NEW YORK – Additional analysis from the ADAURA trial presented during the European Society for Medical Oncology's Virtual Congress on Saturday, particularly data showing that adjuvant osimertinib (AstraZeneca's Tagrisso) may curb central nervous system (CNS) disease recurrence, is further bolstering the case for the drug.
In the months since the ADAURA trial was unblinded early due to what an independent data monitoring committee deemed "overwhelming efficacy," oncologists have been engaged in a spirited debate about whether the trial's disease-free survival rates, in the absence of mature overall survival data, provide enough evidence to warrant the adjuvant use of osimertinib to treat patients with stage IB to IIIA, EGFR-mutated non-small cell lung cancer after complete surgical resection.
The Phase III ADAURA trial randomized 682 patients with stage IB to IIIA, EGFR-positive NSCLC who had undergone complete surgical resection to receive either the third-generation EGFR inhibitor osimertinib or a placebo. The primary endpoint for the still-ongoing trial is disease-free survival, specifically in the subgroup of patients with stage II to IIIA disease. Disease-free survival in the overall population —including the patients with earliest-stage disease — is a secondary endpoint.
Of note, though patients were enrolled in the trial regardless of whether they had received prior treatment with adjuvant chemotherapy, most enrolled patients with stage II to IIIA disease (76 percent) and about a quarter of patients with stage IB disease (26 percent) did indeed received post-surgery platinum-based chemotherapy before enrollment. All patients on the trial were confirmed to have tumors harboring one of the two EGFR mutations known to be associated with sensitivity to EGFR tyrosine kinase inhibitors (Ex19del or L858R), and none of them had received prior treatment with earlier-generation EGFR inhibitors.
The efficacy results that so impressed the independent data monitoring committee showed that, after two years, 90 percent of patients with stage II to IIIA disease who received adjuvant osimertinib were alive and disease-free, compared with 44 percent of patients who received the placebo. The New England Journal of Medicine published the ADAURA results on Saturday in tandem with the ESMO presentation. In an interview, Roy Herbst of Yale Cancer Center, one of the senior authors of the NEJM paper, referred to the efficacy results as "the most incredible disease-free survival you've ever seen."
The results were impressive in the overall population as well. After two years, 89 percent of patients in the osimertinib group were alive and disease-free, compared with 52 percent of patients in the placebo group. Because the trial — for which the initial end date was set at February 2022 — was unblinded early and this analysis was unplanned, many of the key data points, including median disease-free survival, and, importantly, overall survival, remain unknown. However, the percentage of patients alive and disease-free at two years translate to an 83 percent and 80 percent reduction in the risk of disease recurrence or death with adjuvant osimertinib versus placebo for patients with stage II to IIIA disease and patients with stage IB to IIIA disease, respectively. Â
Central nervous system disease recurrence
While the disease-free survival rates were publicly announced in May during the American Society of Clinical Oncology's virtual annual meeting, the answer to whether osimertinib could penetrate the blood-brain barrier and, in turn, keep patients from developing brain metastases was not available at that time.
According to Herbst, the unplanned nature of the interim analysis made it such that the central nervous system (CNS) disease recurrence data were still being audited at the time of the ASCO presentation. Now that the review is complete, the ESMO presentation provided an answer to the question of CNS disease recurrence: after two years, 98 percent of patients with all stages of disease treated with osimertinib were alive without CNS disease recurrence, versus 85 percent of those on the placebo. This translated to an 82 percent reduction in the risk of CNS disease recurrence or death with osimertinib.
"Patients with EGFR-mutated lung cancer tend to recur in the brain," Herbst said, explaining that one of the factors that sets osimertinib apart from earlier-generation EGFR inhibitors such as gefitinib (AstraZeneca's Iressa) and erlotinib (Genentech/Astellas Oncology's Tarceva) is that it has been specifically designed to penetrate the blood-brain barrier, and its effect on CNS metastases has been demonstrated in previous studies. In the first-line treatment setting for metastatic, EGFR-positive NSCLC, for instance, a setting in which osimertinib is already FDA approved, the Phase III FLAURA trial demonstrated the drug's superiority in reducing CNS progression versus earlier-generation TKIs.
"For the patient with resected non-small cell lung cancer, disease recurrence may be local, regional, or distant, and the type of recurrence impacts outcomes," Masahiro Tsuboi of the National Cancer Center Hospital East in Japan, one of the lead ADAURA investigators, said in his presentation of the data during ESMO. "Local recurrence is associated with longer post-recurrence survival outcomes than distant metastases."
"This decrease in brain metastases is huge, because it really speaks to morbidity," Herbst said on the same point, explaining that once the brain is involved, patients face far fewer effective treatment options.
Although cross-trial comparisons are imperfect, Tsuboi noted in his presentation that previously, when the earlier EGFR TKI erlotinib was evaluated as adjuvant treatment in the RADIANT trial, it did not demonstrate a CNS disease recurrence benefit. In fact, 37 percent of patients who experienced disease recurrence on that trial developed brain metastases, which was much higher than with placebo. In ADAURA, only six patients treated with osimertinib experienced CNS disease-free survival events, defined as CNS recurrence or death.
Based on these data, Tsuboi concluded his presentation, "the reduced risk of local and distant recurrence and improved CNS disease-free survival reinforce adjuvant osimertinib as a highly effective, practice-changing treatment for patients with stage IB to IIIA, EGFR mutation-positive non-small cell lung cancer following complete tumor resection."
Importantly, either head CT scans or brain MRIs were permitted as methods to ensure that patients did not have CNS metastases prior to enrollment on ADAURA, but data are not available at this time detailing how many patients were staged according to a CT scan versus MRI. This will be important to know, several oncologists have pointed out, since it is possible that some patients on the trial had baseline CNS metastases that were missed in the absence of an MRI.
"There's a very significant chance that the difference seen here is the effect of osimertinib versus placebo in patients with undetected pre-existing brain metastases who were enrolled because of a willful decision to pursue substandard staging," said Jack West, a medical oncologist at City of Hope Cancer Center in Los Angeles. "If the breakdown of CNS recurrence shows that most patients had undergone a brain MRI, or that those with brain MRIs show a comparable pattern of relapse as those who had a baseline head CT, then I'd say that this is a clinically significant benefit for osimertinib."
But without these data, West's view is that it is not possible to definitively say whether osimertinib is actually preventing CNS disease recurrence as opposed to treating pre-existing but undetected brain metastases better than placebo. Though MRIs may not have been available to all patients enrolled across ADAURA's 228 global study sites, just as they may not be available to all patients globally in a real-world setting, the breakdown is nonetheless valuable information in the context of assessing osimertinib's benefit.
Overall survival question remains
Many oncologists agree with Tsuboi and Herbst that the data are strong enough to support the use and regulatory approval of adjuvant osimertinib. "The results [at ESMO] confirm the efficacy of osimertinib in the adjuvant setting, with a demonstrated effect in the prevention of CNS relapse," said Gilberto de Lima Lopes from the University of Miami Sylvester Cancer Center, calling the degree of benefit "clinically relevant" enough to support using the targeted agent in this setting. Â
But some oncologists maintain that in the absence of a demonstrated overall survival benefit, the evidence just isn't there. In a discussion of the data following the ESMO presentation, Johan Vansteenkiste from the Catholic University of Leuven in Belgium said, "I feel that overall survival data are very important in this setting, and until [we have them], I would not implement the strategy" of giving osimertinib to all patients with EGFR-positive NSCLC after surgery.
"A lot of people are saying, 'Well, what about overall survival?'," Herbst acknowledged. "But that's going to take a few years to answer, and in the meantime, imagine you're a patient with cancer and you know that there's an 82 percent chance that you'll reduce the risk of your tumor occurring in your brain. That's enormous."
When the overall survival data do become available, the effect of crossover for patients in the placebo arm who are given osimertinib upon progression will need to be factored into the analysis. Crossover has been written into the trial design as a new addendum, Herbst said, predicting that it will likely improve overall survival results in the placebo arm down the line, bringing the survival curves closer together. That said, he predicted that the overall survival in the osimertinib arm will still be superior because the patients received osimertinib earlier on.
This unanswered question of adjuvant osimertinib's overall survival benefit is critical in the context of EGFR inhibitors for early-stage disease, because it's not uncommon for patients' tumors to respond well to the treatments early on, only to develop acquired resistance mutations down the line and stop responding. This phenomenon is part of the reason why earlier EGFR TKIs that initially showed disease-free survival benefit have not, ultimately, resulted in improved overall survival. Such was the case with the ADJUVANT CTONG1104 trial comparing gefitinib to chemotherapy in the adjuvant setting, which initially showed a disease-free survival benefit with gefitinib, but later showed that the drug did not improve overall survival.
A combination of osimertinib's demonstrated effect on CNS disease recurrence and its ability to overcome common mutations associated with acquired resistance to EGFR TKIs, including T790M, however, have oncologists like Herbst optimistic, even in the absence of overall survival data. Herbst did acknowledge the risk of acquired resistance to TKIs, however, and in response to a question about this possibility said "We're not done yet. We still need … to figure out what to do in patients who are resistant and what are the next steps."
In this regard, Herbst shared that the next steps for the ADAURA investigators will be to analyze DNA in patients' blood and tissue samples so as to "start understanding who progresses and when." Also Importantly, he added, the ADAURA data should not be seen as cause to replace adjuvant chemotherapy with osimertinib.
"Chemotherapy works in the adjuvant setting," he said. "Chemo still has its place, and I would not avoid chemo." Down the line, at least in patients with the earliest-stage disease, further research might be warranted to determine if osimertinib could be beneficial in the adjuvant setting without chemo, he said, but right now, "we don't have the data to tell us that."
These unanswered questions will take time to address. As Vansteenkiste put it in discussing the latest data, "Adjuvant studies need a lot of patients and patience."
In the meantime, Vansteenkiste, who said he would not be inclined to treat all patients with adjuvant osimertinib in the absence of data on overall survival benefit, spoke to the possibility of treating only patients with minimal residual disease following surgery with adjuvant osimertinib. More research is needed to determine whether this strategy might be viable, but he said it might help to prevent unnecessarily treating patients who might not end up experiencing disease recurrence following surgery at all. Osimertinib, he noted, "has a certain physical and financial toxicity" to it. Indeed, about half of patients treated with osimertinib experienced diarrhea and a quarter experienced skin problems, and, and as of 2018, the monthly cost of osimertinib in the approved, later-line setting was over $17,000.
Meanwhile, the jury is still out on whether the FDA will approve adjuvant osimertinib, based on the disease-free survival benefit and the recently seen CNS disease recurrence benefit. "Everyone is watching carefully," Herbst said. "If it gets an approval, that would be huge, because it would be the first time in lung cancer that one of these targeted therapies gets approved for the earliest stages of disease. It would be a paradigm shift."