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NSCLC | Image Credit: © catalin – stock.adobe.com Subcutaneous (SC) pembrolizumab (Keytruda; pembrolizumab with berahyaluronidase alfa) was noninferior to intravenous (IV) pembrolizumab with respect to cycle 1 overall exposure and steady-state trough concentration in patients with treatment-naive, metastatic non–small cell lung cancer (NSCLC), beating the prespecified noninferiority margin of 0.
8 for both end points, according to data from the phase 3 3475A-D77 trial (NCT05722015) presented during the 2025 European Lung Cancer Congress . 1 Theresults revealed that thecycle 1 area under the curve from week 0 to week 6 (AUC 0-6 )geometric mean was 1633.24 μg·day/mL (95% CI, 1555.
23-1715.15) in the SC arm (n = 245) vs 1437.58 μg·day/mL (95% CI, 1373.
68-1504.46) in the IV arm (n = 126), reflecting a geometric mean ratio of 1.14 (96% CI, 1.
06-1.22; P <.0001).
The percentages for the geometric coefficient of variation (CV) were 40.4% and 26.2% in the SC and IV arms, respectively.
The steady-state trough concentration (C trough ) at cycle 3 geographic mean was 39.23 μg/mL (95% CI, 37.04-41.
55) in the SC arm (n = 202) vs 23.49 μg/mL (95% CI, 21.61-25.
54) in the IV arm (n = 101), reflecting a geometric mean ratio of 1.67 (94% CI, 1.52-1.
84; P <.0001). The geometric CV values were 43.
3% and 44.2% in the SC and IV arms, respectively. Additional findings indicated that the median progression-free survival (PFS) was 8.
1 months (95% CI, 6.3-8.3) in the SC arm vs 7.
8 months (95% CI, 6.2-9.7) in the IV arm (HR, 1.
05; 95% CI, 0.78-1.43).
The objective response rates (ORRs) were 45.4% (95% CI, 39.1%-51.
8%) and 42.1% (95% CI, 33.3%-51.
2%) in the SC and IV arms, respectively (odds ratio, 1.08; 95% CI, 0.85-1.
37). The median duration of response (DOR) was 9.1 months (95% CI, 6.
9-not reached [NR]) in the SC arm vs 8.0 months (95% CI, 7.4-NR) in the IV arm.
The median overall survival (OS) was NR in both arms (HR, 0.81; 95% CI, 0.53-1.
22). “Our findings demonstrate that [SC] pembrolizumab is a treatment option in all indications where [the IV formulation of] pembrolizumab can be used,” Enriqueta Felip, MD, PhD, lead study author and section chief at the Vall d’Hebron University Hospital, and head of the thoracic tumors group at the Vall d’ Hebron Institute of Oncology in Barcelona, Spain, said in a presentation during the meeting. 3475A-D77 was a phase 3, randomized, open-label trial comparing SC pembrolizumab with IV pembrolizumab in combination with platinum-doublet chemotherapy.
Eligibility criteria required that patients be at least 18 years of age with untreated stage IV NSCLC without EGFR , ALK , and ROS1 sensitizing mutations. An ECOG performance status of 0 or 1 and no pneumonitis or interstitial lung disease were also required. Patients were randomly assigned 2:1 to treatment with 790 mg of SC pembrolizumab every 6 weeks plus platinum doublet chemotherapy or 400 mg of IV pembrolizumab every 6 weeks plus platinum doublet chemotherapy.
After completing 2 cycles of therapy, patients went on to receive up to 16 cycles of SC or IV pembrolizumab, plus pemetrexed maintenance for those with nonsquamous histology. The dual primary end points were cycle 1 AUC 0-6 and steady-state C trough at cycle 3. Secondary end points included immunogenicity, ORR, PFS, and DOR by blinded independent central review.
Other secondary end points included OS, safety and tolerability, and quality of life. At a median follow-up of 9.6 months (range, 6.
2-16.4), 377 patients had been randomly assigned to SC (n = 251) and IV (n = 126) pembrolizumab. The median injection time for those who received SC pembrolizumab was 2.
0 minutes (range, 1-12). In the SC arm 53.8% of patients are continuing treatment; the remaining 46.
2% discontinued because of progressive disease (24.3%), an adverse effect (AE; 14.3%), clinical progression (4.
0%), participant withdrawal (3.2%), and physician decision (0.4%).
In the IV arm 47.6% of patients are continuing treatment; the remaining 52.4% discontinued because of progressive disease (32.
5%), an AE (12.7%), clinical progression (2.4%), participant withdrawal (2.
4%), loss to follow-up (1.6%), and protocol noncompliance (0.8%).
Baseline characteristics were largely well balanced. In the SC arm the median age was 65.0 years (range, 39-87), and most patients were at least 65 years of age (52.
6%) as well as male (72.5%). Most patients did not come from East Asia (29.
1%) or North America, western Europe, Australia, or New Zealand (4.4%) but from the rest of the world (66.5%), and most were former smokers (56.
6%). Additionally, most patients had nonsquamous histology (66.5%), a PD-L1 tumor proportion score below 50% (72.
1%), and an ECOG performance status of 1 (64.5%). Few patients had brain (7.
6%) or liver (18.3%) metastases. In the SC arm, any injection site AE (2.
4%) consisted of erythema (0.4%), hemorrhage (0.4%), induration (0.
4%), pain (0.4%), and reaction (0.8%).
“Injection-site reactions were infrequent, mild in severity, and nonserious,” Felip stated. Any-grade treatment-related AEs (TRAEs) occurred in 90.0% of patients (grade ≥3, 47.
0%), and 21.1% of events were characterized as serious. A total of 8.
4% of patients discontinued SC pembrolizumab, and 15.1% discontinued chemotherapy; 3.6% of patients died.
In the IV arm, any-grade TRAEs occurred in 96.0% of patients (grade ≥3, 47.6%), and 19.
8% of events were listed as serious. A total of 8.7% and 11.
9% of patients discontinued IV pembrolizumab and chemotherapy, respectively; 2.4% of patients died. In the SC arm, TRAEs that occurred in at least 10% of patients included anemia (52.
2%), neutropenia (41.8%), thrombocytopenia (28.3%), leukopenia (27.
9%), nausea (22.3%), increased aspartate aminotransferase (AST) levels (13.1%), fatigue (13.
1%), hypothyroidism (12.4%), increased alanine aminotransferase (ALT) levels (11.6%), pruritus (10.
4%), alopecia (8.4%), and decreased appetite (6.8%).
In the IV arm TRAEs included anemia (64.3%), neutropenia (31.0%), thrombocytopenia (27.
0%), leukopenia (25.4%), nausea (21.4%), increased AST levels (9.
5%), fatigue (11.9%), hypothyroidism (11.1%), increased ALT levels (10.
3%), pruritus (7.9%), alopecia (10.3%), and decreased appetite (15.
9%). “[SC] pembrolizumabprovides the same proven efficacy and established safety profile of pembrolizumab IV, while enhancing the patient experience and reducing time demands, potentially streamlining treatment center workflows and lowering healthcare resource utilization,” Felip concluded. Disclosures : Felip disclosed grants/research funding from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co.
, Inc., Rahway, NJ, USA (to institution); honoraria and/or consulting fees from AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, F. Hoffmann – La Roche, Genentech, Gilead,Glaxo Smith Kline, Iteos Therapeutics, Janssen, Johnson & Johnson,Medical Trends, Medscape, Merck Serono, Merck Sharp & Dohme LLC, Novartis, PeerVoice, Pierre Fabre, Pfizer, Regeneron, and Turning Point; support for meeting attendance and/or travel from AstraZeneca, Janssen, and Roche; and other from Grifols (independent board member).
Felip E, Rojas CI, Schenker M, et al. Subcutaneous versus intravenous pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer: the phase 3 3475A-D77 trial. Presented at: 2025 European Lung Cancer Congress; March 26-29, 2025; Paris, France.
Abstract 8MO..
