Late Breaking Abstract – ESMO 2021: Keytruda® Plus Chemotherapy in Advanced Cervical Cancer

SUMMARY: The American Cancer Society estimates that for cervical cancer in the US for 2021, about 14,480 new cases of invasive cervical cancer will be diagnosed and about 4,290 women will die of the disease. Cervical pre-cancers are diagnosed far more often than invasive cervical cancer. Cervical cancer is most frequently diagnosed in women between the ages of 35 and 44 and in the US. Hispanic women are most likely to develop cervical cancer, followed by African-Americans, Asians and Pacific Islanders, and whites.

Patients with persistent, recurrent, or metastatic cervical cancer often receive Platinum-based chemotherapy, (Cisplatin or Carboplatin along with Paclitaxel) plus Bevacizumab. The addition of Bevacizumab to chemotherapy improved the median Overall Survival from 13.3 months to 17 months in a randomized study.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells. In the KEYNOTE-158 trial, the Objective Response Rate (ORR) with single agent KEYTRUDA® in previously treated recurrent or metastatic cervical cancer patients with PD-L1 positive tumors was 14.3%. KEYNOTE-826 trial was conducted to assess whether adding KEYTRUDA® to Platinum-based chemotherapy with or without Bevacizumab would improve efficacy, as compared with chemotherapy with or without Bevacizumab, as first line therapy for persistent, recurrent, or metastatic cervical cancer.

KEYNOTE-826 is a global, multicenter, double-blind, randomized Phase III trial, in which 617 women with recurrent, persistent, or metastatic cervical cancer were randomly assigned in a 1:1 ratio to receive KEYTRUDA® 200 mg IV or placebo, every 3 weeks for up to 35 cycles. Patients in both treatment groups received Paclitaxel 175 mg/m2 IV and the investigator’s choice of Cisplatin 50 mg/m2 or Carboplatin AUC 5 IV every 3 weeks. Chemotherapy was limited to 6 cycles, although patients with ongoing clinical benefit without unacceptable side effects could continue beyond 6 cycles. Bevacizumab at a dose of 15 mg/kg IV every 3 weeks was allowed at the investigator’s discretion. Enrolled patients were not previously treated for advanced disease and were not considered curable. The median patient age was 50 years, and close to two thirds of the patients had persistent or recurrent disease with distant metastases. Patients were stratified according to metastatic disease at diagnosis, planned Bevacizumab use and PD-L1 Combined Positive Score (CPS) less than 1, 1-9 and 10 or more. All the treatment groups were well balanced and about 63% of patients in each treatment group received Bevacizumab. Eighty eight percent (88%) of patients had PD-L1 CPS 1 or more at baseline, and 51% had CPS 10 or more. Approximately 72% of the patients had Squamous Cell Carcinoma, 56% received previous chemoradiotherapy with or without surgery, and 20% had previously untreated metastatic disease at trial entry. The dual Primary endpoints were Progression Free Survival (PFS) and Overall Survival (OS). The median follow up for the first interim analysis was 22.0 months.

The median PFS in those patients with a PD-L1 CPS of 1 or more (N=548) was 10.4 months in the KEYTRUDA® group and 8.2 months in the placebo group (HR for disease progression or death=0.62; P<0.001). This represented a 38% reduction in the risk of disease progression or death in the KEYTRUDA® group. The PFS in all enrolled patients (N=617) was 10.4 months and 8.2 months, respectively (HR=0.65; P<0.001). The PFS in patients with a PD-L1 CPS of 10 or more (N=317) was 10.4 months and 8.1 months, respectively (HR=0.58; P<0.001).

The OS at 24 months was significantly longer in the KEYTRUDA® group, compared to the placebo group, among patients with a PD-L1 CPS of 1 or more, and was 53% in the KEYTRUDA® group and 41.7% in the placebo group (HR for death= 0.64; P<0.001), 50.4% and 40.4% among all enrolled patients (HR=0.67; P<0.001), and 54.4% and 44.6% among patients with a PD-L1 CPS of 10 or more (HR=0.61; P=0.001), respectively. The confirmed Response Rates were also higher and Duration of Response longer in all patient groups receiving KEYTRUDA®, compared to placebo. Side effects with the combination therapy were manageable and were as expected, based on known adverse events with the individual drugs.

It was concluded that the addition of KEYTRUDA® to chemotherapy, with or without Bevacizumab, significantly prolonged Progression Free and Overall Survival, among patients with persistent, recurrent, or metastatic cervical cancer.

Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer. Colombo N, Dubot C, Lorusso D, et al. for the KEYNOTE-826 Investigators. September 18, 2021. DOI: 10.1056/NEJMoa2112435.

FDA Approves KEYTRUDA® for Cervical Cancer

SUMMARY: The FDA on June 12, 2018, approved KEYTRUDA® (Pembrolizumab) for patients with recurrent or metastatic Cervical cancer with disease progression on or after chemotherapy, whose tumors express PD-L1 (Combined Positive Score-CPS, of 1 or more) as determined by an FDA-approved test. The American Cancer Society estimates that for Cervical cancer in the US for 2018, about 13,240 new cases of invasive Cervical cancer will be diagnosed and about 4,170 women will die of the disease. Cervical pre-cancers are diagnosed far more often than invasive Cervical cancer. Cervical cancer is most frequently diagnosed in women between the ages of 35 and 44 and in the US. Hispanic women are most likely to get Cervical cancer, followed by African-Americans, Asians and Pacific Islanders, and whites.

Approximately 5% of new diagnoses of Cervical cancer accounts for stage IV disease. However, metastatic disease develops in 15-60% of women, usually within the first two years of completing primary treatment. A select group of women with locally recurrent or limited metastatic disease may be potentially cured with surgical resection or radiotherapy. This however may not be feasible in the majority of cases. Patients with recurrent and metastatic Cervical cancer have a poor prognosis, with limited systemic treatment options. There is currently no consensus on the standard of care for second-line systemic treatment of recurrent or metastatic Cervical cancer, and as such represents a significant unmet clinical need.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells.

The FDA approval was based on KEYNOTE-158 study, which is a multicenter, non-randomized, open-label, multi-cohort phase II basket study trial, investigating the antitumor activity of KEYTRUDA® in 11 different advanced cancer types, who had progressed on standard-of-care therapy. Basket Trial by definition allows the testing of one drug on a single mutation in a variety of tumor types, at the same time, thereby potentially increasing the number of patients who are eligible to receive certain drugs. KEYTRUDA® was investigated in 98 patients with recurrent or metastatic Cervical cancer, enrolled in a single cohort of the KEYNOTE- 158 trial.

Key eligibility criteria for this cohort included patients with histologically or cytologically confirmed advanced Cervical cancer who had progressed on or intolerant to one or more lines of standard therapy and had tumor sample available for biomarker analysis. Patients were treated with KEYTRUDA® 200 mg IV every 3 weeks until documented disease progression or unacceptable toxicity..PD-L1 positivity, defined as a Combined Positive Score (CPS) of 1 or more, was evaluated retrospectively by ImmunoHistoChemistry (IHC) using the PD-L1 IHC 22C3 pharmDx Kit. Median age was 46 years and 77 patients (79%) of enrolled patients had PD-L1 positive tumors. Primary endpoint was Objective Response Rate (ORR) assessed by independent central review. Secondary endpoints included Duration of Response (DOR), Progression Free Survival (PFS), Overall Survival (OS) and safety.

With a median follow up time of 11.7 months, the ORR in the 77 PD-L1 positive patients was 14.3% including 2.6% Complete Responses and 11.7% Partial Responses. The estimated median response duration was not reached, 91% had response duration of 6 months or more, and no responses were observed in patients whose tumors did not have PD-L1 expression (CPS less than 1). The most common adverse reactions in at least 10% of patients were fatigue, fever, nausea, vomiting, diarrhea/colitis, abdominal pain, constipation, hypothyroidism, and dyspnea. KEYTRUDA® was discontinued due to adverse reactions in 8% of patients.

It was concluded that KEYTRUDA® is the first anti-PD-1 therapy approved for the treatment of advanced Cervical cancer, providing an important new second-line option for certain patients with this disease, with durable antitumor activity and manageable toxicity profile. Pembrolizumab treatment of advanced cervical cancer: Updated results from the phase 2 KEYNOTE-158 study. Chung HC, Schellens JH, Delord J, et al. J Clin Oncol 36, 2018 (suppl; abstr 5522)

KEYTRUDA® (Pembrolizumab)

The FDA on June 12, 2018 approved KEYTRUDA® for patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy, whose tumors express PD-L1 (CPS 1 or more), as determined by an FDA-approved test. KEYTRUDA® is a product of Merck and Co., Inc.

Improved Survival with Bevacizumab in Advanced Cervical Cancer

SUMMARY: Cervical cancer is the fourth most common cancer affecting women, worldwide. It is also the fourth most common cause of cancer death. With the availability of widespread screening techniques and HPV vaccination in the U.S., the incidence of cervical cancer is declining. Treatment of advanced cervical cancer continues to be a challenge. The FDA recently approved AVASTIN® (Bevacizumab) for the treatment of persistent, recurrent or metastatic cervical cancer, in combination with TAXOL® (Paclitaxel) and Cisplatin or TAXOL® and HYCAMTIN® (Topotecan). The approval was based on the results of an international, randomized, four-arm, 2×2 factorial design trial with two primary comparisons of Overall Survival (OS). The first comparison was between AVASTIN® plus chemotherapy versus chemotherapy alone. The second comparison of OS was between the platinum doublet versus the non-platinum doublet chemotherapy irrespective of addition of AVASTIN®. AVASTIN®, a humanized Vascular Endothelial Growth Factor (VEGF) targeted monoclonal antibody, has demonstrated single-agent activity in heavily pretreated patients with recurrent cervical carcinoma in phase II trials. In this randomized study, 452 enrolled patients with metastatic, persistent or recurrent cervical cancer received one of the four treatment regimens using a 2×2 factorial design. The four treatment groups included a) Cisplatin 50 mg/m2 plus TAXOL® (Paclitaxel) 135 or 175 mg/m2 (N=114), b) HYCAMTIN® (Topotecan) 0.75 mg/m2 given on D1 thru D3 plus TAXOL® 175 mg/m2 given on Day 1 (N=111), c) Cisplatin 50 mg/m2 plus TAXOL® 135 or 175 mg/m2 given along with AVASTIN® 15mg/kg on Day 1 (N=115) and d) HYCAMTIN® 0.75 mg/m2 given on D1 thru D3 plus TAXOL® 175 mg/m2 given on Day 1, along with AVASTIN® 15mg/kg on day 1 (N=112). Treatment was given every 21 days until disease progression, the development of unacceptable toxicities or a complete response was noted. The primary end point was Overall Survival and secondary endpoints included Progression Free Survival (PFS) and Response Rate (RR). When outcomes were analyzed, HYCAMTIN® based chemotherapy was not superior to Cisplatin based chemotherapy, regardless of prior exposure to Cisplatin. At a median follow-up of 20.8 months, the addition of AVASTIN® to chemotherapy resulted in a significantly longer median Overall Survival (17 vs 13.3 months; HR=0.71; P=0.004), significantly longer median PFS (8.2 vs 5.9 months; HR=0.67; P=0.002) and Response Rate (48% vs 36%; P=0.008), compared to combination chemotherapy alone. With regards to the second primary comparison of Overall Survival, the TAXOL® plus HYCAMTIN® with or without AVASTIN® groups did not demonstrate an improvement in Overall Survival compared to the TAXOL® plus Cisplatin with or without AVASTIN® groups. The benefit with added AVASTIN® was noted in all subgroups regardless of age, race, performance status and prior platinum exposure. Treatment was in general well tolerated without significant reduction in quality of life. As was seen in other tumor types, AVASTIN® based chemotherapy regimen was associated with a higher incidence of hypertension and thromboembolic events. The authors concluded that the addition of AVASTIN® to combination chemotherapy significantly decreased the risk of death in patients with recurrent, persistent, or metastatic cervical cancer. It can also be concluded from this study that the TAXOL® with HYCAMTIN® plus AVASTIN® is an acceptable alternative for women with advanced cervical cancer, who are not candidates for Cisplatin based chemotherapy. Tewari KS, Sill MW, Long HJ, et al. N Engl J Med 2014; 370:734-743

Improved Survival with Bevacizumab in Advanced Cervical Cancer

SUMMARY: Cervical cancer is the fourth most common cancer affecting women, worldwide. It is also the fourth most common cause of cancer death. With the availability of widespread screening techniques and HPV vaccination in the U.S., the incidence of cervical cancer is declining. Treatment of advanced cervical cancer continues to be a challenge. To address this further, the authors in this study evaluated the benefit of adding AVASTIN® (Bevacizumab) to conventional chemotherapy regimens, for patients with advanced cervical cancer. AVASTIN®, a humanized Vascular Endothelial Growth Factor (VEGF) targeted monoclonal antibody, has demonstrated single-agent activity in heavily pretreated patients with recurrent cervical carcinoma in phase II trials. In this randomized study, 452 enrolled patients with metastatic, persistent or recurrent cervical cancer received one of the four treatment regimens using a 2×2 factorial design. The four treatment groups included a) Cisplatin 50 mg/m2 plus TAXOL® (Paclitaxel) 135 or 175 mg/m2 (N=114), b) HYCAMTIN® (Topotecan) 0.75 mg/m2 given on D1 thru D3 plus TAXOL® 175 mg/m2 given on Day 1 (N=111), c) Cisplatin 50 mg/m2 plus TAXOL® 135 or 175 mg/m2 given along with AVASTIN® 15mg/kg on Day 1 (N=115) and d) HYCAMTIN® 0.75 mg/m2 given on D1 thru D3 plus TAXOL® 175 mg/m2 given on Day 1, along with AVASTIN® 15mg/kg on day 1 (N=112). Treatment was given every 21 days until disease progression, the development of unacceptable toxicities or a complete response was noted. The primary end point was Overall Survival and secondary endpoints included Progression Free Survival (PFS) and Response Rate (RR). When outcomes were analyzed, HYCAMTIN® based chemotherapy was not superior to Cisplatin based chemotherapy, regardless of prior exposure to Cisplatin. The addition of AVASTIN® to chemotherapy resulted in a significantly longer median Overall Survival (17 vs 13.3 months; HR=0.71; P=0.004), significantly longer median PFS (8.2 vs 5.9 months; HR=0.67; P=0.002) and RR (48% vs 36%; P=0.008), compared to combination chemotherapy alone. The benefit with added AVASTIN® was noted in all subgroups regardless of age, race, performance status and prior platinum exposure. Treatment was in general well tolerated without significant reduction in quality of life. As was seen in other tumor types, AVASTIN® based chemotherapy regimen was associated with a higher incidence of hypertension and thromboembolic events. The authors concluded that the addition of AVASTIN® to combination chemotherapy significantly decreased the risk of death in patients with recurrent, persistent, or metastatic cervical cancer. Tewari KS, Sill MW, Long HJ, et al. N Engl J Med 2014; 370:734-743