Adjuvant Therapy for EGFR Mutant Early-Stage NSCLC: ADAURA

Solange Peters, MD, PhD: Looking at early-stage non-small cell lung cancer, and after complete resection, we have established 15 years ago the rule for an adjuvant chemotherapy. Adjuvant chemotherapy in resected non-small cell lung cancer has a modest but significant overall survival benefit above observation or placebo. What I mean by that is, in unselected non-small cell lung cancer, like stage 2 or stage 3, an adjuvant chemotherapy with 4 cycles of chemotherapy is recommended. There’s a discussion still about the end 0 disease. There are 2 trials, the Canadian 1 and the American 1, showing that if no lymph nodes are affected by the disease, it’s about the tumor size. Chemotherapy and adjuvant chemotherapy might be recommended above 4 cm of the size of the tier—the size of the tumor. That’s the modest, but beneficial adjuvant chemotherapy to be given to all patients irrespective of molecular iterations and biomarker. That’s the standard of care of the recent decade. We have been exposed recently to 2 new standards of care. The first 1 is on the top of the chemotherapy, which is to add targeted therapy, osimertinib [Tagrisso]. This is an EGFR third generation TKI [tyrosine kinase inhibitor] that lasts up to 3 years in this patient with EGFR-mutated non-small cell lung cancer. This has shown, per trial design, the benefits, according to the seventh TNM classification in stage 2 and in stage 3a in progression-free survival. We still don’t have the OS [overall survival] data in the secondary end point, also in stage 1b, in that trial according to the seventh TNM classification. Meaning more than 3 cm. So basically, on the top of the standard chemotherapy, osimertinib for 3 years has become a standard of care in many countries because of the huge magnitude of disease-free survival benefit ranging from 2.12 in stage 3 to 0.39 in stage 1b, which is still very significant. This means that we should test these patients for EGFR mutation. In my center again, it’s done routinely in all patients with non-squamous non-small cell lung cancer. We routinely do an NGS [next-generation sequencing] on the biopsies. In centers where it is not reflex testing, I think it has to be established in non-squamous non-small cell lung cancer. EGFR mutation, per se, or part of an NGS testing, is performed to be able to offer this adjuvant osimertinib after chemotherapy. Remember that in the ones without EGFR and without ALK, adjuvant immunotherapy can also be offered. We have data from the IMpower010 [clinical trial], which is now telling us that in the adjuvant setting, adding atezolizumab [Tecentriq] can also improve the disease-free survival in patients without EGFR mutation. This is related to the PD-L1 [programmed death-ligand 1] expression. It’s validated in positive PD-L1 expression and even more, I would say, validated in high PD-L1 expression. To answer your question, you have EGFR testing for chemotherapy followed by adjuvant osimertinib. You might have PD-L1 testing for chemotherapy plus adjuvant atezolizumab. That’s my current opinion on what you should do in addition to the old days chemotherapy.

Tony S.K. Mok, MD: Our decision and planning is based on the ADAURA study that was published in 2020 by Professor Yi-Long Wu. In this particular study, the patients are post-op, stage 1b, 2, or 3. All the patients may not receive chemotherapy or may end up receiving the placebo for 3 years instead of the randomized osimertinib. The ratio is quite tremendous at 0.17, thus showing the large impact the disease has on survival. The FDA approved it this way, but in Asia it is more so present at independent centers. In my own personal practice, I routinely ask for EGFR mutation testing in the respectable setting. If they are positive for EGFR exon 19 or 21 mutation, for stage 2 and 3, I will offer them the treatment. If a patient is stage 1b, I discuss with the patient the best options as this stage may not require the treatment. It is now integrated as part of the standard practice. The government may not reimburse the drug, but we should at least inform the patient of the diagnosis and inform them of their EGFR mutation status.

ADAURA is a large scale, multi-center, international study that randomized phase 3 for all patients with a respectable stage 1b, 2, and 3. The patient must be mutation exon 19 or 21 positive to begin. After surgical resection, they have the option of rethinking chemotherapy. It is up to the doctor whether or not the patient will receive chemotherapy. After the adjuvant chemotherapy, they randomize it to 3-year osimertinib versus placebo control. The primary end point is a disease-free survival. In the outcome they recently published, in New England Journal of Medicine, a group as a whole had the chance of having an improvement of the hazard ratio, which is still 0.17. In other words, there were significant differences in the osimertinib of 3-year versus the control, made from observations only. Now, the overall survival data is too early to make any conclusions from. However, the key decision on whether we want to offer the patient the treatment or not would depend on the stage of the disease. The second thing to consider is whether the patient, so called in Asia Pacific, can afford it, because 3-year adjuvant therapy is relatively expensive. In my practice, in stage 2 and 3. I definitely would offer it, but the sample size in stage 1b is slightly less. Although they still have the hazard ratio of 0.39. There is still controversy in this regard, so I would have to explain to the patient about the data and help them make the decision. Now toxicity wise, osimertinib is a well-tolerated TKI. The main toxicity, including some skin rash, mild diarrhea, some patients may have weight loss, and there is also the concern about the ILD [interstitial lung disease], which occur in less than 1% of the patient. Hepatic toxicity has the potential to impact the QoTc interval and has to be observed very closely. But generally, most patients can tolerate the drug quite well. Over 78% of the patients can complete the entire course of the treatment in the ADAURA study.

This transcript has been edited for clarity.