CE / CME
Pharmacists: 1.25 contact hours (0.125 CEUs)
Nurses: 1.25 Nursing contact hours
Physicians: Maximum of 1.25 AMA PRA Category 1 Credits™
Released: September 30, 2022
Expiration: September 29, 2023
Edward B. Garon, MD, MS:
The next question in our survey was, “Are you using adjuvant osimertinib in clinical practice for your patients with resectable stage IB-IIIA EGFR mutation–positive NSCLC?” Of the 77 participating HCPs, one quarter confirmed they do use this approach in these settings. However, another one quarter reported using adjuvant osimertinib only in patients with stage II and IIIA disease. Slightly more than 40% responded “No” to this question and 10% responded, “I’m not sure.”
Table 4. Are you using adjuvant osimertinib in clinical practice for your patients with resectable stage IB-IIIA EGFR mutation–positive NSCLC?
We also looked at responses across the globe and saw some variation by region, which may be attributable to differences in regulatory approvals.
Table 5. Are you using adjuvant osimertinib in clinical practice for your patients with resectable stage IB-IIIA EGFR mutation–positive NSCLC?
Edward B. Garon, MD, MS:
Dr. Yu, would you elaborate on the available data behind the use of adjuvant osimertinib for resectable stage IB-IIIA EGFR-mutated NSCLC?
Helena A. Yu, MD:
Sure, Dr. Garon. In 2020, the FDA approved adjuvant therapy with osimertinib following resection in patients with stage IB-IIIA NSCLC harboring an EGFR exon 19 deletion or L858R mutation based on the positive DFS results from the phase III ADAURA trial, which compared adjuvant therapy with osimertinib vs placebo in patients with completely resected stage Ib-IIIA EGFR-mutated NSCLC.1,3
Helena A. Yu, MD:
ADAURA met its primary endpoint by demonstrating that adjuvant osimertinib significantly improved the median DFS vs placebo in the subpopulation with stage II/IIIA disease (not reached vs 19.6 months with placebo; HR: 0.17; 99.06% CI: 0.11-0.26; P <.001).1 The median DFS was also significantly improved in the overall population of patients with stage IB-IIIA disease (not reached vs 27.5 months with placebo; HR: 0.20; 99.12% CI: 0.14-0.30; P <.001).
Recently at the 2022 European Society for Medical Oncology Congress, Tsuboi and colleagues63 reported updated DFS results from ADAURA with an additional 2 years of follow-up, which allowed all participating patients to complete the full 3 years of adjuvant therapy. In the overall population of patients with stage IB-IIIA disease, the median DFS was 65.8 months with osimertinib vs 28.1 months with placebo (HR: 0.27; 95% CI: 0.21-0.34), with 3-year DFS rates of 85% and 44%, respectively.
Helena A. Yu, MD:
When we look at the subgroup analysis, we see that the DFS benefit was more pronounced in patients with more advanced disease.1 However, patients with stage IB disease still had a DFS benefit with adjuvant osimertinib (HR: 0.39; 95% CI: 0.18-0.76). This remained the case in the updated analysis.63
OS data were immature at the time the interim analysis was published in 2020.
Edward B. Garon, MD, MS:
Thank you, Dr. Yu. Returning to our survey results, I found it interesting that of the almost 50% of HCPs who responded that they use adjuvant osimertinib, one half indicated they would use it across its approved indication, which is stage IB-IIIA, while the other one half chose to use it only for patients with stage II and IIIA disease. How do you use adjuvant osimertinib in your clinical practice, Dr. Yu?
Helena A. Yu, MD:
Considering the challenge of interpreting ADAURA when we only have DFS results and are still waiting on the OS results, I counsel patients as best I can on the data and let them decide instead of mandating anything. I do adhere to the FDA approval and offer this option to those with stage IB, II, and IIIA disease. However, I can see why some in the survey chose only patients with stage II and IIIA disease, seeing as the DFS benefit was more pronounced in these patients. That said, the HR for DFS for those with stage IB disease was significant, so presumably, adjuvant osimertinib is providing benefit to this population as well. In fact, the American Society of Clinical Oncology recently released an update recommending adjuvant osimertinib for patients with stage IB NSCLC harboring sensitizing EGFR mutations based on the ADAURA data.9
Edward B. Garon, MD, MS:
I agree that although the DFS HR for the subgroup with stage IB disease in ADAURA was notable, it is comparable with that reported in other studies of adjuvant EGFR TKI therapy, which ultimately did not demonstrate an OS benefit.10
Dr. Piotrowska, how are you using osimertinib in the adjuvant setting?
Zofia Piotrowska, MD, MHS:
Like Dr. Yu, I discuss adjuvant osimertinib as an option for patients with stage IB-IIIA disease but vary how strongly I endorse this option by disease stage. I most strongly recommend adjuvant osimertinib for patients with stage II and IIIA disease. By contrast, I consider the DFS benefit to be modest in stage IB disease, and I think it would be very important to see positive OS data before strongly recommending adjuvant osimertinib for these patients. Although 3 years of osimertinib treatment is well tolerated by most patients, it can affect their quality of life and some patients experience rare but serious adverse events, so the risk-benefit profile just isn’t quite where it needs to be yet for me to strongly recommend adjuvant osimertinib to my patients with stage IB disease. I do offer it but don’t push as hard as with my patients with stage II or IIIA NSCLC.
Although most of my patients have chosen to start adjuvant osimertinib and have been satisfied with their decision, I did have a patient with stage III disease who, at the end of chemotherapy, just said, “I’ve had enough. I can’t deal with this anymore.” Unfortunately, this was a patient I strongly wanted to start on adjuvant osimertinib. There is variability in patient preference, of course, and it is necessary to take their preferences into consideration, particularly given that we do not yet have the OS data.
I will note that adjuvant osimertinib is under investigation for stage IA disease in the ongoing phase III ADAURA2 trial (NCT05120349), so I look forward to what those data tell us.
Edward B. Garon, MD, MS:
Dr. Socinski, you mentioned earlier that several of your recent patients with early-stage NSCLC and an EGFR mutation declined adjuvant therapy with osimertinib. Would you elaborate on why?
Mark A. Socinski, MD:
As is the case for all of my patients with resectable early-stage EGFR-mutated NSCLC, and similar to what Dr. Yu mentioned above, I of course have the difficult discussion about the difference between DFS and OS followed by talking through results of the ADAURA trial and other considerations that go with taking osimertinib.
One of the patients who declined adjuvant osimertinib was a man who traveled all around the world. His concern was dealing with the potential adverse events associated with osimertinib—especially high‑grade diarrhea—while traveling. He also wanted to know if treatment with adjuvant osimertinib would increase his chance of being cured. I told him that we simply do not know the answer yet, so he based his decision on that unknown.
Edward B. Garon, MD, MS:
That is interesting. My patients have consistently opted for adjuvant treatment with osimertinib, despite my reservations about whether the DFS benefit will translate into an OS benefit in the long run.
It will be interesting to see how practice evolves around the use of adjuvant osimertinib. I had my first patient progress off study on ADAURA and I was surprised because it had only been approximately 1 year since resection. Their disease burden was extensive but not so much that I thought that recurrence was very likely. It then emerged during my discussion with the patient that they had stopped osimertinib for a variety of nonspecific complaints never shared with me, suggesting that they probably did not want me to try and talk them into continuing therapy, but it explained their early progression in any case.
Edward B. Garon, MD, MS:
The FDA has also recently approved adjuvant immunotherapy with atezolizumab for patients with stage II-IIIA NSCLC and PD-L1 expression on ≥1% of tumor cells following resection and platinum-based chemotherapy.11,12 As Dr. Socinski discussed earlier, there are interesting considerations around the use of adjuvant immunotherapy in EGFR-mutated disease.
Dr. Le, would you ever consider adjuvant atezolizumab for a patient who, for example, has a significant smoking history with EGFR-mutated disease and a PD‑L1 expression level of 90%?
Xiuning Le, MD, PhD:
I actually have already encountered a case like this in my practice.
The patient and I discussed the available data and approved agents in this setting: osimertinib and the results of the phase III ADAURA trial, as was just discussed, and atezolizumab and the results of the phase III IMpower010 trial, which compared adjuvant atezolizumab vs best supportive care following cisplatin-based chemotherapy in patients with completely resected stage IB-IIIA NSCLC.13 Of importance, this trial did not exclude participants with EGFR-mutated disease. Rather, 11.6% and 3.3% of all randomized patients had EGFR-mutated and ALK-rearranged tumors, respectively.
After a median follow-up of 32.8 months, the HR for DFS favored atezolizumab over best supportive care in patients with stage II-IIIA NSCLC and PD-L1 expression ≥1% (not reached vs 35.3 months; HR: 0.66; 95% CI: 0.50-0.88; P = .004).13 There are many caveats to a cross‑trial comparison, but the HR for DFS of 0.17 seen with adjuvant osimertinib for stage II-IIIA disease in the ADAURA trial1 is greater than that seen here with adjuvant atezolizumab in the IMpower010 trial.
Furthermore, as Dr. Socinski mentioned earlier, we have data showing that patients who have advanced disease with an EGFR mutation and PD-L1 positivity don’t do well on immunotherapy.8,14 I extrapolate these results from the advanced setting to the adjuvant setting and lean toward suggesting adjuvant osimertinib to these patients.
In addition to discussing the efficacy data with patients, a conversation about how these drugs are delivered is warranted. Adjuvant osimertinib is an oral medication given once daily for up to 3 years, whereas atezolizumab is given intravenously every 2, 3, or 4 weeks for up to 1 year.11,15 These agents also have distinct adverse event profiles. These differences may matter to a patient—such as was the case for Dr. Socinski’s patient who traveled extensively.
Returning to my patient who had both PD‑L1 positivity and an EGFR-mutated tumor, we made the decision to prioritize adjuvant osimertinib.
Edward B. Garon, MD, MS:
Thank you, Dr. Le. Before we move on to discussing the first-line setting, I should note that our panel strongly agrees that combining osimertinib and atezolizumab would not be recommended. Pronounced toxicity occurs when immune checkpoint inhibitors are combined with EGFR inhibitors. Of note, the phase Ib TATTON trial recently reported that the combination of osimertinib plus durvalumab was associated with a 35% rate of pneumonitis in patients with EGFR-mutated advanced NSCLC.16 We also have seen severe immune-related adverse events when osimertinib is given after immune checkpoint inhibitor therapy.17 Due to the toxicity levels we’ve seen, I would advise against this combination of classes even in a clinical trial setting.
Zofia Piotrowska, MD, MHS:
I do want to comment that although we would not consider immunotherapy in the adjuvant or first-line settings for EGFR-mutated disease, immunotherapy could be considered when you have exhausted all other options.
Edward B. Garon, MD, MS:
Thank you, Dr. Piotrowska. We will talk more about the use of immunotherapy in the setting of relapsed EGFR-mutated NSCLC below.
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