Positive results in lung cancer show benefits of subcutaneous bispecifics
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Key takeaways:
- Subcutaneous delivery reduced administration time from several hours to less than 5 minutes.
- Although unexpected, researchers reported improvement in PFS and OS with subcutaneous delivery.
CHICAGO — The addition of subcutaneous amivantamab to lazertinib demonstrated noninferior pharmacokinetics and objective response rate compared with intravenous amivantamab, results from a phase 3 study showed.
The findings — presented at ASCO Annual Meeting — revealed that study participants who received subcutaneous amivantamab also benefitted from longer treatment response, PFS and OS compared with intravenous administration, researchers noted.
“In the initial trial where we were just testing it out, I wasn’t expecting it to be so well tolerated, but it was clear that my patients loved [the combination] and so did the nurses and the staff giving the treatment,” Natasha B. Leighl, clinician investigator at Princess Margaret Cancer Centre in Toronto, told Healio. “We were expecting a shorter administration time and fewer [infusion-related reactions], and I think the data surpassed our expectations.”
Background, methodology
The combination of the bispecific antibody amivantamab (Rybrevant, Janssen) and lazertinib (Leclaza; Yuhan, Janssen) has demonstrated antitumor activity among patients with EGFR-mutated advanced NSCLC.
With the administration of subcutaneous amivantamab taking no more than 7 minutes and low infusion-related reaction rates reported, researchers conducted the randomized controlled PALOMA-3 trial to assess pharmacokinetics, efficacy and safety among patients with EGFR Ex19del or L858R-mutated advanced non-small cell lung cancer and disease progression on osimertinib (Tagrisso, AstraZeneca) and platinum-based chemotherapy.
Researchers randomly assigned 418 patients (median age, 61 years; 67% women; 61% Asian; median of two prior lines) to receive either 1,600 mg subcutaneous amivantamab weekly for the first 4 weeks before then administering every 2 weeks (n = 206) or 1,050 mg intravenous amivantamab (n = 212). Researchers administered lazertinib orally at 240 mg daily.
Trough concentration and C2 area under the curve served as co-primary pharmacokinetic noninferiority endpoints, with objective response rate and PFS serving as key secondary endpoints. Study investigators also evaluated median OS as a predefined exploratory endpoint.
Results
The trial met both co-primary endpoints with a median follow-up of 7 months. Researchers reported calculated geometric mean ratios comparing subcutaneous vs. intravenous administration for Ctrough of 1.15 (90% CI, 1.04-1.26) for C2D1 and 1.43 (90% CI, 1.27-1.61) for C4D1.
Leighl and colleagues also reported a geometric mean ratio for C2 AUCD1-D15 of 1.03 (90% CI, 0.98-1.09).
Additionally, they observed an ORR of 30.1% (95% CI, 24-37) in the subcutaneous arm and 32.5% (95% CI, 26-39) in the intravenous arm (relative risk = 0.92), thus meeting the noninferiority criteria.
Among secondary endpoints, researchers observed the median duration of response to be longer in the subcutaneous arm (11.2 vs. 8.3 months among confirmed responders), with a more favorable median PFS trend (6.1 months vs. 4.3 months; HR = 0.84) and longer median OS (HR = 0.62; 95% CI, 0.42-0.92).
At 1 year, 65% of patients in the subcutaneous arm were still alive, compared with 51% of patients in the intravenous arm.
Immune-related reactions occurred five-times less frequently in the subcutaneous arm compared with the intravenous arm (13% vs. 66%); 81% of patients received prophylactic anticoagulants, with venous thromboembolism reported by 9% of patients in the subcutaneous arm and 14% in the intravenous arm.
Next steps
According to researchers, intravenous amivantamab has a first administration time of 2 to 5 hours, compared to a median of 5 minutes via subcutaneous delivery of the agent, while also reducing infusion-related reactions 6-fold.
Despite the noticeable benefits, coupled with improved survival, researchers are unsure exactly how or why the benefits occur. They plan to explore the reasons why as part of their next investigation.
“I think it’s still in the design phase because these data are hot off the press, but I guess what we do need to look at is, with the subcutaneous version, are we activating the immune system?” Leighl told Healio. “But we’ll also look at other things; is there some reason that somehow it gets to the target or the cancer better? If drugs are given intravenously, first they have to go through the liver, which tries to clean everything up ... so we’ll be designing studies to look at that and ... some different combinations.”
Perspective
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Erminia Massarelli, MD, PhD, MS
Previous results from the MARIPOSA trial showed that amivantamab plus lazertinib significantly reduced the risk for progression or death by 30% and improved PFS by 7.1 months compared with osimertinib monotherapy as first-line treatment for metastatic EGFR-mutated NSCLC. Among the most common treatment-related adverse events occurring in at least 20% of patients enrolled in the amivantamab plus lazertinib arm included paronychia, infusion-related reactions, rash, and venous thromboembolism (VTE), representing a burden for patients treated with this regimen. Grade 3 or higher treatment-related adverse events occurred significantly more frequently on amivantamab plus lazertinib vs. osimertinib.
The PALOMA 3 study was part of a patient-centered program to reduce administration time, exploring the subcutaneous administration route of amivantamab to improve the toxicity profile.
The important findings of this trial include improved convenience due to a decrease to less than 5 minutes administration time of the subcutaneous route vs. 5 hours IV infusion for the first infusion and 2 hours for subsequent infusions. The safety profile for subcuenous administration is consistent with the IV profile, however, with less infusion-related reactions and VTE, which represent an important relief for patients treated with this regimen.
Surprisingly, a numerically longer duration of response and significantly improved OS occurred in patients treated with subcutaneous regimen. This finding needs confirmation, with particular attention to studying the mechanism of action underlying the prolonged benefit for subcutaneous administration. If confirmed, this represents a new key finding that can be applied to other bispecific antibodies.
Overall, the subcutaneous administration of amivantamab opens an important chapter to reduce administration times, cost and treatment-related toxicity while improving outcomes for individuals treated with bispecific antibodies.
Perspective
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Robert Chun-Hao Hsu, MD
The PALOMA-3 study is a global, randomized phase 3 trial that compared subcutaneous amivantamab and lazertinib with IV amivantamab and lazertinib in EGFR Exon 19 deletion or L858R-mutated NSCLC with disease progression on osimertinib and platinum-based chemotherapy.This presentation met its primary endpoint of noninferior trough pharmacokinetics. It also met its key secondary endpoint of objective response rate (30.1% in the subcutaneous arm vs. 32.5% in the IV arm). Further, median duration of response was longer with subcutaneous amivantamab vs. IV (11.2 months vs. 8.3 months).
There also was a favorable PFS trend with subctuaneous amivantamab (median, 6.1 months vs. 4.3 months; HR=0.84; P = .02), and OS was longer in the subctuaneous group (HR = 0.62; 95% CI, 0.42-0.92; P = .017).
What stands out, though, and what will make this study practice changing, is that infusion-related reactions — which can be very challenging for patients at the outset of therapy — were fivefold lower (13% vs. 66%), with grade 3 or higher rates being 0.5% vs. 4%. Among patients who receive prophylactic coagulants, venous thromboembolism was reported in 9% of patients in the subcutaneous arm and 14% in the IV arm.
From these findings, subcutaneous amivantamab has demonstrated clear noninferiority compared with IV amivantamab in terms of efficacy and survival. It is much more practical, as administration takes 7 minutes or less with much fewer infusion reactions. If subcutaneous amivantamab is available, based on these findings, subctuaneous administration should be preferred as it will greatly impact quality of life and minimize use of resources like infusion center space.
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Leighl NB, et al. Abstract LBA8505. Presented at: ASCO Annual Meeting; May 30–June 3, 2024; Chicago.
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