The combination of quavonlimab and pembrolizumab was found to be generally well tolerated and to have modest antitumor activity in patients with advanced melanoma that progressed on a PD-1/PD-L1 inhibitor, according to data from a phase 1/2 trial (NCT03179436).
The combination of quavonlimab (MK-1308) and pembrolizumab (Keytruda) was found to be generally well tolerated and to have modest antitumor activity in patients with advanced melanoma that progressed on a PD-1/PD-L1 inhibitor, according to data from a phase 1/2 trial (NCT03179436).
The findings, which were presented during the 2022 AACR Annual Meeting, showed that the doublet (n = 111) elicited an objective response rate (ORR) of 9.0% (95% CI, 4.4%-15.9%) per RECIST v1.1 criteria by blinded independent central review (BICR) vs 2.5% (95% CI, 0.1%-13.2%) with quavonlimab monotherapy (n = 40).
In the quavonlimab/pembrolizumab arm, the complete response rate was 0.9%, the partial response (PR) rate was 8.1%, and the stable disease (SD) rate was 28.8%); 53.2% experienced disease progression, 1.8% were not evaluable for response, and 7.2% were not assessed. In the quavonlimab monotherapy arm, 2.5% of patients achieved a PR, 35.0% had stable disease, and 57.5% experienced disease progression; 2.5% were not evaluable and 2.5% were not assessed.
“Quavonlimab monotherapy had minimal antitumor activity, and future studies will evaluate quavonlimab as part of combination therapy for this patient population,” lead study author Sanjeev Deva, MD, of Auckland City Hospital, and colleagues, wrote in a poster on the data.
For patients with advanced melanoma, anti–PD-1 monotherapy serves as the standard of care for the frontline setting. However, after achieving an initial response to this approach, many patients will relapse. Combinations comprised of an anti–PD-1 agent and a CTLA-4 inhibitor have demonstrated activity in patients who are refractory to anti–PD-1/PD-L1 monotherapy. Specifically, the combination of ipilimumab (Yervoy) plus pembrolizumab has been shown to induce an ORR of 29% in those with PD-1–refractory, advanced melanoma.
These data have led to the launch of the ongoing, open-label, multi-arm, dose-escalation study, in which investigators set out to examine another CTLA-4/PD-1 combination in the form of quavonlimab and pembrolizumab, respectively, as a potential regimen for patients with advanced solid tumors.
Previous findings from arms A through E of the dose-confirmation portion of the study showed that the combination had antitumor activity when used in the frontline treatment of patients with advanced non–small cell lung cancer and of those with previously treated, extensive-stage small cell lung cancer.
At the meeting, investigators shared findings from the efficacy-expansion phase of the trial, which examined the regimen in patients with advanced melanoma that progressed on a PD-1/PD-L1 inhibitor who had been enrolled to arms F and G.
The trial enrolled patients with histologically or cytologically confirmed, unresectable, stage III or IV melanoma, with at least 1 measurable lesion per RECIST v1.1 criteria. To be eligible for participation, patients must have progressed on treatment with an anti–PD-1/PD-L1 inhibitor.
A total of 151 study participants were randomized 1:1 to receive 25 mg of intravenous (IV) quavonlimab every 6 weeks for up to 18 cycles in combination with IV pembrolizumab administered at 400 mg for up to 18 cycles (arm F; n = 111) or IV quavonlimab alone at 25 mg for up to 18 cycles (arm G; n = 40).
The primary end points of the research were safety/tolerability and ORR per RECIST v1.1 criteria by BICR, and a key secondary end point as duration of response (DOR) per RECIST v1.1 criteria by BICR. Progression-free survival (PFS) per RECIST v1.1 criteria by BICR and overall survival (OS) served as exploratory end points.
The median age of patients in the combination arm was 65 years (range, 24-93) vs 62 years (range, 37-79) in the monotherapy arm; 69.4% and 55.0%, respectively, were male. Regarding performance status, 75.7% of those in the combination arm had an ECOG performance status of 0 vs 70.0% of those in the monotherapy arm; 24.3% and 30.0% of patients, respectively, had a status of 1.
Regarding PD-L1 status, 50.5% of those in the doublet arm had positivity and 42.5% of those in the monotherapy arm. In the quavonlimab/pembrolizumab arm, 45.9% had a normal lactate dehydrogenase (LDH) level, 53.2% had elevated LDH, and 0.9% had missing information; these rates were 57.5%, 42.5%, and 0%, respectively, in the quavonlimab-alone arm. Regarding BRAF status in the combination arm, 35.1% had BRAF-mutant disease and 64.0% had BRAF wild-type disease; in the monotherapy arm, these rates were 27.5% and 72.5%, respectively.
The median time from first dose or randomization to the database cutoff of May 6, 2021 was 7.7 months (range, 0.1-22.1), and the median treatment duration in those who received the combination regimen was 2.8 months (range, 0.03-15.3) vs 1.4 months (range, 0.03-8.6) with the monotherapy.
Of those on the quavonlimab/pembrolizumab arm, 28 were still receiving treatment at the data cutoff and 83 had discontinued. The most common reason for treatment discontinuation was radiographic progression (n = 53), followed by toxicity (n = 14), clinical progression (n = 10), physician decision (n = 5), and patient withdrawal (n = 1).
Only 3 of the 40 patients in the monotherapy arm were still receiving treatment. The most common reasons for discontinuation were radiographic progression (n = 30), toxicity (n = 2), and clinical progression (n = 5).
Additional data showed that 38% of 111 patients experienced a reduction in target lesion size with quavonlimab plus pembrolizumab vs 25% of the 40 patients who received quavonlimab monotherapy.
The median PFS with quavonlimab/pembrolizumab was 2.1 months (95% CI, 2.1-3.2) vs 2.1 months (95% CI, 2.1-2.5) with quavonlimab monotherapy. The 6-month PFS rates in the combination and monotherapy arms were 20.8% and 12.5%, respectively. The median OS with the combination regimen was not yet reached (NR; 95% CI, 11.2-NR) vs 7.8 months (95% CI, 6.3-NR) with the monotherapy. The 6-month OS rate with quavonlimab/pembrolizumab was 73.9% vs 72.5% with quavonlimab monotherapy.
Treatment-related adverse effects (TRAEs) of any grade occurred in 78.4% (n = 87) of patients on the combination arm and 60.0% (n = 24) of those on the monotherapy arm. Moreover, grade 3 to 5 TRAEs occurred in 14.4% (n = 16) of patients on the combination arm and 7.5% (n = 3) of those on the monotherapy treatment.
The most common TRAEs observed in the combination arm included pruritus (any-grade, 28.8%), diarrhea (any-grade, 18.9%; grades 3-5, 1.8%), rash (any-grade, 15.3%), fatigue (all-grade, 16.2%), alanine aminotransferase increase (any-grade, 7.2%; grades 3-5, 0.9%), asthenia (any-grade, 7.2%), arthralgia (any-grade, 6.3%), decreased appetite (any-grade, 6.3%), aspartate aminotransferase (AST) increase (any-grade, 5.4%; grades 3-5, 0.9%), and dry mouth (any-grade, 5.4%), nausea (any-grade, 5.4%).
In the monotherapy arm, the most common TRAEs were pruritus (any-grade, 17.5%), rash (any-grade, 5.0%), fatigue (any-grade, 7.5%), asthenia (any-grade, 5.0%), arthralgia (any-grade, 5.0%), decreased appetite (any-grade, 2.5%), AST increase (any-grade, 2.5%; grades 3-5, 2.5%), nausea (any-grade, 5.0%), and eosinophilia (any-grade, 5.0%).
Notably, 6.3% of those in the combination arm and 2.5% of those in the monotherapy arm discontinued any drug because of a TRAE. In the quavonlimab/pembrolizumab arm, 6.3% discontinued quavonlimab and 6.3% discontinued pembrolizumab; in the quavonlimab monotherapy arm, 2.5% discontinued quavonlimab.
Serious TRAEs occurred in 9.9% of those in the doublet arm vs 2.5% of those in the monotherapy arm. No treatment-related deaths occurred on either treatment regimen.
“Quavonlimab and pembrolizumab in combination and as a coformulation will be further investigated in the phase 1/2 KEYMAKER-U02 umbrella study [NCT04305041],” the study authors concluded.
Here, the combination of quavonlimab plus pembrolizumab will be evaluated with either the anti-TIGIT therapy vibostolimab or lenvatinib (Lenvima) in patients with PD-1–refractory melanoma.
Deva S, Mackiewicz J, Dalle S, et al. Phase 1/2 study of quavonlimab (Qmab) + pembrolizumab (pembro) in patients (pts) with advanced melanoma that progressed on a PD-1/PD-L1 inhibitor. Cancer Res. 2022;82(suppl 12):CT557. doi:10.1158/1538-7445.AM2022-CT557