Isabelle Ray-Coquard, MD, PhD:
At ESMO 2023, we saw data presented for the phase III AtTEnd trial evaluating atezolizumab, a PD‑L1 inhibitor, together with the standard of care of carboplatin with paclitaxel followed by atezolizumab maintenance until disease progression vs carboplatin with paclitaxel alone followed by placebo maintenance in patients with newly diagnosed or recurrent endometrial cancer (N = 671).²⁸ The coprimary endpoints of the study were improving PFS per RECIST v1.1 in the MSI-H/dMMR and the ITT population, and OS.

Isabelle Ray-Coquard, MD, PhD:
Regarding baseline patient characteristics, the 2 arms were relatively well balanced. Approximately 25% of patients had a dMMR status, most (>60%) in either arm had recurrent disease, and 70% to 80% had received previous chemotherapy. It is important to note that this trial included carcinosarcoma, clear‑cell carcinoma, and undifferentiated tumor histologies. In this trial, approximately 20% of patients in either arm were of Asian descent and 75% to 80% were White. In addition, approximately 24% in either arm was PD‑L1 positive and approximately 30% had RAD1 gene loss.

Isabelle Ray-Coquard, MD, PhD:
After a median follow-up of 26.2 months, we saw a significantly prolonged median PFS with addition of atezolizumab vs placebo in the dMMR group of NE (95% CI: 12.3-NE) vs 6.9 months (95% CI: 6.2-9.0; HR: 0.36; P = .0005) and the all-comer groups (10.1 vs 8.9 months; HR: 0.74; P = .0219).

Isabelle Ray-Coquard, MD, PhD:
There also was significantly prolonged median OS with the addition of atezolizumab to carboplatin with paclitaxel compared with placebo in the dMMR population (NE vs 25.7 months; HR: 0.41). In the all-comer population, the coprimary endpoint of OS was improved by 8.5 months (38.7 vs 30.2 months; HR: 0.82; P = .0483). Of note, the data are not yet mature, with only 43% of events to date.

Isabelle Ray-Coquard, MD, PhD:
By contrast, median PFS in the pMMR population was not substantially different compared with placebo (9.5 vs 9.2 months; HR: 0.92). Here again there was no noticeable benefit in OS with the addition of atezolizumab compared with placebo in the pMMR population (31.5 vs 28.6 months; HR: 1.0).

Isabelle Ray-Coquard, MD, PhD:
Looking into the response rates and the DoR, the results were clearly in favor of atezolizumab vs placebo in the dMMR population for both response (82.4% vs 75.7%) and median DoR was NE vs 4.9 months (HR: 0.27).

Results were not much different in the pMMR population.

Isabelle Ray-Coquard, MD, PhD:
Looking at the AE profile, there were no new safety signals and AEs were in line with what is expected with a PD‑L1 inhibitor. Most frequent grade >3 AEs for the atezolizumab-containing arm vs control were neutropenia (39.9% vs 38.9%), anemia (40.7% vs 35.1%), and thrombocytopenia (28.4% vs 27.0%). There was 1 death reported for each treatment arm which were attributed to pneumonia related to treatment as assessed by the investigator.

Isabelle Ray-Coquard, MD, PhD:
The second study in endometrial cancer that I would like to highlight from ESMO 2023 was reported by Westin and colleagues. The phase III DUO‑E trial explored the addition of durvalumab to carboplatin with paclitaxel followed by durvalumab with or without olaparib as maintenance in patients with newly diagnosed, previously untreated stage III/IV or recurrent endometrial cancer (N = 718). The primary endpoint was PFS by RECIST v1.1 in durvalumab with or without olaparib vs the control arm.^29,30

Isabelle Ray-Coquard, MD, PhD:
Looking at PFS in the ITT population, we saw a meaningful and clinically significant improvement in median PFS for the durvalumab arm (10.2 vs 9.6 months; HR: 0.71; P = .003) and durvalumab plus olaparib arm (15.1 vs 9.6 months; HR: 0.55; P <.0001) compared with the control arm. Of importance, the observed PFS benefit was seen across most patient subgroup analyzed in the durvalumab arm and durvalumab plus placebo arm when compared with the control arm.

Isabelle Ray-Coquard, MD, PhD:
When looking at the PFS data based on mismatch repair status, we saw that those in the dMMR population (20%) experienced similar benefit regardless of whether they were receiving durvalumab or durvalumab plus olaparib compared with placebo (HR: 0.42 vs 0.41). By contrast, in the pMMR population (80%) there appears to be increased benefit for those receiving dual maintenance with durvalumab plus olaparib vs durvalumab alone (HR: 77) and compared with the control arm (HR: 0.57).

Isabelle Ray-Coquard, MD, PhD:
Looking at data based on PD-L1 status ≥1% (69% of the population), there was increased benefit in PFS with dual maintenance of durvalumab plus olaparib and durvalumab alone vs the control arm (HR: 0.42 and 0.63, respectively). By contrast, in patients with tumor area positivity <1% (31% of the population), no clear benefit was seen between patients who received durvalumab alone or durvalumab plus olaparib maintenance vs placebo (HR: 0.89 and 0.80, respectively).

Isabelle Ray-Coquard, MD, PhD:
After a median follow-up of 18.6 months, OS data remain immature, with only 27% of OS events reported to date, but there was a trend favoring durvalumab plus olaparib maintenance compared with durvalumab maintenance or the control arm (HR: 0.59 and 0.77, respectively). However, there was a modest increase in incidence of AEs, and in the maintenance phase, approximately 11% of patients discontinued olaparib and 5% discontinued durvalumab. In total, 14% discontinued study treatment because of any immune-related AEs during the maintenance phase.

Isabelle Ray-Coquard, MD, PhD:
As expected, durvalumab plus olaparib maintenance led to slightly more grade ≥3 AEs (67.2% vs 54.9% vs 56.4%, respectively) and serious AEs (35.7% vs 31.1% vs 30.9%, respectively) compared with the durvalumab containing arm vs chemotherapy alone arms. However, a modest increase in the incidence of AEs was mostly acceptable and approximately 10% of patients discontinued olaparib in the maintenance phase, 5% discontinued durvalumab, and 14% in total had discontinued study treatment. And I think this is what we might expect for this treatment regimen.

Isabelle Ray-Coquard, MD, PhD:
Looking specifically at any-grade AEs observed in ≥20% of patients in each arm, most were very comparable between treatments. The most frequently reported AEs for the durvalumab plus olaparib arm compared with durvalumab alone maintenance or control arm, respectively, were anemia (62% vs 48% vs 54%), alopecia (51% vs 50% vs 50%), fatigue and asthenia (54% vs 43% vs 44%), nausea (55% vs 41% vs 44%), and neutropenia (42% vs 36% vs 42%).

Isabelle Ray-Coquard, MD, PhD:
Moving on to ovarian cancer, I presented the first results from the phase II BOUQUET trial exploring an innovative design for evaluating several therapies in a single trial for patients with rare epithelial ovarian cancers exhibiting resistance to the standard of care with platinum and/or nonhormonal systemic treatments (NCT04931342).³² In this study, patients underwent biomarker testing with the FoundationOne companion diagnostic platform, looking for biomarkers that could inform potential targeted treatments or combinations. At ESMO 2023, we presented results for an arm evaluating cobimetinib monotherapy and for another arm receiving atezolizumab plus bevacizumab. The primary endpoint of the study is confirmed ORR by the investigator.

Isabelle Ray-Coquard, MD, PhD:
In the cobimetinib arm, approximately 40%, 25%, 25%, 5%, and 5% of patients had low grade serous ovarian cancer, mucinous carcinoma, clear cell, carcinosarcoma, and mesonephric like adenocarcinoma, respectively. In the arm receiving atezolizumab plus bevacizumab, 71%, 14%, 9%, and 5% had low-grade serous ovarian cancer, clear cell, mucinous carcinoma, and carcinosarcoma, respectively.

The safety profile of the cobimetinib arm was encouraging. Grade 3/4 AEs were reported in 35% of patients, treatment-related serious AEs in 5% of patients, and AEs leading to dose reductions/interruptions in 35%/25% of patients.

Similarly, the safety profile of the atezolizumab plus bevacizumab also was encouraging. Grade 3/4 AEs were reported in 43% of patients, treatment-related serious AEs in 14% of patients, and AEs leading to treatment interruption/discontinuation in 33%/10% of patients.

Isabelle Ray-Coquard, MD, PhD:
When we look at the efficacy of cobimetinib in all evaluable patients (n = 21), confirmed ORR was 16%, the disease control rate was 42%, and the 6-month PFS rate was 41%. Responses were durable, and most patients experienced a DoR of >6 months. Of importance, we see promising activity in low‑grade serous ovarian cancer and mesonephric‑like adenocarcinoma, where the DoR was 90%.

Isabelle Ray-Coquard, MD, PhD:
By contrast, when looking at efficacy with atezolizumab and bevacizumab, the confirmed ORR was slightly lower at 14%, the disease control rate was 71%, and the 6-month PFS rate was 75%. What I find most interesting is that responses lasted more than 6 months in patients who have been deemed resistant to the current standard of care of platinum and nonhormonal systemic treatments.

Ana Oaknin, MD, PhD:
First, I would like to highlight data reported for the highly anticipated phase III KEYNOTE‑A18 trial of pembrolizumab with concurrent chemoradiotherapy (cCRT) vs cCRT alone in patients with newly diagnosed, high-risk, previously untreated, LACC (N = 1060).³³ The cCRT regimen consisted of 5 cycles (with an optional sixth dose) of weekly cisplatin 40 mg/m² with external-beam radiotherapy, followed by brachytherapy. High-risk disease was defined as having positive lymph node involvement, either pelvic or para‑aortic positive lymph nodes, or stage III and IVA disease. The experimental arm was adding pembrolizumab concurrently with chemoradiation, followed by pembrolizumab as maintenance for 15 cycles. The study coprimary endpoints were PFS per RECIST v1.1 (by investigator/histopathologic confirmation) and OS.

Ana Oaknin, MD, PhD:
KEYNOTE‑A18 enrollment was diverse, including White patients (~49%), Asian patients (~29%), multiple races (~15%), American Indian/Alaska native patients (~4%), and Black/African American patients (~2%). PD‑L1 status is important for interpreting studies evaluating immunotherapy in cervical cancer trials, and we saw that approximately 94% of the patients on either arm had tumor PD‑L1‒positive disease. Of note, the percentage of patients with positive lymph node involvement was 60%, which suggests a higher-risk population, and this is important for putting these results into context.

Ana Oaknin, MD, PhD:
When you look at the 24‑month PFS rate, it was 67.8% (61.8%-73.0%) vs 57.3% (51.2%-62.9%) with pembrolizumab with cCRT vs cCRT alone. I would like to emphasize that the median PFS has not yet been reached after a median follow-up of approximately 18 months, but we know that with immunotherapy these outcomes are likely to improve over time. PFS improvement was consistent across several subgroups analyzed, including age, race, International Federation of Gynecology and Obstetrics (FIGO) 2014 stage, performance status, and planned radiotherapy dose.

Ana Oaknin, MD, PhD:
A key outcome for the study is that the addition of pembrolizumab to cCRT did not jeopardize the standard of care of weekly cisplatin with radiotherapy. Discontinuation of any treatment because of immune-related AEs was low for pembrolizumab plus cCRT vs cCRT alone (2.3% vs 0.4%). Moreover, discontinuation of any treatment for all-cause AEs was comparable between treatment arms (17.4% vs 14.2%) and was discontinuation for treatment-related AEs (15.3% vs 12.6%) for the experimental arm compared with control.

Regarding specific AEs, the main concern was that addition of pembrolizumab to cCRT would increase the incidence of diarrhea, and that was not the case, with the incidence of diarrhea reported to be similar for pembrolizumab plus cCRT vs cCRT alone (50.4% vs 51.1%).

Ana Oaknin, MD, PhD:
During the ESMO 2023 congress and later highlighted at IGCS 2023, Professor Mary McCormack presented data from the international, multicenter phase III INTERLACE trial evaluating induction chemotherapy with weekly paclitaxel and carboplatin for 6 weeks followed by chemoradiotherapy (CRT) vs CRT alone in patients with newly diagnosed FIGO 2008 stage IB1N+, IB2, II, IIIB, IVA squamous, adeno, and adenosquamous LACC (N = 500).^34,35 The coprimary endpoints were PFS and OS.

Ana Oaknin, MD, PhD:
A key distinction between the INTERLACE trial and the KEYNOTE-A18 trial is the inclusion of a higher-risk subset in KEYNOTE-A18. In INTERLACE, the inclusion criteria also were for LACC, but not all patients had positive lymph nodes. For example, 57% and 58% of patients on the control and experimental arms were lymph node negative. Another key distinction was that the patient pool in KEYNOTE-A18 was more diverse than that of INTERLACE, where the majority of patients originated from the United Kingdom (76%) and Mexico (20%).

Ana Oaknin, MD, PhD:
Regarding efficacy outcomes, we can see that the INTERLACE trial met its coprimary endpoint of statistically improving PFS with induction chemotherapy followed by CRT vs CRT alone (5-year PFS: 73% vs 64%; HR: 0.65; P = .013).

Ana Oaknin, MD, PhD:
Although median OS has not been reached in either arm after a median follow-up of 64 months, we also see a positive trend in OS favoring the experimental arm (5-year OS: 80% vs 72%; HR: 0.61; P = .04).

Thus far, at ESMO 2023, we had 2 positive trials in the LACC space that I believe are going to change the current standard of care.

Ana Oaknin, MD, PhD:
Regarding patterns of recurrence, although the number of total local/pelvic relapses was comparable between the 2 treatment arms, the proportion of total distant relapses was much lower with induction chemotherapy plus CRT vs CRT alone (12% vs 20%).

Ana Oaknin, MD, PhD:
Unfortunately, despite recent advances, locally advanced disease often relapses and will require effective systemic therapy. I presented the results from the phase III BEATcc trial of the addition of atezolizumab to the standard of care of bevacizumab and platinum-based chemotherapy as first-line treatment for patients with persistent, recurrent, or metastatic cervical cancer who were not amenable for curative intent (N = 410).³⁶  Patients received treatment until disease progression or unacceptable toxicity. If patients achieved a complete response after ≥6 treatment cycles, they could stop chemotherapy and continue biological treatment alone (bevacizumab with or without atezolizumab). Crossover from the control arm to the experimental arm containing immunotherapy was not allowed. The coprimary endpoints of the study were PFS per RECIST v1.1 by the investigator and OS.

Ana Oaknin, MD, PhD:
Baseline characteristics in the study were consistent with what we typically see in the first-line recurrent/metastatic setting. In total, 21% to 23%, 73% to 74%, and 3% to 6% of the patients enrolled on this trial had metastatic, recurrent, or persistent disease, respectively, at study entry in either arm.

Ana Oaknin, MD, PhD:
After a median follow-up of approximately 32 months, we showed that the addition of atezolizumab to bevacizumab and chemotherapy improved median PFS compared with the standard-of-care arm (13.7 vs 10.4 months; HR: 0.62; P = .0001). PFS benefit in favor of the atezolizumab-containing arm was seen across most subgroups analyzed including age, disease status, chemotherapy backbone, previous chemoradiotherapy, and tumor histology.

Ana Oaknin, MD, PhD:
Regarding interim analyses for OS, we also showed improvement in median OS of approximately 10 months with the addition of atezolizumab to standard of care compared with standard of care alone (32.1 vs 22.8 months; HR: 0.68; P = .0046). Of note, when you look at OS at 24 months and 36 months, it was 61% vs 49% and 42% vs 26%, respectively, in favor of the experimental arm.

Here as well, OS benefit with atezolizumab was seen across most subgroups analyzed including age, disease status, chemotherapy backbone, previous chemoradiotherapy, and tumor histology.

Ana Oaknin, MD, PhD:
Regarding safety, we saw that the addition of atezolizumab did not lead to a significant increase in AEs compared with the standard-of-care arm. Overall incidence of grade ≥3 AEs was 79% vs 75% in the experimental vs control arm, respectively. When we look at the overall discontinuation rate because of AEs, it was 15% vs 16% in the atezolizumab arm compared with the control arm.

Ana Oaknin, MD, PhD:
Finally, we saw that the most frequent all-cause AEs with atezolizumab vs the experimental arm were very comparable including for peripheral/sensory neuropathy (54% vs 51%), asthenia (52% each), nausea (49% vs 48%), alopecia (43% vs 39%), and anemia (42% vs 37%). The exception was constipation (42% vs 34%), diarrhea (40% vs 26%), arthralgia (33% vs 20%), pyrexia (24% vs 11%), and rash (21% vs 9%) where the AEs with atezolizumab were slightly higher.

This is first‑line therapy for recurrent or metastatic disease, but what happens when the disease relapses after platinum‑based therapy with or without immunotherapy? Then we need to look for new options.

Ana Oaknin, MD, PhD:
At the ESMO 2023, Vergote and colleagues³⁷ presented the first interim analysis from the phase III innovaTV 301 trial evaluating tisotumab vedotin vs investigator’s choice of chemotherapy for patients with recurrent or metastatic cervical cancer who had experienced disease progression on or after platinum-doublet chemotherapy with or without bevacizumab (N = 502). The primary endpoint of the innovaTV 301 study is OS, with key secondary endpoints of PFS and ORR per investigator.

As you may recall, in the phase II innovaTV 204 tisotumab vedotin was shown to yield promising ORR and PFS in this patient population.³⁸

Ana Oaknin, MD, PhD:
The baseline characteristics for innovaTV 301 show that approximately 27% of patients had previously received immunotherapy. This is important to note because as we are moving immunotherapy use to earlier lines of treatment, either to locally advanced or first‑line therapy, we will find an unmet need for treatment in patients who relapse. In addition, approximately 60% and 40% of the patients had received 1 or 2 previous systemic therapies, respectively.

Ana Oaknin, MD, PhD:
When we look at the interim primary endpoint of OS, we see that tisotumab vedotin is superior to investigator’s choice of chemotherapy (HR: 0.70; P = .0038). In other words, patients who received tisotumab vedotin experienced a 30% reduction in the risk of death, which is remarkable.

Ana Oaknin, MD, PhD:
Similarly, when we look at the key secondary endpoint of PFS, it also was significant (HR: 0.67; P = .0001). The ORR was 17.8% vs 5.2% with tisotumab vedotin vs chemotherapy. Of note, 6 patients (2.4%) in the tisotumab vedotin arm achieved a complete response vs none with chemotherapy.

Ana Oaknin, MD, PhD:
Regarding the AEs of special interest with tisotumab vedotin—ocular toxicity, peripheral neuropathy, and bleeding—these were much more common with tisotumab vedotin, but most were grade 1/2. Grade ≥3 ocular events, events of peripheral neuropathy, and bleeding episodes were reported in 3.2%, 5.2%, and 0.8% of patients receiving tisotumab vedotin vs none in those receiving chemotherapy—but the bottom line is that innovaTV 301 was positive and showed an improvement in survival compared with chemotherapy.

But these AEs are expected and can be mitigated and managed with the mitigation and management plan with tisotumab vedotin.