Promising overall survival (OS) trends continued after longer follow-up with Rybrevant (amivantamab) plus chemotherapy vs chemotherapy alone in EGFR-mutant advanced non-small cell lung cancer (NSCLC) whose disease progressed on Tagrisso (osimertinib), according to findings from the second interim analysis of the MARIPOSA-2 trial.
Results from a median follow-up of 18.1 months were presented at the 2024 ESMO Congress. Of note, OS is defined at the time when a patient with cancer is still alive.
“Indeed, [Rybrevant’s] multi-targeted mechanism of action and immune cell-directed activity, combined with chemotherapy's nonspecific anti-tumor effects, likely contributes to this observed durability,” Sanjay Popat, consultant medical oncologist at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research in London, said during the presentation of the data.
Study Highlights:
- Rybrevant plus chemotherapy continued to demonstrate a positive trend in overall survival compared to chemotherapy alone, though statistical significance was not reached.
- Patients treated with Rybrevant plus chemotherapy experienced a significant delay in the progression of symptoms compared to those receiving chemotherapy alone.
- Patients on Rybrevant plus chemotherapy were more likely to remain on treatment for a longer duration.
- Patients in the Rybrevant plus chemotherapy group had a longer interval before needing additional treatment.
Rybrevant plus chemotherapy continued to demonstrate a meaningful and improved OS trend compared with chemotherapy, although it did not reach statistical significance (the observed difference between groups might be due to chance rather than a real effect of the treatment). Patients assigned Rybrevant plus chemotherapy had a median OS of 17.7 months compared with 15.3 months in patients assigned chemotherapy alone. OS was 50% for the Rybrevant plus chemotherapy group versus 40% in the chemotherapy alone group.
“The curves separate after six months of follow-up and continue to separate thereafter, with an absolute survival difference of 7% at the 12-month landmark, 70% versus 63%, increasing to 10 months at the 18-month landmark of 50% versus. 40%,” Popat said. “MARIPOSA-2 is ongoing and will proceed to final overall survival analysis, as planned.”
Post-Progression Endpoints
Time to symptomatic progression (TTSP) was significantly improved in patients treated with Rybrevant plus chemotherapy compared with chemotherapy, with rates at 43% and 34%, respectively. The median TTSP was 16 months in the Rybrevant plus chemotherapy group and 11.8 months in the chemotherapy group. This represented a 27% reduction in the risk for symptomatic progression with Rybrevant plus chemotherapy versus chemotherapy alone.
“Exploratory endpoints included time to symptomatic progression, which is clinically meaningful, as this captures not only radiographic progression, but also symptomatic progression, defined as time from randomization until deterioration of lung cancer-associated symptoms or new symptoms resulting in clinical change in systemic therapy,” Popat said.
Time to treatment discontinuation (TTD) was also significantly prolonged with Rybrevant plus chemotherapy compared with chemotherapy alone (22% versus 4%, respectively).
“Time to treatment discontinuation, again, remains a meaningful endpoint in clinical practice, as this captures the additional time beyond progression of systemic therapy,” Popat said.
The median TTD was 10.4 months and 4.5 months, respectively.
“Indeed, at the 18-month landmark, five-fold more patients remained on treatment with a combination of [Rybrevant]-chemotherapy than chemotherapy alone,” Popat added.
In addition, time to subsequent therapy (TTST) was also significantly prolonged with Rybrevant plus chemotherapy compared with chemotherapy alone (31% versus 12%, respectively).
“Time to subsequent therapy is an important landmark endpoint, insofar as it captures time from randomization until commencement of next line of systemic therapy in those that commence it, and is important for our reimbursement agencies,” Popat explained.
The median TTST was 12.2 months in patients treated with Rybrevant plus chemotherapy compared with 6.6 months in those treated with chemotherapy alone.
“TTST was two-fold longer with the combination than chemotherapy,” Popat said.
Regarding first subsequent therapy, fewer patients in the Rybrevant-chemotherapy arm had disease progression compared with the chemotherapy arm (68% versus 83%). Most patients in both groups went on to receive a subsequent therapy.
Popat noted that in both groups, there was a diversity of subsequent therapies used, including a tyrosine kinase inhibitor (TKI) combination, other TKIs, Tagrisso or other third-generation TKIs, and others.
“We see that there is no clear single therapy class identified as the most prominent subsequent therapy, reiterating that most patients in this third-line setting are often re-exposed to previously used therapies, highlighting the importance of maximizing not only first but also second-line treatment duration,” he explained.
Progression-free survival (the time during and after treatment when a patient with cancer lives with the disease without worsening) after first subsequent therapy (PFS2) was significantly prolonged with Rybrevant plus chemotherapy versus chemotherapy alone. At 18 months, the PFS2 rate was 39% versus 27%, respectively. The median PFS2 was 16 months in the Rybrevant plus chemotherapy arm compared with 11.6 months in the chemotherapy alone arm.
Study Background
Popat explained that progression on or after TKI monotherapy is “nearly inevitable, with resistance mechanisms that can be diverse and mostly polyclonal.”
At the 2023 ESMO Congress, findings were presented that demonstrated that at a median follow-up of 8.7 months, the trial met its primary endpoint, as Rybrevant plus chemotherapy significantly improved PFS compared with chemotherapy in patients with EGFR-mutant advanced NSCLC after disease progression on Tagrisso. Combination treatment also showed a favorable trend for OS at the first analysis.
Popat noted that Rybrevant plus chemotherapy is currently pending FDA approval to treat patients with EGFR-mutant advanced NSCLC after disease progression on an EGFR TKI.
Design of the MARIPOSA-2 Trial
Patients were eligible for the MARIPOSA-2 trial if they had locally advanced or metastatic EGFR-mutated NSCLC with EGFR exon 19 deletion or L858R and whose disease progressed on or after Tagrisso monotherapy as the most recent line of therapy. Patients also had to have good performance status, with an ECOG performance score of 0 or 1 (meaning that a patient is fully active or is restricted in physically strenuous activity).
In this trial, 657 patients were randomly assigned to receive either Rybrevant plus Lazcluze (lazertinib) and chemotherapy (263 patients), chemotherapy alone (362 patients), or Rybrevant plus chemotherapy (131 patients).
“The focus of this presentation will be on the latter two arms, specifically chemotherapy or [Rybrevant]-chemotherapy,” Popat explained.
The areas of interesting for researchers conducting this study included OS, TTSP, TTD, TTST, and PFS2.
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