HARMONi-A

20 evidence topics · 8 sources

Objective

Comparison against chemotherapy alone after EGFR-TKI progression

“To compare the efficacy of ivonescimab plus chemotherapy with chemotherapy alone for patients with relapsed advanced or metastatic non–small cell lung cancer with the epidermal growth factor receptor (EGFR) variant.” (opens the source at this quote in a new tab)
“For patients with non–small cell lung cancer whose disease progressed while receiving EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy, particularly third-generation TKIs, optimal treatment options remain limited.” (opens the source at this quote in a new tab)

Location and study date

HARMONi-A: setting

Evidence element	Direct quotation
Setting	“55 sites in China”

Study design

Study masking

“Double-blind” (opens the source at this quote in a new tab)

Eligibility criteria

ECOG performance status eligibility

“0 or 1” (opens the source at this quote in a new tab)

Treatment

Study treatment combinations

“ivonescimab plus chemotherapy or placebo plus chemotherapy” (opens the source at this quote in a new tab)

Study outcomes

Rationale for using IRRC-assessed progression-free survival as the primary endpoint

Primary endpoint

“IRRC-assessed PFS” (opens the source at this quote in a new tab)

Statistical analysis description

Number of participants (Planned and analyzed)

HARMONi-A: enrollment

Evidence element	Direct quotation
Enrollment	“322”

Planned statistical design

Design element	Quoted value
Planned participants	“320”
Planned PFS events	“225”
Power	“89%”
Target hazard ratio	“0.65”
Interim significance boundary	“.024”

Description of analysis sets

Efficacy analysis population

“all randomized patients” (opens the source at this quote in a new tab)

Time-to-event estimation method

“Kaplan-Meier method” (opens the source at this quote in a new tab)

Results

Participant disposition

Screened participants

“501” (opens the source at this quote in a new tab)

Baseline characteristics

Median age at the final survival analysis

“59.4 years” (opens the source at this quote in a new tab)

Efficacy results

HARMONi-A: initial progression-free survival

Evidence element	Direct quotation
Median progression-free survival, ivonescimab plus chemotherapy, months	“7.1 (95% CI, 5.9-8.7)”
Median progression-free survival, placebo plus chemotherapy, months	“4.8 (95% CI, 4.2-5.6)”
Progression-free survival comparison	“hazard ratio [HR], 0.46 [95% CI, 0.34-0.62]; P < .001”

HARMONi-A: final overall survival

Evidence element	Direct quotation
Median overall survival, ivonescimab plus chemotherapy versus placebo plus chemotherapy	“16.8 months vs 14.1 months”
Overall survival comparison	“hazard ratio, 0.74; 95% CI, 0.58-0.95; P = .02”

HARMONi-A: objective response and prespecified subgroups

“The prespecified subgroup analysis showed progression-free survival benefit favoring patients receiving ivonescimab over placebo across almost all subgroups, including patients whose disease progressed while receiving third-generation EGFR-TKI therapy (HR, 0.48 [95% CI, 0.35-0.66]) and those with brain metastases (HR, 0.40 [95% CI, 0.22-0.73]).” (opens the source at this quote in a new tab)
“The objective response rate was 50.6% (95% CI, 42.6%-58.6%) with ivonescimab and 35.4% (95% CI, 28.0%-43.3%) with placebo (difference, 15.6% [95% CI, 5.3%-26.0%]; P = .006).” (opens the source at this quote in a new tab)

Health-related quality of life and patient-reported outcomes

No evidence found.

Safety results

HARMONi-A: final safety analysis

Evidence element	Direct quotation
Safety outcome	“Grade 3 or higher treatment-emergent adverse events”
Ivonescimab plus chemotherapy	“67.1%”
Placebo plus chemotherapy	“54.7%”

HARMONi-A: adverse events of special interest at the primary analysis

“Grade 3 or higher treatment-emergent adverse events occurred in 99 patients (61.5%) in the ivonescimab group vs 79 patients (49.1%) in the placebo group, the most common of which were chemotherapy-related.” (opens the source at this quote in a new tab)
“Grade 3 or higher immune-related adverse events occurred in 10 patients (6.2%) in the ivonescimab group vs 4 (2.5%) in the placebo group.” (opens the source at this quote in a new tab)
“Grade 3 or higher vascular endothelial growth factor–related adverse events occurred in 5 patients (3.1%) in the ivonescimab group vs 4 (2.5%) in the placebo group.” (opens the source at this quote in a new tab)

Study limitations

Summary

All 322 participants were enrolled at sites in China, which limits direct geographic generalization. The initial publication reported PFS; the subsequent final OS publication should be considered separately rather than treating early survival immaturity as a continuing limitation. The final OS comparison favored ivonescimab, but grade 3 or higher TEAEs were reported in 67.1% versus 54.7%. HARMONi incorporates an overlapping third-generation TKI-treated population, so its findings are not wholly independent replication.

HARMONi-A correspondence: methodology and interpretation concerns

“some concerns about the methodology and interpretation” (opens the source at this quote in a new tab)

HARMONi-A correspondence: authors’ reply

“our study reported progression-free survival as the primary end point.” (opens the source at this quote in a new tab)