Highlights in cervical cancer

In 2020, more than 600,000 new cases of cervical cancer were diagnosed. Its mortality rate reached 57 % with more than 340,000 deaths; cervical cancer was the ninth leading cause of cancer-related death worldwide and therefore a concerning global health issue.

In young women (aged 15 to 44 years), it is the second most common cancer and cause of cancer death [1]. So far, according to ESMO and NCCN guidelines, standard treatment for persistent, recurrent, or metastatic cervical cancer was a platinum-based chemotherapy [2, 3], the preferred regimen being platinum, paclitaxel and bevacizumab (in eligible patients) [4]. However, the immune checkpoint inhibitor (ICI) pembrolizumab has proven efficacy in the KEYNOTE-158 study as second-line monotherapy in patients previously treated for cervical cancer [5, 6].

Pembrolizumab plus chemo­therapy: survival benefit in 1L

The protocol-specified first interim analysis of the randomized, double-blind, phase III study KEYNOTE-826 (NCT03635567) was presented at this year’s virtual ESMO meeting [7]. This trial evaluated the benefit of adding the anti-PD-1 inhibitor pembrolizumab to a chemotherapy backbone (paclitaxel + cisplatin or carboplatin IV, Q3W for up to 6 cycles) with or without bevacizumab (15mg/kg IV, Q3W) for the first-line treatment of persistent, recurrent, or metastatic cervical cancer which was not curatively treatable. The dual primary endpoints were overall survival (OS) and progression-free survival (PFS) per RECIST v1.1 by investigator assessment; secondary endpoints enclosed objective response rate (ORR), duration of response (DoR), 12-month PFS and safety.

In both arms (pembrolizumab versus placebo), the median age of the study participants was approximately 50 years, with a majority of patients having squamous cell carcinoma (SCC) and around 30 % of them being in stage IVB at initial diagnosis. Overall, bevacizumab was used in more than 60 % of all patients during the study. Among the 617 patients randomized irrespectively of their PD-L1 status, a statistically significant improvement in the median PFS was reported for pembrolizumab versus placebo in the PD-L1 low combined positive score group (CPS ≥ 1; 10.4 vs 8.2 months; HR, 0.62; 95 % CI, 0.50-0.77; p<0.001), in the PD-L1 high-expressing group (CPS ≥ 10; 10.4 vs 8.1 months; HR, 0.58; 95 % CI, 0.44-0.77; p<0.001), as well as in the all-comer population (CPS ≥ 1; 10.4 vs 8.2 months; HR, 0.65; 95 % CI, 0.53-0.79; p<0.001). A PFS benefit was seen for all analyzed protocol-specified subgroups. Moreover, the pembrolizumab combination led similarly to a significantly longer median OS in the all-comer population (24.4 vs 16.5 months; HR, 0.67; 95 % CI, 0.54-0.84; p<0.001). Across subgroups defined by PD-L1 CPS, OS HRs were similar for pembrolizumab versus placebo in all comers (HR, 0.67), in those with PD-L1 CPS ≥1 (HR, 0.64) and in those with PD-L1 CPS ≥10 (HR, 0.61) (Figure 1). In the overall study population, the ORR was 65.9 % in the combination arm versus 50.8 % in the placebo arm, while the DoR reached 18.0 versus 10.4 months, respectively.

The quality of life, as assessed through the EuroQol EQ-5D-5L VAS questionnaire, showed that the time to deterioration (time from first EQ-5D-5L VAS assessment to first onset of a ≥10-point decrease in score from baseline with confirmation under the right censoring rule or death, whichever occurred first) improved in the pembrolizumab arm (proportion of patients without deterioration at 12-month, 58.2 with pembrolizumab vs 44.8 % with placebo).

In total, the incidence of grade ≥3 adverse events (AEs) reached 81.8 % in the investigational arm compared to 75.1 % in the placebo arm, the most frequent ones being anaemia (30.3 % in the pembrolizumab group vs 26.9 % in the placebo group) and neutropenia (12.4 % versus 9.7 %, respectively).

A clinically significant benefit of the combined therapy (pembrolizumab + chemotherapy) was observed, regardless of the addition of bevacizumab and of the PD-L1 status at initial diagnosis. The authors concluded that pembrolizumab plus chemotherapy (with or without bevacizumab) may be a new 1L standard option for women with persistent, recurrent, or metastatic cervical cancer. Based on the outcomes of the KEYNOTE-826 study, this combination therapy was approved by the US FDA in the first-line setting; this led thus to an accelerated approval of pembrolizumab monotherapy in the second-line setting. Both first- and second-line FDA approvals of pembrolizumab concerned only patients presenting with a PD-L1 CPS score of 1 or greater.

Figure 1: Overall survival in all-comer population (A) and in patients with high PD-L1 expression (CPS ≥10) (B)

Figure 1: Overall survival in all-comer population (A) and in patients with high PD-L1 expression (CPS ≥10) (B)

EMPOWER-Cervical 1: cemiplimab versus chemotherapy

After progression on standard first-line therapy (platinum-based chemotherapy ± bevacizumab), salvage chemotherapy does not result in survival benefit for patients with recurrent or metastatic cervical cancer [8-11]. EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 is an open-label, randomized, multicenter, phase III study (NCT03257267) evaluating the efficacy and safety of cemiplimab monotherapy versus investigator’s choice chemotherapy in this population in 2L or 3L setting. The preliminary results were presented at ESMO 2021 meeting [6]. In total, 608 patients with recurrent or metastatic cervical cancer who progressed after 1L treatment were randomized (1:1) regardless of PD-L1 expression to receive either cemiplimab (350 mg IV, Q3W) or a chemotherapy regimen up to 96 weeks.

At baseline, the median age of the patients was 51 years, most of them were less than 65 years old and presented with a metastatic disease. At the interim analysis, the median OS – the primary endpoint – for the overall population was superior in the cemiplimab arm compared to the chemotherapy arm (12.0 vs 8.5 months; HR, 0.69; 95 % CI, 0.56-0.84; p=0.00011). In the SCC population, a similar advantage was observed for the investigational group (11.1 vs 8.8 months; HR, 0.73; 95 % CI, 0.58-0.91; p=0.00306), whereas the adenocarcinoma group seemed to benefit the most from this anti-PD-1 therapy (13.3 vs 7.0 months; HR, 0.56; 95 % CI, 0.36-0.85; p<0.005). In all analyzed prespecified subgroups, OS data favored cemiplimab. Although patients with PD-L1 expression ≥1 % showed a larger OS benefit, patients with PD-L1 <1 % profited from the ICI therapy too. ORR benefit was observed in the overall and adenocarcinoma population, regardless of PD-L1 status.

Concerning the quality of life of the study patients, patients who received cemiplimab improved or maintained their global health status from baseline compared to those who were treated by chemotherapy.

Most common grade ≥3 treatment-emergent adverse events (TEAEs) for ­cemiplimab versus chemotherapy were anemia (12.0 vs. 26.9 %), asthenia (2.3 vs. 1.0 %), fatigue (1.3 vs. 1.4 %) and neutropenia (1.0 vs. 9.0 %). Discontinuation due to grade ≥3 TEAEs occurred in 6.7 % (cemiplimab) and 3.8 % (chemotherapy) of patients.

Cemiplimab showed a favorable toxicity profile and an OS superiority versus chemotherapy for the treatment of patients with recurrent or metastatic cervical cancer regardless of the PD-L1 expression. Although it is not yet approved for the treatment of cervical cancer, the PDUFA date for cemiplimab in this setting is set for end of January 2022.

Balstilimab (anti-PD-1) combined to zalifrelimab (anti-CTLA-4)

The second-line treatment of recurrent or metastatic cervical cancer is still very challenging. In many malignant solid entities, the combination of PD-1 and CTLA-4 inhibitors has proven to be efficient. The aim of the global phase II study C-550 (NCT03495882) was to evaluate the efficacy and safety of the dual blockade of balstilimab – an anti-PD-1 agent – and zalifrelimab – an CTLA-4 inhibitor. While the preliminary results were shown at last year’s ESMO meeting [12], Dr. O’Malley presented the final data at ESMO 2021 [13]. Eligible patients had a measurable disease, a good ECOG performance status (0-1) and a histologically confirmed SCC, adenosquamous carcinoma or adenocarcinoma of the cervix which relapsed after platinum-based treatment. The 155 enrolled patients were administered balstilimab (3 mg/kg, Q2W) and zalifrelimab (1 mg/kg, Q6 W) for up to 24 months. The primary endpoint was ORR by RECIST v1.1 per independent review committee, while the DoR, PFS and OS were secondarily analyzed.

The patients had a median age of 50 years (24-76) and presented predominantly with SCC tumor histology (70.3 % of patients). At this final analysis, the ORR reached 25.6 %, with ten complete responses (CRs) and 22 partial responses (PRs) (Figure 2); the ORR was 32.8 % among PD-L1-positive patients and 9.1 % in the PD-L1-negative group. The median DoR was not reached, whereas the 6-month DoR was 86.5 % and the 12-month DoR 64.2 %. After a median duration of follow-up of 21 months, the median PFS was 2.7 months (95 % CI, 1.5-3.7) and the median OS 12.8 months (95 % CI, 8.8-17.6). Moreover, in the PD-L1 expressing population, the median OS reached 15.7 months (95 % CI, 7.6-21.1).

No new safety signals were identified with this combined therapy. Overall, 31 patients (20.0 %) experienced grade ≥3 TEAEs, most frequently ALT elevation (2.6 %) and diarrhea (1.9 %). Treatment discontinuations due to a TEAE occurred in 19 pts (12.3 %). In total, 69 patients (44.5 %) had immune-related AEs (irAEs) any grade, most commonly hypothyroidism (14.2 %), hyperthyroidism or diarrhea (each 7.1 %), and pruritus (4.5 %).

Balstilimab plus zalifrelimab exhibited a durable efficacy and a manageable tolerability in the largest study to date investigating this dual combination in recurrent or metastatic cervical cancer. Thus, this new regimen constitutes a novel promising 2L therapeutic option for those pretreated patients.

Figure 2: Waterfall plot of the C-550 study according to PD-L1 expression

Figure 2: Waterfall plot of the C-550 study according to PD-L1 expression

Efficacy of tisotumab vedotin in several clinical settings

Tisotumab vedotin, an antibody drug conjugate that targets tissue factor, is currently under development for the treatment of a broad range of solid tumors [14]; it already showed an antitumoral activity and a manageable safety profile in a pivotal, single-arm, phase II trial in patients with pretreated recurrent or metastatic cervical cancer, a patient collective presenting an unmet need for efficient therapies [15]. The first data regarding the combination of tisotumab vedotin with pembrolizumab, carboplatin, and bevacizumab in this population have already been shown at the IGCS 2021 meeting [16]; Dr. Vergote presented the outcomes of two further cohorts (1L tisotumab vedotin + carboplatin and 2L/3L tisotumab vedotin + pembrolizumab) at this year’s ESMO 2021 [17].

The design of the multicohort phase Ib/II trial ENGOT-cx8/GOG-3024/innovaTV 205 (NCT03786081) evaluating the efficacy and safety of both dose expansion cohorts with tisotumab vedotin is described in Figure 3. The primary endpoint was the ORR per RECIST v1.1, while the secondary endpoints included safety, DoR, time to response, PFS and OS. At the time of the study enrollment, the median age of patients was 51.0 years for tisotumab vedotin plus carboplatin versus 47.0 years in the tisotumab vedotin plus pembrolizumab arm; most of the patients presented with a squamous tumor histology.

For the first-line therapy (tisotumab vedotin + carboplatin), the confirmed response rate (ORR) was 55 % (95 % CI, 36-72), including four CRs and 14 PRs. The median DoR was 8.3 months (95 % CI, 42-NR); the median PFS was 9.5 months (95 % CI, 4.0-NR) and the median OS has not yet been reached. In this study group, grade ≥3 AEs related to tisotumab vedotin occurred in 57.6 % of patients and serious AEs (SAEs) related to the investigational drug were reported in 15.2 % of them.

In pretreated patients who received tisotumab vedotin plus pembrolizumab as second- or third-line treatment, the ORR reached 38 % (95 % CI, 22-56, including 2 CRs and 11 PRs), while the median DoR was 13.8 months (95 % CI, 2.8-NR), the median PFS 5.6 months (95 % CI, 2.7-13.7) and the median OS not available so far. Overall, 45.7 % of patients experienced grade ≥3 AEs related to tisotumab vedotin and 14.3 % of them SAEs associated with the investigational drug.

Despite the small sample size of the study groups in this early-phase clinical trial, both arms (1L and 2L/3L) showed promising and durable antitumoral activity, with an acceptable safety profile. A ­further dose expansion cohort of tisotumab vedotin plus pembrolizumab as first-line treatment of recurrent or metastatic cervical cancer is currently ­under evaluation. In the second- or third-line of treatment, ­tisotumab monotherapy was approved shortly before pembrolizumab; to note, the use of tisotumab is not biomarker-restricted.

Figure 3: Stiudy design of the ENGOTcx8/GOG 3024 innovaTV 205 trail

Figure 3: Stiudy design of the ENGOTcx8/GOG 3024 innovaTV 205 trail


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Preface – ESMO 2021 Yelena Y. Janjigian, MD Memorial Sloan Kettering Cance