Primary results from the phase 3 PALOMA-3 trial demonstrate that subcutaneous amivantamab (Rybrevant) was noninferior to intravenous administration based on pharmacokinetics and objective response rate in patients with refractory EGFR-mutated, advanced non-small cell lung cancer (NSCLC). The findings, presented at the 2024 ASCO Annual Meeting, revealed unexpected improvements in survival outcomes that researchers are now working to understand.
Trial Design and Patient Population
The randomized controlled PALOMA-3 trial enrolled 418 patients with EGFR Ex19del or L858R-mutated advanced NSCLC whose disease had progressed on osimertinib and platinum-based chemotherapy. Patients were randomly assigned to receive either subcutaneous amivantamab (n=206; median age 61 years; 67% female) or intravenous amivantamab (n=212; median age 62 years; 67% female), both in combination with lazertinib.
Subcutaneous amivantamab was administered at 1600 mg (or 2240 mg for patients ≥80 kg) weekly for the first 4 weeks, then every 2 weeks. Intravenous amivantamab was given at 1050 mg (or 1400 mg for those ≥80 kg). Both groups received 240 mg of lazertinib orally daily.
Pharmacokinetic Noninferiority Achieved
The trial met both coprimary endpoints of area under the curve at cycle 2 and trough concentration after a median follow-up of 7.0 months. The geometric mean ratios comparing subcutaneous with IV amivantamab for trough concentration were 1.15 (90% CI, 1.04-1.26) at cycle 2 day 1 and 1.43 (90% CI, 1.27-1.61) at cycle 4 day 1. The geometric mean ratio for area under the curve at cycle 2 between days 1 and 15 was 1.03 (90% CI, 0.98-1.09).
The objective response rate was 30% (95% CI, 24%-37%) in the subcutaneous arm compared with 33% (95% CI, 26%-39%) in the IV arm (relative risk, 0.92; 95% CI, 0.70-1.23; P = .001), meeting noninferiority criteria.
Unexpected Survival Benefits
"Compared to the IV arm, we saw a numerically longer duration of response and PFS and a significant improvement in overall survival," said Natasha B. Leighl, clinical investigator at the Princess Margaret Cancer Centre in Toronto, Canada. "Further studies are needed to elucidate the mechanism of this effect."
Among confirmed responders, patients receiving subcutaneous amivantamab plus lazertinib had a longer median duration of response compared with IV amivantamab (11.2 months [95% CI, 6.1-not estimable] vs 8.3 months [95% CI, 5.4-not estimable]). The subcutaneous arm showed a favorable progression-free survival trend with a median of 6.1 months (95% CI, 4.3-8.1) compared with 4.3 months (95% CI, 4.1-5.7) in the IV arm (HR, 0.84; 95% CI, 0.64-1.10; P = .20).
Most notably, patients assigned subcutaneous amivantamab plus lazertinib had significantly longer overall survival versus those assigned IV amivantamab (HR, 0.62; 95% CI, 0.42-0.92; nominal P = .02). At 12 months, 65% of patients in the subcutaneous arm were alive compared with 51% in the IV arm.
Safety and Tolerability Advantages
Infusion-related reactions were approximately 5-fold lower in patients assigned subcutaneous amivantamab versus IV amivantamab (13% vs 66%, respectively). No grade 4 or 5 infusion-related reactions occurred, and most reactions happened during cycle 1. Importantly, no infusion-related reactions led to hospitalization in the subcutaneous arm compared with 2 events in the IV arm, and there were no infusion reaction-related discontinuations in the subcutaneous group compared with 4 events in the IV arm.
Prophylactic Anticoagulation Impact
"PALOMA-3 is the first study to prospectively look at the impact of prophylactic anticoagulation on the risk of VTE [venous thromboembolism] in patients receiving amivantamab and lazertinib," Leighl noted. The majority of patients in both arms received prophylactic anticoagulants (80% and 81%, respectively).
Venous thromboembolism occurred in 9% of patients in the subcutaneous arm versus 14% in the IV arm. Among patients who received prophylactic anticoagulants, VTE was observed in 10% compared with 21% of those who did not receive prophylaxis. Grade 3 or higher bleeding events were uncommon in both arms (2% subcutaneous, 1% IV) among those receiving prophylactic anticoagulation.
"We conclude that administering prophylaxis to our patients receiving amivantamab plus lazertinib does impact the rate of VTE and should be routine," Leighl added.
Administration Convenience
Treatment administration time was dramatically reduced to less than 5 minutes for subcutaneous amivantamab, compared with 5 hours for the first infusion of IV amivantamab and 2 hours for subsequent infusions. At the end of treatment, 85% of patients reported that subcutaneous amivantamab was convenient or very convenient compared with 35% for IV amivantamab.
Future Research Directions
Despite the clear benefits observed with subcutaneous delivery, researchers remain uncertain about the underlying mechanisms. "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 explained. "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."
The researchers plan to design studies to explore these mechanisms and investigate different combinations as they work to understand why subcutaneous delivery appears to provide superior clinical outcomes beyond the expected improvements in convenience and tolerability.
