Promising Therapies Emerging for Recurrent/Metastatic Cervical Cancer

Frontline Fulvestrant, Palbociclib Combo Is Effective for Endocrine-Sensitive, HR+/HER2- Metastatic Breast Cancer

Data from the phase 2 FLIPPER trial (GEICAM/2014-12; NCT02690480) indicated that frontline fulvestrant (Faslodex) in combination with palbociclib (Ibrance) demonstrated an improvement in progression-free survival (PFS) at 1 year compared with fulvestrant and placebo alone in patients with endocrine-sensitive hormone receptor–positive, HER2-negative metastatic breast cancer.¹

The findings, which were presented at the 2020 European Society of Medical Oncology (ESMO) Virtual Congress, also demonstrated that the doublet regimen led to improvements in median PFS, objective response rate (ORR), and clinical benefit rate (CBR) compared with fulvestrant alone.

After a median follow-up of 28.6 months (range, 1.5-44.8), the PFS rate at 1 year was 83.5% with fulvestrant and palbociclib versus 71.9% with fulvestrant and placebo (HR 0.55; 80% CI, 0.36-0.83; P = .064), meeting the trial’s primary end point.

Median PFS was 31.8 months (80% CI, 30.3-33.4) with the doublet and 22 months (80% CI, 18.5-25.1) with fulvestrant alone (adjusted HR, 0.52; 80% CI, 0.39-0.68; P = .002).

A total of 189 patients were enrolled and randomized to either the experimental arm of fulvestrant and palbociclib (n = 94) or the control arm of fulvestrant and placebo (n = 95). Patients were stratified by visceral versus nonvisceral metastases and metastatic de novo presentation versus recurrent presentation at study entry.

Fulvestrant was administered at 500 mg on days 1 and 15 of the first cycle and then once every 28 days thereafter. Palbociclib was given at 125 mg for
3 weeks on and 1 week off of every 28-day cycle. Treatment was given until disease progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent.

Those with visceral disease who were treated with fulvestrant and palbociclib (n = 57) had a median PFS of 30.9 months vs 19.4 months with fulvestrant and placebo (n = 57; HR, 0.53; 80% CI, 0.38-0.73; P = .013). At 1 year, the PFS rate was 81.8% vs 69.6% with the doublet and fulvestrant monotherapy, respectively (HR, 0.55; 80% CI, –0.33-0.92; P = .1397).

The ORR was 68.3% in the investigational arm compared with 42.2% in the control arm (odds ratio [OR], 2.9; 80% CI, 1.79-4.62; P = .004). The CBR, which was defined as responses plus stable disease for at least 24 weeks, was 90.4% with the combination regimen versus 80.0% with fulvestrant alone (OR, 2.3; 80% CI, 1.33-4.03; P = .048).

Treatment-related adverse events (AEs) were observed in 89.4% of patients who received fulvestrant and palbociclib compared with 62.1% in those who received fulvestrant alone. About 15% of patients in the investigational arm discontinued palbociclib and 4.3% discontinued all study drugs whereas 4.2% in the control arm discontinued treatment. Serious AEs were reported in 26.6% of patients in the combination arm vs 20.0% in the monotherapy arm. Two on-study treatment deaths were reported in the fulvestrant and palbociclib arm, but neither were considered due to treatment.

REFERENCE

1. Albanell J, Martinez MTM, Ramos M, et al. GEICAM/2014-12 (FLIPPER) study: First analysis from a randomized phase II trial of fulvestrant (F)/palbociclib (P) versus (vs.) F/placebo (PL) as first-line therapy in postmenopausal women with HR (Hormone Receptor)+/HER2– endocrine sensitive advanced breast cancer (ABC). Ann Oncol. 2020. 31(suppl_4): S1142-S12-15. 10.1016/aanonc/annonc325

Balstilimab Monotherapy, Combination Shows Promise in Recurrent/Metastatic Cervical Cancer

Results from 2 independent phase 2 trials presented during the 2020 ESMO Virtual Congress indicated that the investigative PD-1 inhibitor balstilimab (AGEN2034) demonstrated promising objective response rates (ORRs), either as a single agent or combined with the CTLA-4 inhibitor zalifrelimab (AGEN1884), in patients with recurrent or metastatic cervical cancer.¹

In the modified intent-to-treat (ITT) population, treatment with single-agent balstilimab elicited a 14% ORR, which included 3 complete responses (CRs) and 20 partial responses (PRs). When patients were treated with balstilimab in combination with zalifrelimab, the ORR increased to 22%, with 8 CRs and 23 PRs. The median duration of response (DOR) for balstilimab monotherapy was 15.4 months (1.1+ to 15.4) while median DOR for the balstilimab/zalifrelimab was not reached (1.3+ to 16.6+).

The presentation follows a September 2020 announcement from the manufacturer of balstilimab, Agenus Inc., which stated that a rolling submission of a biologics license application to the FDA has been initiated for single-agent balstilimab for the treatment of patients with recurrent/metastatic cervical cancer.²

Balstilimab was administered at 3 mg/kg every 2 weeks for both trials, with zalifrelimab added at a dose of 1 mg/kg every 6 weeks (NCT03495882) for the combination study. Imaging was conducted every 6 weeks for 2 years.

The primary end point was ORR via RECIST v1.1 criteria, as assessed by an independent review committee; secondary end points were progression-free survival, overall survival, DOR, and safety.

In the single-agent trial, 161 patients comprised the safety population, and 160 were in the modified ITT population; 138 patients had received 1 or more prior line of chemotherapy. The median age was 53 years, and 47% of patients had an ECOG performance status of 0.

In the combination trial, 155 patients were in the safety population, and 119 had received 1 or more lines of chemotherapy. A total 143 patients comprised the modified ITT population with baseline measurable disease. The median age was 50 years, and 57% of patients had an ECOG performance status of 0.

In patients who received 1 or more lines of prior chemotherapy, the ORR in the single-agent balstilimab trial was 13%, with 3 CRs and 15 PRs. For those who received the combination and prior chemotherapy, the ORR was 20%, with 6 CRs and 18 PRs.

The treatment was found to be well tolerated in both studies and no new safety signals were identified. The combination trial saw more immune-related adverse effects (irAEs) than the single-agent study. Specifically, gastrointestinal (GI) disorders occurred in 8.4% and 5.6% of the combination and monotherapy arms, respectively. Grade 3 or higher immune-related treatment-related adverse effects were GI disorders (2.6% with the combination vs 3.1% with balstilimab alone), laboratory abnormalities (3.9% vs 1.2%, respectively), and skin and subcutaneous tissue disorders (1.9% vs 0.6%).

REFERENCES

1. O’Malley DM, Oaknin A, Monk BJ, et al. Single-agent anti–PD-1 balstilimab or in combination with anti–CTLA-4 zalifrelimab for recurrent/metastatic (R/M) cervical cancer (CC): Preliminary results of two independent phase II trials. Presented at: 2020 ESMO Congress; September 19-21, 2020; virtual. Abstract LBA34.

2. Agenus initiates rolling BLA submission of balstilimab for recurrent/metastatic cervical cancer. News release. Agenus Inc. September 18, 2020. Accessed September 18, 2020. https://investor.agenusbio.com/news-releases/news-release-details/agenus-initiates-rolling-bla-submission-balstilimab

Study Sees Encouraging Responses With Tisotumab Vedotin in Recurrent/Metastatic Cervical Cancer

Findings from the single-arm innovaTV 204 trial indicated that tisotumab vedotin demonstrated an objective response rate (ORR) of 24% (95% CI, 15.9%-33.3%) in patients with recurrent and/or metastatic cervical cancer who were previously treated with doublet chemotherapy and bevacizumab (Avastin), if eligible.¹

The ORR, which was assessed by an independent imaging review committee (IRC), comprised a 7% complete
response rate and a 17% partial response rate, and the median duration of response (DOR) was 8.3 months (95% CI, 4.2-not reached). Most responses were rapid, with a median time to response of 1.4 months (range, 1.1-5.1), and investigators noted that activity was observed within the first 2 treatment cycles.

Tisotumab vedotin is an investigational antibody-drug conjugate directed to tissue factor (TF) and is covalently linked to the microtubule-disrupting agent MMAE via a protease-cleavable linker.

In the pivotal, single-arm, multicenter, phase 2 innovaTV 204 trial (NCT03438396), 101 patients with a median age of 50 years (range, 31-78) with previously treated recurrent and/or metastatic cervical cancer were given tisotumab vedotin at 2.0 mg/kg intravenously every 3 weeks until either disease progression or unacceptable toxicity. Tumor responses were assessed using CT/MRI at baseline every 6 weeks for the first 30 weeks, and then every 12 weeks thereafter.

The median duration of treatment was 4.2 months (range, 1-16), with a median 6 doses (range 1-21) of tisotumab vedotin received and a high dose intensity was observed (95.9%). Four patients had treatment ongoing, and the majority of patients discontinued therapy due to radiographic disease progression (65%), followed by adverse events (AEs; 13%), clinical progression (8%), withdrawal of consent (5%), death (4%), and investigator decision (1%). Thirty-three percent of patients remain in follow-up for survival.

At a median follow-up of 10.0 months (range, 0.7-17.9), additional findings showed that 49% of patients achieved stable disease and 24% of patients had progressive disease; 4% of patients were not evaluable, all via IRC. Moreover, target lesions were reduced in 79% of patients with 1 or more postbaseline scan.

Clinical meaningful responses were also observed regardless of tumor histology (squamous, 23%; nonsquamous, 25%), lines of prior therapy (1, 28%; 2, 13%), responses to prior systemic treatment (responded, 26%; did not respond, 21%), and whether or not they received frontline doublet chemotherapy with bevacizumab (yes, 19%; no, 32%).

Tisotumab vedotin showcased a manageable and tolerable safety profile, with no new safety signals identified. The most common treatment-related AEs (TRAEs) with a 10% or higher incidence rate included alopecia (38%), epistaxis (30%), nausea (27%), conjunctivitis (26%), fatigue (24%), dry eye (23%), myalgia (15%), anemia (12%), asthenia (12%), arthralgia (12%), decreased appetite (11%), keratitis (11%), and pruritis (10%). Grade 3/4 TRAEs occurred in 28% of patients. Of the 4 patients who died, 1 was due to septic shock that was considered to be treatment related.

REFERENCES

1. Coleman RL, Lorusso D, Gennigens A, et al. Tisotumab vedotin in previously treated recurrent or metastatic cervical cancer: results from the phase 2 innovaTV 204/GOG-3023/ENGOT-cx6 study. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract LBA32.

2. Hong DS, Concin N, Vergote I, et al. Tisotumab vedotin in previously treated recurrent or metastatic cervical cancer. Clin Cancer Res. 2020;26(6):1220-1228. doi:10.1158/1078-0432.CCR-19-2962