KEYTRUDA (Page 16 of 23)

14.11 Cervical Cancer

FIGO 2014 Stage III-IVA Cervical Cancer with Chemoradiotherapy

The efficacy of KEYTRUDA in combination with CRT (cisplatin and external beam radiation therapy [EBRT] followed by brachytherapy [BT]) was investigated in KEYNOTE-A18 (NCT04221945), a multicenter, randomized, double-blind, placebo-controlled trial that enrolled 1060 patients with cervical cancer who had not previously received any definitive surgery, radiation, or systemic therapy for cervical cancer. There were 596 patients with FIGO 2014 Stage III-IVA (tumor involvement of the lower vagina with or without extension onto pelvic sidewall or hydronephrosis/non-functioning kidney or has spread to adjacent pelvic organs) with either node-positive or node-negative disease, and 462 patients with FIGO 2014 Stage IB2-IIB (tumor lesions >4 cm or clinically visible lesions that have spread beyond the uterus but have not extended onto the pelvic wall or to the lower third of vagina) with node-positive disease; two patients had FIGO 2014 Stage IVB disease. Randomization was stratified by planned type of EBRT (Intensity-modulated radiation therapy [IMRT] or volumetric modulated arc therapy [VMAT] vs. non-IMRT and non-VMAT), stage at screening of cervical cancer (FIGO 2014 Stage IB2-IIB vs. FIGO 2014 Stage III-IVA), and planned total radiotherapy dose (EBRT + brachytherapy dose of <70 Gy vs. ≥70 Gy as per equivalent dose [EQD2]).

Patients were randomized (1:1) to one of two treatment arms:

  • KEYTRUDA 200 mg IV every 3 weeks (5 cycles) concurrent with cisplatin 40 mg/m2 IV weekly (5 cycles, an optional sixth infusion could be administered per local practice), and radiotherapy (EBRT followed by BT), followed by KEYTRUDA 400 mg IV every 6 weeks (15 cycles)
  • Placebo IV every 3 weeks (5 cycles) concurrent with cisplatin 40 mg/m2 IV weekly (5 cycles, an optional sixth infusion could be administered per local practice), and radiotherapy (EBRT followed by BT), followed by placebo IV every 6 weeks (15 cycles)

Treatment continued until RECIST v1.1-defined progression of disease as determined by investigator or unacceptable toxicity.

Assessment of tumor status was performed every 12 weeks from completion of CRT for the first two years, followed by every 24 weeks in year 3, and then annually. The major efficacy outcome measures were PFS as assessed by investigator according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, or histopathologic confirmation, and OS.

Among the 596 patients with FIGO 2014 Stage III-IVA disease, the baseline characteristics were: median age of 52 years (range: 22 to 87), 17% age 65 or older; 36% White, 34% Asian, 1% Black; 38% Hispanic or Latino; 68% ECOG PS 0 and 32% ECOG PS 1; 93% with CPS ≥1; 70% had positive pelvic and/or positive para-aortic lymph node(s) and 30% had neither positive pelvic nor para-aortic lymph node(s); 83% had squamous cell carcinoma and 17% had non-squamous histology. Regarding radiation, 85% of patients received IMRT or VMAT EBRT, and the median EQD2 dose was 87 Gy (range: 7 to 114).

The trial demonstrated a statistically significant improvement in PFS in the overall population. In an exploratory subgroup analysis for the 462 patients (44%) with FIGO 2014 Stage IB2-IIB disease, the PFS HR estimate was 0.91 (95% CI: 0.63, 1.31), indicating that the PFS improvement in the overall population was primarily attributed to the results seen in the subgroup of patients with FIGO 2014 Stage III-IVA disease. OS data were not mature at the time of PFS analysis, with 10% deaths in the overall population.

The efficacy results in the exploratory subgroup analysis of 596 patients with FIGO 2014 Stage III-IVA disease are summarized in Table 86 and Figure 23.

Table 86: Efficacy Results in KEYNOTE-A18 (Patients with FIGO 2014 Stage III-IVA Cervical Cancer)
EndpointKEYTRUDA200 mg every 3 weeks and400 mg every 6 weekswith CRTn=293Placebowith CRTn=303
CRT = ChemoradiotherapyNR = not reached
*
Based on the unstratified Cox proportional hazard model
PFS by Investigator
Number of patients with event (%)61 (21%)94 (31%)
Median in months (95% CI)NR (NR, NR)NR (18.8, NR)
12-month PFS rate (95% CI)81% (75, 85)70% (64, 76)
Hazard ratio * (95% CI)0.59 (0.43, 0.82)
Figure 23: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-A18 (Patients with FIGO 2014 Stage III-IVA Cervical Cancer)

Figure 23
(click image for full-size original)

Persistent, Recurrent, or Metastatic Cervical Cancer

The efficacy of KEYTRUDA in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab, was investigated in KEYNOTE-826 (NCT03635567), a multicenter, randomized, double-blind, placebo-controlled trial that enrolled 617 patients with persistent, recurrent, or first-line metastatic cervical cancer who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent. Patients were enrolled regardless of tumor PD-L1 expression status. Patients with autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by metastatic status at initial diagnosis, investigator decision to use bevacizumab, and PD-L1 status (CPS <1 vs. CPS 1 to <10 vs. CPS ≥10). Patients were randomized (1:1) to one of the two treatment groups:

  • Treatment Group 1: KEYTRUDA 200 mg plus chemotherapy with or without bevacizumab
  • Treatment Group 2: Placebo plus chemotherapy with or without bevacizumab

The investigator selected one of the following four treatment regimens prior to randomization:

  1. Paclitaxel 175 mg/m2 + cisplatin 50 mg/m2
  2. Paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 + bevacizumab 15 mg/kg
  3. Paclitaxel 175 mg/m2 + carboplatin AUC 5 mg/mL/min
  4. Paclitaxel 175 mg/m2 + carboplatin AUC 5 mg/mL/min + bevacizumab 15 mg/kg

All study medications were administered as an intravenous infusion. All study treatments were administered on Day 1 of each 3-week treatment cycle. Cisplatin could be administered on Day 2 of each 3-week treatment cycle. Treatment with KEYTRUDA continued until RECIST v1.1-defined progression of disease, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed every 9 weeks for the first year, followed by every 12 weeks thereafter. The main efficacy outcome measures were OS and PFS as assessed by investigator according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures were ORR and DoR, according to RECIST v1.1, as assessed by investigator.

Of the 617 enrolled patients, 548 patients (89%) had tumors expressing PD-L1 with a CPS ≥1. Among these 548 enrolled patients with tumors expressing PD-L1, 273 patients were randomized to KEYTRUDA in combination with chemotherapy with or without bevacizumab, and 275 patients were randomized to placebo in combination with chemotherapy with or without bevacizumab. Sixty-three percent of the 548 patients received bevacizumab as part of study treatment. The baseline characteristics of the 548 patients were: median age of 51 years (range: 22 to 82), 16% age 65 or older; 59% White, 18% Asian, 6% American Indian or Alaska Native, and 1% Black; 37% Hispanic or Latino; 56% ECOG performance status 0 and 43% ECOG performance status 1. Seventy-five percent had squamous cell carcinoma, 21% adenocarcinoma, and 5% adenosquamous histology, and 32% of patients had metastatic disease at diagnosis. At study entry, 21% of patients had metastatic disease only and 79% had persistent or recurrent disease with or without distant metastases, of whom 39% had received prior chemoradiation only and 17% had received prior chemoradiation plus surgery.

A statistically significant improvement in OS and PFS was demonstrated in patients randomized to receive KEYTRUDA compared with patients randomized to receive placebo. An updated OS analysis was conducted at the time of final analysis when 354 deaths in the CPS ≥1 population were observed. Table 87 and Figure 24 summarize the key efficacy measures for KEYNOTE-826 for patients with tumors expressing PD-L1 (CPS ≥1).

Table 87: Efficacy Results in Patients with Persistent, Recurrent, or Metastatic Cervical Cancer (CPS ≥1) in KEYNOTE-826
EndpointKEYTRUDA200 mg every 3 weeksand chemotherapy * with or without bevacizumabn=273Placeboand chemotherapy * with or without bevacizumabn=275
+ Denotes ongoing responseNR = not reached
*
Chemotherapy (paclitaxel and cisplatin or paclitaxel and carboplatin)
Based on the stratified Cox proportional hazard model
p-Value (one-sided) is compared with the allocated alpha of 0.0055 for this interim analysis (with 72% of the planned number of events for final analysis)
§
p-Value (one-sided) is compared with the allocated alpha of 0.0014 for this interim analysis (with 82% of the planned number of events for final analysis)
Response: Best objective response as confirmed complete response or partial response
OS
Number of patients with event (%)118 (43.2)154 (56.0)
Median in months (95% CI)NR (19.8, NR)16.3 (14.5, 19.4)
Hazard ratio (95% CI)0.64 (0.50, 0.81)
p-Value 0.0001
Updated OS
Number of patients with event (%)153 (56.0%)201 (73.1%)
Median in months (95% CI)28.6 (22.1, 38.0)16.5 (14.5, 20.0)
Hazard ratio (95% CI)0.60 (0.49, 0.74)
PFS
Number of patients with event (%)157 (57.5)198 (72.0)
Median in months (95% CI)10.4 (9.7, 12.3)8.2 (6.3, 8.5)
Hazard ratio (95% CI)0.62 (0.50, 0.77)
p-Value §< 0.0001
Objective Response Rate
ORR (95% CI)68% (62, 74)50% (44, 56)
Complete response rate23%13%
Partial response rate45%37%
Duration of Response
Median in months (range)18.0 (1.3+, 24.2+)10.4 (1.5+, 22.0+)
Figure 24: Kaplan-Meier Curve for Overall Survival in KEYNOTE-826 (CPS ≥1)* ,
*
Treatment arms include KEYTRUDA plus chemotherapy, with or without bevacizumab, versus placebo plus chemotherapy, with or without bevacizumab.
Based on the protocol-specified final OS analysis

Figure 24
(click image for full-size original)

Previously Treated Recurrent or Metastatic Cervical Cancer

The efficacy of KEYTRUDA was investigated in 98 patients with recurrent or metastatic cervical cancer enrolled in a single cohort (Cohort E) in KEYNOTE-158 (NCT02628067), a multicenter, non-randomized, open-label, multi-cohort trial. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression. Patients with initial radiographic disease progression could receive additional doses of treatment during confirmation of progression unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Patients without disease progression could be treated for up to 24 months. Assessment of tumor status was performed every 9 weeks for the first 12 months, and every 12 weeks thereafter. The major efficacy outcome measures were ORR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR, and DoR.

Among the 98 patients in Cohort E, 77 (79%) had tumors that expressed PD-L1 with a CPS ≥ 1 and received at least one line of chemotherapy in the metastatic setting. PD-L1 status was determined using the IHC 22C3 pharmDx kit. The baseline characteristics of these 77 patients were: median age of 45 years (range: 27 to 75); 81% White, 14% Asian, and 3% Black; 32% ECOG PS of 0 and 68% ECOG PS of 1; 92% had squamous cell carcinoma, 6% adenocarcinoma, and 1% adenosquamous histology; 95% had M1 disease and 5% had recurrent disease; and 35% had one and 65% had two or more prior lines of therapy in the recurrent or metastatic setting.

No responses were observed in patients whose tumors did not have PD-L1 expression (CPS <1). Efficacy results are summarized in Table 88 for patients with PD-L1 expression (CPS ≥1).

Table 88: Efficacy Results in Patients with Recurrent or Metastatic Cervical Cancer (CPS ≥1) in KEYNOTE-158
EndpointKEYTRUDA200 mg every 3 weeksn=77*
+ Denotes ongoing responseNR = not reached
*
Median follow-up time of 11.7 months (range 0.6 to 22.7 months)
Based on patients (n=11) with a response by independent review
Objective Response Rate
ORR (95% CI)14.3% (7.4, 24.1)
Complete response rate2.6%
Partial response rate11.7%
Duration of Response
Median in months (range)NR (4.1, 18.6+)
% with duration ≥6 months91%

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