4 cm and node negative. Is there benefit for chemotherapy there, and if there is [then] do you use cisplatin or carboplatin? If they have EGFR mutations, do you use EGFR tyrosine kinase inhibitors plus immunotherapy? For patients with N1 node-positive status, I’m not very clear about [chemotherapy benefit].

LISBERG: What chemotherapy backbone do you usually use?

YEH: I use platinum-based chemotherapy because that’s based on all the studies; cisplatin is the way to go. Pemetrexed is what I use for adenocarcinoma. Then, if it’s squamous cell carcinoma, I probably choose docetaxel.

LISBERG: In stage IIB, which is N0 or N1 disease with negative margins, the NCCN guidelines show chemotherapy and osimertinib [Tagrisso] as a category 1 recommendation.¹

CASE UPDATE:

Following resection, the patient receives 4 cycles of adjuvant chemotherapy with cisplatin and pemetrexed​. Her ECOG performance status is 1​. Molecular testing discovers an EGFR exon 19 deletion.

DISCUSSION QUESTIONS:

• What are your reactions to the data from the ADAURA trial (NCT02511106) of adjuvant osimertinib?​ Do you consider them practice changing?​

LISBERG: What are your reactions to the ADAURA data?

SAI-HONG OU, MD: ADAURA is paradigm changing. Results were [published in] the New England Journal of Medicine.³ It’s [led to approval of adjuvant osimertinib] by the FDA for stage IB to IIIA NSCLC [for patients with EGFR exon 19 deletions or exon 21 L858R].⁴ I don’t have any problems with that. I’m a true believer because it dovetails into a bigger [question] of lung cancer screening in patients who are never-smokers.^4,5 One of the things [individuals] say is that you don’t screen because we can’t find [which] patients with lung cancer are smokers, and that’s not true. Hopefully, in 2022, we will present some data, a meta-analysis.

But, if we detect disease in the early stage, then osimertinib improves disease-free survival [DFS]; there is no question about it.

Patients are not stratified for adjuvant chemotherapy or not, so the free stratification factors did not include adjuvant chemotherapy. A paper in the Journal of Thoracic Oncology shows, essentially, [that patients in ADAURA who received] adjuvant chemotherapy [before receiving osimertinib] had no benefit to DFS [versus those who did not receive adjuvant chemotherapy before osimertinib].⁶ That’s just from looking at the absolute numbers, stage by stage. You can plot the bar graph and they are the same.

It is practice changing, and this will point the way to other adjuvant therapies to check for not just EGFR but ALK, ROS1, NTRK, MET exon 14, [and other targets]. It is huge. You can see the DFS, [though] whether it’s 3 years, 5 years, [or] indefinite is the key.

LISBERG: The data from the Journal of Thoracic Oncology are very interesting. I think it’s an open question, because certainly, from a quality-of-life perspective and toxicities, all of us would like to avoid adjuvant chemotherapy if possible in our EGFR-positive patients. I don’t know whether the data are there, and I think that it’s a subgroup analysis, but it’s very interesting.

_References

_{1. NCCN. Clinical Practice Guidelines in Oncology. Non–small cell lung cancer, version 3.2022. Accessed May 26, 2022. https://bit.ly/3NC4OI1}

_{2. Uramoto H, Tanaka F. Recurrence after surgery in patients with NSCLC. Transl Lung Cancer Res. 2014;3(4):242-249. doi:10.3978/j.issn.2218-6751.2013.12.05}

_{3. FDA approves osimertinib as adjuvant therapy for non-small cell lung cancer with EGFR mutations. FDA. December 18, 2022. Accessed May 26, 2022. https://bit.ly/3sYuSp8}

_{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):1711-1723. doi:10.1056/NEJMoa2027071}

_{5. Final recommendation statement lung cancer: screening. U.S. Preventive Services Task Force. March 9, 2021. Accessed May 26, 2022. https://bit.ly/3NRziG2}

_{6. Wu YL, John T, Grohe C, et al. Postoperative chemotherapy use and outcomes from ADAURA: osimertinib as adjuvant therapy for resected EGFR-mutated NSCLC. J Thorac Oncol. 2022;17(3):423-433. doi:10.1016/j.jtho.2021.10.014}