Subcutaneous amivantamab compares favourably with intravenous dosing in EGFR-mutant NSCLC

In previously treated patients with EGFR-mutated advanced non-small-cell lung cancer (NSCLC), subcutaneous (SC) amivantamab combined with lazertinib shows noninferior pharmacokinetic and efficacy profiles compared with the approved intravenous (IV) formulation of amivantamab, according to the phase III PALOMA-3 trial.

The co-primary pharmacokinetic endpoints were met, with SC amivantamab achieving similar levels of trough concentration at cycle 2, day 1 (C_trough: geometric mean ratio, 1.15; 90 percent confidence interval [CI], 1.04–1.26) and total systemic exposure (area under the serum concentration time curve from day 1 to 15: geometric mean ratio, 1.0;, 90 percent CI, 0.98–1.09) as the IV formulation, reported first author Dr Natasha Leighl from the Princess Margaret Cancer Centre in Toronto, Ontario, Canada. [Leighl N, et al, ASCO 2024, abstract LBA8505]

“We saw an increase in the levels at steady state at cycle 4, day 1, as expected, for SC amivantamab, with a geometric mean ratio of 1.43 [90 percent CI, 1.27–1.61],” Leighl added.

As for the secondary endpoints, overall response rate (ORR) in the SC arm was noninferior to that in the IV arm (30 vs 33 percent; relative risk [RR], 0.92; 95 percent CI, 0.70–1.23; p=0.001). Disease control rates were 75 and 71 percent, respectively.

"Treatment resulted in a rapid response in both arms, with a median time of 1.5 months," Leighl noted. The duration of response was longer by 3 months in the SC arm (11.2 vs 8.3 months), and 29 percent of patients in the SC arm had a response lasting at least 6 months compared with 15 percent in the IV arm.

Over a median follow-up time of 7 months, progression-free survival (PFS) was longer by almost 2 months with SC vs IV amivantamab (median, 6.1 vs 4.3 months), although the difference was not significant (hazard ratio [HR], 0.84; 95 percent CI, 0.64–1.10; p=0.20).

“Median overall survival [OS] has not yet been reached in either arm. However, we observed that OS was improved with the use of SC amivantamab plus lazertinib with an HR of 0.62 in this preplanned exploratory analysis and a p-value of 0.02, which was statistically significant,” Leighl said.

Reduced IRRs

SC and IV amivantamab had similar safety profiles. Grade 3 treatment-emergent AEs were reported in 52 and 56 percent of patients in the respective groups, while serious AEs were documented in 29 and 30 percent. The most common AEs were EGFR- (eg, paronychia and rash) and MET-mediated (eg, hypoalbuminemia). "Most were grade 1 and grade 2 and consistent with previous studies of amivantamab and lazertinib," Leighl noted.

Treatment-related discontinuations were low (9 vs 12 percent), and AEs leading to death were uncommon (3 vs 5 percent). The median duration of treatment was 4.7 months in the SC arm and 4.1 months in the IV arm.

Of note, infusion-related reactions (IRRs) decreased by around fivefold in the SC arm (13 vs 66 percent). IRRs were mostly grade 1–2 and occurred early in cycle 1; no grade 4–5 IRRs were reported. IRRs leading to hospitalization or discontinuation of treatment did not occur in the SC arm, but there were two and four events, respectively, in the IV arm.

In addition, Leighl and colleagues looked at the impact of prophylactic anticoagulation on the risk of venous thromboembolism (VTE). Prophylaxis was administered to more than 80 percent of patients, and VTE occurred in 10 percent of those receiving prophylaxis compared with 21 percent of those who did not. Grade 3 bleeding events were rare.

“We conclude that administering prophylaxis to our patients receiving amivantamab and lazertinib does impact the rate of VTE and should be routine,” Leighl said.

More convenient

Leighl also pointed to the substantially shortened administration time with SC amivantamab, with the injections taking less than 5 minutes as compared with up to 5 hours for the IV formulation.

Significantly more patients in the SC arm than in the IV arm reported greater convenience with their treatment both at cycle 1 day 1 (85 vs 52 percent; p<0.001) and at end of treatment (85 vs 35 percent; p<0.001).

Taken together, the present data “meet the criteria required for bridging from intravenous to subcutaneous formulation,” said study discussant Dr Jessica Lin from the Center for Thoracic Cancers at Massachusetts General Hospital in Boston, Massachusetts, US.

“These findings [from PALOMA-3] represent an important and clinically meaningful advance for patients and healthcare providers. And if approved, I would favour SC over IV dosing of amivantamab as this should alleviate toxicity and improve outcomes for patients and care efficiency,” Lin said.

PALOMA-3 included 418 patients with locally advanced or metastatic NSCLC harbouring epidermal EGFR exon 19 deletion (ex19del) or L858R mutations. These patients were randomly assigned to receive either SC (n=206, median age 61 years, 33 percent male, 61 percent Asian) or IV (n=212, median age 62 years, 33 percent male, 61 percent Asian) amivantamab, both in combination with lazertinib, in 28-day cycles.

The patients had good performance status and received a median of two prior lines of therapy. Around 34 percent of the entire population had brain metastases at baseline.