Targeted therapies

Anastrozole: Estrogen receptor (ER) expression is noted in most LGSCs and is a potential target. The PARAGON phase II basket trial evaluated the activity of anastrozole in patients with ER-positive tumors, including 36 patients with recurrent LGSC.[7][Level of evidence C3]

Anastrozole: Estrogen receptor (ER) expression is noted in most LGSCs and is a potential target. The PARAGON phase II basket trial evaluated the activity of anastrozole in patients with ER-positive tumors, including 36 patients with recurrent LGSC.[7][Level of evidence C3]

The trial demonstrated clinical benefit in 61% of patients at 6 months and 34% of patients at 12 months. Notably, the study included patients with LGSC and other ER-positive tumors.

Anastrozole: Estrogen receptor (ER) expression is noted in most LGSCs and is a potential target. The PARAGON phase II basket trial evaluated the activity of anastrozole in patients with ER-positive tumors, including 36 patients with recurrent LGSC.[7][Level of evidence C3]

The median duration of clinical benefit was 9.5 months.

Trametinib: Trametinib is a selective, reversible, allosteric inhibitor of MEK1/MEK2. A recent international, randomized, multicenter, phase II/III trial evaluated trametinib in patients with LGSC. An unlimited number of prior therapies, including chemotherapy or hormone therapy, was allowed. Patients must have received at least one prior platinum-based regimen, but not all five standard-of-care drugs. Patients received either oral trametinib (2 mg once daily) or the standard of care with the physician’s choice of chemotherapy (paclitaxel, pegylated liposomal doxorubicin, topotecan, oral letrozole, or oral tamoxifen).[8][Level of evidence B1]

Trametinib: Trametinib is a selective, reversible, allosteric inhibitor of MEK1/MEK2. A recent international, randomized, multicenter, phase II/III trial evaluated trametinib in patients with LGSC. An unlimited number of prior therapies, including chemotherapy or hormone therapy, was allowed. Patients must have received at least one prior platinum-based regimen, but not all five standard-of-care drugs. Patients received either oral trametinib (2 mg once daily) or the standard of care with the physician’s choice of chemotherapy (paclitaxel, pegylated liposomal doxorubicin, topotecan, oral letrozole, or oral tamoxifen).[8][Level of evidence B1]

The median PFS was 13.0 months (95% confidence interval [CI], 9.9–15.0) in the trametinib group and 7.5 months (95% CI, 5.6–9.9) in the standard-of-care group (hazard ratio [HR], 0.48; 95% CI, 0.36–0.64; one-sided P < .0001).

Trametinib: Trametinib is a selective, reversible, allosteric inhibitor of MEK1/MEK2. A recent international, randomized, multicenter, phase II/III trial evaluated trametinib in patients with LGSC. An unlimited number of prior therapies, including chemotherapy or hormone therapy, was allowed. Patients must have received at least one prior platinum-based regimen, but not all five standard-of-care drugs. Patients received either oral trametinib (2 mg once daily) or the standard of care with the physician’s choice of chemotherapy (paclitaxel, pegylated liposomal doxorubicin, topotecan, oral letrozole, or oral tamoxifen).[8][Level of evidence B1]

A post hoc analysis was performed on a subgroup of 87 patients who were preplanned to receive letrozole if randomly assigned to the standard-of-care group. The PFS was 15.0 months (95% CI, 7.7–23.1) in the trametinib group and 10.6 months (95% CI, 6.5–12.8) in the letrozole group (HR, 0.58; 95% CI, 0.36–0.95; one-sided P = .0085).

Trametinib: Trametinib is a selective, reversible, allosteric inhibitor of MEK1/MEK2. A recent international, randomized, multicenter, phase II/III trial evaluated trametinib in patients with LGSC. An unlimited number of prior therapies, including chemotherapy or hormone therapy, was allowed. Patients must have received at least one prior platinum-based regimen, but not all five standard-of-care drugs. Patients received either oral trametinib (2 mg once daily) or the standard of care with the physician’s choice of chemotherapy (paclitaxel, pegylated liposomal doxorubicin, topotecan, oral letrozole, or oral tamoxifen).[8][Level of evidence B1]

The overall response rate was 26% (34 of 130 patients) in the trametinib group. An additional 59% of patients (77 of 130) had stable disease for at least 8 weeks.

Trametinib: Trametinib is a selective, reversible, allosteric inhibitor of MEK1/MEK2. A recent international, randomized, multicenter, phase II/III trial evaluated trametinib in patients with LGSC. An unlimited number of prior therapies, including chemotherapy or hormone therapy, was allowed. Patients must have received at least one prior platinum-based regimen, but not all five standard-of-care drugs. Patients received either oral trametinib (2 mg once daily) or the standard of care with the physician’s choice of chemotherapy (paclitaxel, pegylated liposomal doxorubicin, topotecan, oral letrozole, or oral tamoxifen).[8][Level of evidence B1]

The median OS was 37.6 months (95% CI, 32.0–not evaluable) in the trametinib group and 29.2 months (95% CI, 23.5–51.6) in the standard-of-care group (HRdeath, 0.76; 95% CI, 0.51–1.12; one-sided P = .056).

Trametinib: Trametinib is a selective, reversible, allosteric inhibitor of MEK1/MEK2. A recent international, randomized, multicenter, phase II/III trial evaluated trametinib in patients with LGSC. An unlimited number of prior therapies, including chemotherapy or hormone therapy, was allowed. Patients must have received at least one prior platinum-based regimen, but not all five standard-of-care drugs. Patients received either oral trametinib (2 mg once daily) or the standard of care with the physician’s choice of chemotherapy (paclitaxel, pegylated liposomal doxorubicin, topotecan, oral letrozole, or oral tamoxifen).[8][Level of evidence B1]

There was no evidence that BRAF, KRAS, or NRAS variant status predicted PFS.

Binimetinib: MILO/ENGOT-ov11 (NCT01849874) was a phase III trial of binimetinib, a small molecule inhibitor of MEK1/MEK2. The trial included 303 patients with recurrent LGSC who had received one to three prior lines of chemotherapy. Patients were randomly assigned in a 2:1 ratio to receive either binimetinib (45 mg orally twice daily) or physician’s choice of chemotherapy (pegylated liposomal doxorubicin, paclitaxel, or topotecan).[9]

Binimetinib: MILO/ENGOT-ov11 (NCT01849874) was a phase III trial of binimetinib, a small molecule inhibitor of MEK1/MEK2. The trial included 303 patients with recurrent LGSC who had received one to three prior lines of chemotherapy. Patients were randomly assigned in a 2:1 ratio to receive either binimetinib (45 mg orally twice daily) or physician’s choice of chemotherapy (pegylated liposomal doxorubicin, paclitaxel, or topotecan).[9]

The median PFS was 9.1 months (95% CI, 7.3–11.3) for patients who received binimetinib and 10.6 months (95% CI, 9.2–14.5) for patients who received chemotherapy. The study closed early according to the prespecified futility boundary.

Binimetinib: MILO/ENGOT-ov11 (NCT01849874) was a phase III trial of binimetinib, a small molecule inhibitor of MEK1/MEK2. The trial included 303 patients with recurrent LGSC who had received one to three prior lines of chemotherapy. Patients were randomly assigned in a 2:1 ratio to receive either binimetinib (45 mg orally twice daily) or physician’s choice of chemotherapy (pegylated liposomal doxorubicin, paclitaxel, or topotecan).[9]

The overall response rate was 16% for patients who received binimetinib (including 32 patients with complete/partial responses), and 13% for patients who received chemotherapy (including 13 patients with complete/partial responses).

Binimetinib: MILO/ENGOT-ov11 (NCT01849874) was a phase III trial of binimetinib, a small molecule inhibitor of MEK1/MEK2. The trial included 303 patients with recurrent LGSC who had received one to three prior lines of chemotherapy. Patients were randomly assigned in a 2:1 ratio to receive either binimetinib (45 mg orally twice daily) or physician’s choice of chemotherapy (pegylated liposomal doxorubicin, paclitaxel, or topotecan).[9]

The median duration of response was 8.1 months (range, 0.03 to ≥12.0) for patients who received binimetinib and 6.7 months (range, 0.03 to ≥9.7) for patients who received chemotherapy.

Binimetinib: MILO/ENGOT-ov11 (NCT01849874) was a phase III trial of binimetinib, a small molecule inhibitor of MEK1/MEK2. The trial included 303 patients with recurrent LGSC who had received one to three prior lines of chemotherapy. Patients were randomly assigned in a 2:1 ratio to receive either binimetinib (45 mg orally twice daily) or physician’s choice of chemotherapy (pegylated liposomal doxorubicin, paclitaxel, or topotecan).[9]

The OS was 25.3 months for patients who received binimetinib and 20.8 months for patients who received chemotherapy.

Binimetinib: MILO/ENGOT-ov11 (NCT01849874) was a phase III trial of binimetinib, a small molecule inhibitor of MEK1/MEK2. The trial included 303 patients with recurrent LGSC who had received one to three prior lines of chemotherapy. Patients were randomly assigned in a 2:1 ratio to receive either binimetinib (45 mg orally twice daily) or physician’s choice of chemotherapy (pegylated liposomal doxorubicin, paclitaxel, or topotecan).[9]

OS was similar and viewed as no better or worse than chemotherapy.

Binimetinib: MILO/ENGOT-ov11 (NCT01849874) was a phase III trial of binimetinib, a small molecule inhibitor of MEK1/MEK2. The trial included 303 patients with recurrent LGSC who had received one to three prior lines of chemotherapy. Patients were randomly assigned in a 2:1 ratio to receive either binimetinib (45 mg orally twice daily) or physician’s choice of chemotherapy (pegylated liposomal doxorubicin, paclitaxel, or topotecan).[9]

A post hoc analysis was conducted on tumor molecular testing samples from 215 patients. KRAS variants were seen in 32% to 34% of patients. The analysis showed that KRAS variants were associated with a response to treatment with binimetinib (odds ratio, 3.4; 95% CI, 1.53–7.66; unadjusted P = .003) and with prolonged PFS in patients treated with binimetinib (median PFS: KRAS variant, 17.7 months [95% CI, 12–not reached]; KRAS wild-type, 10.8 months [95% CI, 5.5–16.7]; P = .006).

Bevacizumab: Bevacizumab is an anti-VEGFA monoclonal antibody. A single institution enrolled 13 patients with LGSC and 4 patients with borderline tumors. Two patients received bevacizumab as a single agent while the other patients received bevacizumab in combination with chemotherapy (i.e., paclitaxel, topotecan, oral cyclophosphamide, gemcitabine, or gemcitabine and carboplatin).[10][Level of evidence C3]

Bevacizumab: Bevacizumab is an anti-VEGFA monoclonal antibody. A single institution enrolled 13 patients with LGSC and 4 patients with borderline tumors. Two patients received bevacizumab as a single agent while the other patients received bevacizumab in combination with chemotherapy (i.e., paclitaxel, topotecan, oral cyclophosphamide, gemcitabine, or gemcitabine and carboplatin).[10][Level of evidence C3]

After a median duration of 23 weeks (range, 6–79.4), there were no patients with a complete response and six patients with partial responses (five of whom had received concurrent paclitaxel, and one who received concurrent gemcitabine). The overall response rate was 40% among all evaluable patients, and 55% among the subgroup of LGSC patients.

Ribociclib and letrozole: GOG-3026 (NCT03673124) was a phase II trial evaluating the combination of ribociclib and letrozole in patients with recurrent LGSC. Patients received ribociclib, a CDK4/6 inhibitor, at 600 mg daily on a 3-weeks-on/1-week-off schedule, plus 2.5 mg of oral letrozole once daily for a 28-day cycle.[11]

Ribociclib and letrozole: GOG-3026 (NCT03673124) was a phase II trial evaluating the combination of ribociclib and letrozole in patients with recurrent LGSC. Patients received ribociclib, a CDK4/6 inhibitor, at 600 mg daily on a 3-weeks-on/1-week-off schedule, plus 2.5 mg of oral letrozole once daily for a 28-day cycle.[11]

The overall response rate was 23% (90% CI, 13.4%–35.1%), and the clinical benefit rate was 97% (90% CI, 67.2%–88.2%).

Ribociclib and letrozole: GOG-3026 (NCT03673124) was a phase II trial evaluating the combination of ribociclib and letrozole in patients with recurrent LGSC. Patients received ribociclib, a CDK4/6 inhibitor, at 600 mg daily on a 3-weeks-on/1-week-off schedule, plus 2.5 mg of oral letrozole once daily for a 28-day cycle.[11]

The median duration of response was 19.1 months. The median PFS was 19.1 months, and the median OS was not reached.

Selumetinib: Selumetinib is a selective small molecule inhibitor of MEK1/MEK2. A phase II study included 52 patients with recurrent LGSC who received 50 mg of selumetinib twice daily until progression.[12][Level of evidence C3]

Selumetinib: Selumetinib is a selective small molecule inhibitor of MEK1/MEK2. A phase II study included 52 patients with recurrent LGSC who received 50 mg of selumetinib twice daily until progression.[12][Level of evidence C3]

There were 8 patients (15%) with complete responses, 7 patients (13%) with partial responses, and 34 patients (65%) with stable disease.

Selumetinib: Selumetinib is a selective small molecule inhibitor of MEK1/MEK2. A phase II study included 52 patients with recurrent LGSC who received 50 mg of selumetinib twice daily until progression.[12][Level of evidence C3]

The median time to response was 4.8 months, and the median duration of response was 10.5 months.

Selumetinib: Selumetinib is a selective small molecule inhibitor of MEK1/MEK2. A phase II study included 52 patients with recurrent LGSC who received 50 mg of selumetinib twice daily until progression.[12][Level of evidence C3]

The median PFS was 11 months, and 63% of patients had a PFS of more than 6 months.

Selumetinib: Selumetinib is a selective small molecule inhibitor of MEK1/MEK2. A phase II study included 52 patients with recurrent LGSC who received 50 mg of selumetinib twice daily until progression.[12][Level of evidence C3]

Responses were irrespective of BRAF or KRAS variant status.

Imatinib: LGSC has a high expression of PDGFRB and BCR::ABL1. A phase II study evaluated imatinib mesylate in patients with platinum-resistant recurrent LGSC. The trial enrolled 13 patients who had received at least four prior lines of platinum- and/or taxane-containing chemotherapy and had been screened for a targeted biomarker (i.e., c-kit, PDGFRB, or BCR::ABL1). Patients received 600 mg of imatinib mesylate daily for 6 weeks.[13]

Imatinib: LGSC has a high expression of PDGFRB and BCR::ABL1. A phase II study evaluated imatinib mesylate in patients with platinum-resistant recurrent LGSC. The trial enrolled 13 patients who had received at least four prior lines of platinum- and/or taxane-containing chemotherapy and had been screened for a targeted biomarker (i.e., c-kit, PDGFRB, or BCR::ABL1). Patients received 600 mg of imatinib mesylate daily for 6 weeks.[13]

There was no evidence of efficacy in patients who received imatinib mesylate despite high expression of PDGFRB.