NEW YORK – Promising data from two Phase III trials evaluating Johnson & Johnson's Rybrevant (amivantamab) as a first- and second-line treatment in EGFR-mutant advanced non-small cell lung cancer has oncologists wondering if they'll change their preferred first-line targeted treatment in this setting.
Researchers presented data from the Phase III MARIPOSA and MARIPOSA-2 trials at the European Society for Medical Oncology Congress on Monday. The three-arm MARIPOSA trial compared the EGFR-MET bispecific antibody Rybrevant plus J&J's EGFR inhibitor Leclaza (lazertinib) versus Leclaza monotherapy versus AstraZeneca's EGFR inhibitor Tagrisso (osimertinib) monotherapy as a first-line treatment in EGFR-mutant advanced NSCLC. The MARIPOSA-2 study tested Rybrevant plus chemotherapy with or without Leclaza versus chemo alone in EGFR-mutant advanced NSCLC patients who had progressed after treatment with Tagrisso.
Rybrevant received accelerated approval in the US two years ago for treating patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations who have progressed on platinum-based chemotherapy.
Earlier at this same meeting, researchers reported that in the Phase III PAPILLON trial, Rybrevant plus chemotherapy reduced the risk of disease progression or death by 60 percent in patients with advanced EGFR exon 20-positive NSCLC compared to chemo alone. This data, J&J has said, will not only support its bid for full approval of single-agent Rybrevant in previously treated, EGFR exon 20-positive patients but also allow the firm to seek approval for Rybrevant-chemo as a first-line option in this subset of patients.
EGFR mutations can occur in up to 50 percent of NSCLC patients, and up to 90 percent of EGFR mutations occur in exon 19 or exon 21, while the remaining 10 percent are uncommon alterations like EGFR exon 20 insertion mutations.
The MARIPOSA and MARIPOSA-2 studies were designed to explore Rybrevant's activity in combination with other targeted agents in patients with the more common EGFR exon 19 deletions and exon 21 L858R mutations. Data from these studies, if successful, could allow J&J to eventually capture a much bigger portion of the NSCLC market with Rybrevant.
Reflecting on these trials at the meeting, researchers touted the intracranial activity and longer progression-free survival with the Rybrevant combination regimens. Still, it was clear from the discussion at the meeting that experts are carefully weighing the increased risk for toxicity with these combination therapies and that many will wait to see more mature overall survival data before deciding whether to adopt them in practice.
MARIPOSA trial
The MARIPOSA trial enrolled more than 1,000 NSCLC patients, of which 429 received Rybrevant-Leclaza, 429 received Tagrisso, and 216 received Leclaza alone. The trial was powered to compare the Rybrevant-Leclaza combination against Tagrisso, which is the preferred standard treatment option for EGFR-mutated NSCLC among oncologists.
Tagrisso is available in the US for treating early-stage NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations and for metastatic tumors that harbor these EGFR mutations or the EGFR T790M resistance mutation.
"The FLAURA trial established osimertinib, a third-generation EGFR inhibitor, as our preferred first-line therapy," said Zofia Piotrowska, an assistant professor of medicine at Harvard Medical School who discussed both MARIPOSA trial results at ESMO. "Osimertinib is an oral therapy, which is generally well tolerated and leads to a median progression-free survival of about 19 months. As we evaluate these new combinations, we have to keep in mind that our goal is to develop combinations that will improve progression-free and overall survival, while avoiding adding excessive toxicities to our current standards of care."
Patients on Rybrevant-Leclaza as a first-line treatment had a median progression-free survival of 23.7 months compared to 16.6 months on Tagrisso in the MARIPOSA study. Leclaza monotherapy also demonstrated clinically meaningful activity in the trial, with a median progression-free survival similar to Tagrisso.
The researchers also explored Rybrevant-Leclaza's activity in patients with and without brain metastases and found there was a consistent benefit over Tagrisso for both groups of patients. Among patients with a history of brain metastases, progression-free survival on Rybrevant-Leclaza was 18.3 months versus 13 months on Tagrisso. For patients without a history of brain metastases, progression-free survival was 27.5 months on Rybrevant-Leclaza and 19.9 months on Tagrisso.
Rybrevant-Leclaza led to confirmed responses in 80 percent of patients, with 7 percent achieving a complete response. The confirmed response rate on Tagrisso, by comparison, was 76 percent, with 4 percent achieving a complete response. Patients responded for 25.8 months on Rybrevant-Leclaza versus 16.8 months on Tagrisso.
In an early analysis of overall survival data, there was a "strong trend favoring" Rybrevant-Leclaza, said Byoung Chul Cho, a medical oncologist and professor in the division of medical oncology at Yonsei Cancer Center in Seoul, who presented the MARIPOSA results. The two-year survival rate at a median follow-up of 22 months was 74 percent on Rybrevant-Leclaza compared to 69 percent on Tagrisso.
Piotrowska, who was not involved with the MARIPOSA trial, noted that more mature overall survival data are needed to help guide treatment decisions.
"Our goal is to develop new regimens, which improve both progression-free and overall survival to help our patients live longer," she said. "If, however, the new regimen has extension of progression-free survival without improving overall survival, we risk that patients may spend more of their life on the new regimen, and [that's where] the impact on quality of life becomes even more critical."
Piotrowska highlighted that there were increased toxicities on Rybrevant-Leclaza compared to Tagrisso and more patients discontinued treatment on Rybrevant-Leclaza than Tagrisso, 35 percent versus 14 percent, respectively.
"Although many of the dermatologic toxicities [on Rybrevant-Leclaza] were low grade, it's important to keep in mind that chronic dermatologic toxicities can have a significant impact [on quality of life], particularly for patients who are remaining on first-line therapy for two years or more," she added, calling for further research on the treatment's impact on patient quality of life.
Piotrowska said these findings support Rybrevant-Leclaza as a new first-line option in this patient population. She added, however, that Tagrisso will remain her preferred first-line treatment for NSCLC patients with EGFR-mutant NSCLC while awaiting further survival data on Rybrevant.
In results from a separate Phase III study presented at ESMO on Saturday, Rybrevant plus chemo also outperformed chemo alone as a first-line treatment for NSCLC patients harboring EGFR exon 20 insertion mutations. Experts also flagged the toxicity of the Rybrevant-chemo combination in that study, which had 15 percent of patients discontinue treatment.
MARIPOSA-2 trial
The MARIPOSA-2 trial explored the combination of Rybrevant and chemo with or without Leclaza versus chemo alone as a second-line or later treatment for NSCLC patients who progressed on Tagrisso.
Patients on the triplet regimen, Rybrevant-Leclaza-chemo, had a median progression-free survival of 8.3 months; the Rybrevant-chemo doublet regimen yielded a median progression-free survival of 6.3 months; and the median progression-free survival was 4.2 months with chemo alone.
The triplet and doublet regimens also reduced the risk of intracranial progression compared to just chemo. At one year, 54 percent of patients on the triplet and 50 percent on the doublet were intracranial progression-free, compared to 34 percent on chemo.
A similar proportion of patients responded to the doublet and triplet regimens, 64 percent and 63 percent, respectively. The response rate was 36 percent for those on chemo only.
The overall survival data reported at the meeting was from a median follow-up of only 8.7 months, noted Antonio Passaro, a medical oncologist in the division of thoracic oncology at the European Institute of Oncology in Italy who presented the MARIPOSA-2 results. However, Passaro said there was a positive trend suggesting an overall survival benefit with the Rybrevant-Leclaza-chemo triplet.
In terms of the toxicity profile of the triplet combination, Passaro said 92 percent of patients had a grade 3 or higher adverse event and about half (52 percent) had a serious adverse event. Passaro noted that the triplet dosing regimen needed to be amended after researchers identified increased hematologic toxicity in that arm.
On the doublet arm, 72 percent of patients had a grade 3 or higher adverse event and 32 percent had a serious adverse event. About half of those who received chemo (48 percent) had a grade 3 or higher adverse event and 20 percent had a serious adverse event.
"At the present time, we cannot consider giving [Rybrevant-Leclaza-chemo] concurrently, and we need to wait for more follow-up to understand the real impact of the modification of this regimen," he said. But as far as the Rybrevant-chemo doublet, Passaro said based on data from MARIPOSA-2, this "is the new standard of care for patients" who progress on Tagrisso.
In an announcement over the weekend, J&J said the results from MARIPOSA-2 would support "future planned health authority submissions."
Piotrowska also acknowledged that the MARIPOSA-2 data supported the Rybrevant doublet and triplet regimens as an option for patients who progress on Tagrisso. However, once again, Piotrowska said she will await more mature survival data before changing her preferred treatment after Tagrisso. She noted that if these regimens are approved, she would consider them for "fit patients with [central nervous system] progression on osimertinib or, given the high response rate, for those with a high disease burden after osimertinib," she said.
"We have to acknowledge that our selection of first-line therapy [for EGFR-mutant NSCLC] will also have important implications for second-line and third-line therapy and that the treatment journey for patients with EGFR-mutant lung cancer will grow increasingly complex," Piotrowska said. "What we really need here are biomarkers to help select which treatment strategy is best for each individual."
She suggested that baseline stratification factors such as certain co-mutations or dynamic factors like circulating tumor DNA clearance on treatment could help select which patients need these combination regimens.
"Identifying patient subgroups with maximal benefit from new regimens will help us optimize the risk-benefit balance, but most importantly, we have to make treatment decisions that are individualized to meet the specific needs and goals of each patient that we see in clinic," Piotrowska said.