Faculty at an OncLive Scientific Interchange and Workshop discussed factors that help inform treatment selection in advanced EGFR-mutated NSCLC.
Prospective phase 3 data now confirm that adding chemotherapy to osimertinib (Tagrisso) prolongs progression-free survival (PFS) in EGFR-mutated non–small cell lung cancer (NSCLC) with concurrent TP53 mutations, but thoracic oncologists maintain that TP53 status alone does not dictate frontline therapy.1
"I'm curious how many people in the room have long-term responders to single-agent osimertinib who have concurrent p53 mutations in the days before [the phase 3] FLAURA2 [trial (NCT04035486)]. I have many. I'm sure most people do. And so I don't think of p53 in and of itself as the single holy grail of a poor-prognostic risk factor. That wouldn't sway me alone to the FLAURA2 [regimen]. If I see a more highly mutated tumor, I may think [of] more possibilities for early escape mechanisms," moderator Christine M. Lovly, MD, PhD, FASCO, division chief of Thoracic Medical Oncology at City of Hope Comprehensive Cancer Center in Duarte, California, said during a recent OncLive® Scientific Interchange and Workshop.
Held in Seoul, South Korea, during the
In an exploratory FLAURA2 analysis, median overall survival (OS) in patients with TP53-altered disease was 51.1 months (95% CI, 35.0-not calcuable [NC]) with osimertinib plus platinum-pemetrexed (n = 46) vs 43.1 months (95% CI, 34.0-50.1) with osimertinib alone (n = 40; HR, 0.71; 95% CI, 0.40-1.27).2 In the phase 3 MARIPOSA trial (NCT04487080), amivantamab-vmjw (Rybrevant) plus lazertinib (Lazcluze; n = 149) generated a median PFS of 18.2 months (95% CI, 15.3-22.1) vs 12.9 months (95% CI, 11.1-14.7) with osimertinib alone (n = 144) in patients with TP53 comutations (HR, 0.65; 95% CI, 0.48-0.87; P = .003).3
The phase 3 TOP trial (NCT04695925) evaluated osimertinib with or without chemotherapy in patients in China with EGFR-mutated disease and TP53 comutations.4 Findings showed the median PFS was 34.0 months with osimertinib plus pemetrexed-carboplatin (n = 146) vs 15.6 months with osimertinib alone (n = 148; HR, 0.44; 95% CI, 0.32-0.60; P < .001).4 Immature OS data favored the combination (median, 48.4 vs 36.5 months; HR, 0.57; 95% CI, 0.38-0.88), and grade 3 or higher treatment-related adverse effects (TRAEs) occurred in 62.4% vs 14.9% of patients, respectively.5
"[Comutation status] helps in the clinic when we have that patient [with borderline performance status] and they really want to push for the combination. When you see a TP53 [comutation], you're kind of inclined to offer the combination and not try to find an excuse to do monotherapy," Rosas said.
Jänne argued against further confirmatory studies. "I'm not sure we need an additional trial above and beyond what we've already seen. I don't think [we] need to do a prospective trial for every poor prognostic factor," he said, agreeing with Lovly's stance that the more useful question is who should not receive chemotherapy. Faculty cited advanced age, comorbidities, low-burden intrathoracic disease, and renal dysfunction precluding pemetrexed.
Ross described how patient priorities can outweigh genomics. "One of the few patients who I started on osimertinib monotherapy recently has a TP53 mutation, but he had disease that recurred [approximately] 4 years after surgery in a single, tiny site. And the only thing he likes to do is travel around the country visiting his grandkids…. He had none of the other clinical risk factors, was very chemotherapy averse, [and] really didn't want a regimen where he would have to come in frequently. In that case, all of those other factors in my mind trumped the [co]mutation."
With a median follow-up of 42.6 months (range, 0.1-60.4) in FLAURA2, onset of grade 3 or higher TRAEs was 43% during induction, 25% during pemetrexed maintenance, and 14% during the osimertinib-only period; overall, 33% of patients discontinued pemetrexed because of an AE.6
"I don't know how you would design that trial, but that's my question in clinic all the time. I would love to stop the pemetrexed,” Ross said. “Whenever [patients] say they're done, I'm like, 'Oh, that's fine,' but it'd be nice to have data.”
In cohort 1 (n = 124) of the phase 2b COPERNICUS trial (NCT06667076), subcutaneous amivantamab plus lazertinib with prophylactic anticoagulation and enhanced dermatologic care produced lower rates of rash (28% vs 62%), venous thromboembolism (12% vs 37%), and administration-related reactions (12% vs 63%) than historical MARIPOSA data, with a 7% amivantamab discontinuation rate.7
Marmarelis cautioned that the summary omitted a key toxicity.
"One thing that's missing here is the paronychia, which is the one thing that they haven't been able to control well,” she said. “They've been able to reduce the rash. They've been able to reduce the venous thromboembolism, but it's not even on here, which makes me think…that it didn't change, and that can be really difficult for patients."
Langer emphasized the cumulative workload of amivantamab. "One drug begets at least 7 or 8 other drugs that control all the toxicity, and it is so annoying. It's manageable, but it is time-consuming, labor-intensive, annoying to the patient…[and] annoying to our nurses who are fielding all the phone calls."
At the time of the workshop, faculty noted issues with access to sunvozertinib in the United States, but on October 22, 2026, AstraZeneca announced the United States availability of the agent.9
In the phase 3 WU-KONG28 trial (n = 324), first-line sunvozertinib at 300 mg daily improved blinded independent central review–assessed PFS vs platinum-based chemotherapy at a median of 10.3 months vs 7.5 months, respectively (HR, 0.65; 95% CI, 0.50-0.85; P = .0008); the respective confirmed ORRs were 58.9% vs 31.1%.10 Interim OS was similar (29.8 vs 28.8 months), with 90.2% of patients with progressive disease crossing over to sunvozertinib. Grade 3 or higher TRAEs occurred in 61.3% of patients receiving sunvozertinib, 40.5% required dose reductions, and 84.0% experienced any-grade diarrhea.
Faculty called for TP53 data that distinguish alteration types and exclude clonal hematopoiesis, a validated algorithm for identifying patients who can forgo chemotherapy, evidence on the optimal duration of pemetrexed maintenance, and grade-level toxicity and dose-reduction data for exon 20 insertion–directed TKIs.
Panelists agreed that a better frontline backbone will require combinations rather than a new TKI.
"EGFR-mutant lung cancer is not ALK rearrangement, right? It's genomically complex, and until we can sort that out, I don't think we're going to have a [fourth-generation TKi] that's better than osimertinib," Yu said.
