Key Takeaways

• In patients with stage III-IV newly diagnosed or recurrent endometrial carcinoma or carcinosarcoma, addition of atezolizumab to carboplatin/paclitaxel followed by atezolizumab maintenance improves PFS and OS, particularly in those with dMMR status.
• The addition of durvalumab to carboplatin/paclitaxel followed by durvalumab with or without olaparib maintenance for newly diagnosed or recurrent/advanced endometrial cancer significantly improved median PFS and OS.
• Addition of pembrolizumab to concurrent chemoradiation vs concurrent chemoradiation alone for patients with locally advanced cervical cancer significantly improved PFS without jeopardizing the standard of care of weekly cisplatin and radiotherapy.

In this commentary, adapted from a discussion between Isabelle Ray-Coquard, MD, PhD, and Ana Oaknin, MD, PhD, the experts share their thoughts on key new clinical trial data presented at the 2023 ESMO Congress. Drs Ray-Coquard and Oaknin also share their opinion on how these results may potentially change current clinical practice.

Endometrial Cancer

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 followed by placebo maintenance in patients with newly diagnosed or recurrent endometrial cancer (N = 671). The coprimary endpoints of the study were improving progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in the microsatellite instability‒high (MSI-H)/mismatch repair deficient (dMMR) and the intention-to-treat population, and overall survival (OS).

After a median follow up of 28 months, we saw a significantly prolonged median PFS with addition of atezolizumab vs placebo in the dMMR (not estimable [NE] vs 6.9 months; HR: 0.36; P = .0005) and all-comer groups (10.1 vs 8.9 months; HR: 0.74; P = .0219). By contrast, median PFS in the mismatch repair proficient (pMMR) population was not substantially different compared with placebo (9.5 vs 9.2 months; HR: 0.92).

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. 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). Looking into the response rates and the duration of response (DoR), the results were clearly in favor of the dMMR population for both response (82.4% vs 75.7%) and DoR (median DoR: NE vs 4.9 months; HR: 0.27).

Dr Shannon Westin and colleagues reported data from the phase III DUO‑E trial exploring 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.

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. 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 also compared with the control arm (HR: 0.57 vs 0.77).

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 vs durvalumab alone vs the control arm vs placebo (HR: 0.42 vs 0.63). 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 vs 0.80).

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 vs 0.77).

However, there was a modest increase in incidence of adverse events (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 AE during the maintenance phase.

Ana Oaknin, MD, PhD:
Thank you for those wonderful summaries for endometrial cancer, Dr Ray-Coquard. What is clear for me now is that the treatment landscape for advanced endometrial cancer has evolved. I do not think paclitaxel with carboplatin alone will remain the standard of care for much longer. I have a question for you regarding the duration of atezolizumab maintenance in the AtTEnd trial. Given the positive PFS and OS results from the phase III RUBY and phase III NRG GY018 trials presented earlier at SGO 2023 and then ASCO 2023—2 trials of the addition of immunotherapy (dostarlimab or pembrolizumab, respectively) to the standard of care of paclitaxel with carboplatin and immunotherapy maintenance therapy limited to approximately 3 years for dostarlimab and 2 years for pembrolizumab—how do we interpret data from the AtTEnd trial where the duration of atezolizumab maintenance is until progression or unacceptable toxicity? Do you think that we should use maintenance until progression or toxicity, or should we just give maintenance for a fixed period of time?

Isabelle Ray-Coquard, MD, PhD:
I think all 3 trials give us the opportunity to explore several options. At this moment in time, it is not possible to make direct comparisons between the 3 trials. However, I do think that for patients with no residual disease and in complete response, it will be complex for both the physician and the patient to justify unlimited duration maintenance therapy. However, in patients with stable disease, I would likely be in favor of maintaining immunotherapy maintenance. 

Ana Oaknin, MD, PhD:
Dr Ray-Coquard, in the DUO‑E trial, which I believe is the first trial to report positive data for combining immunotherapy with a PARP inhibitor as maintenance therapy in advanced endometrial cancer, we saw PFS benefit for the combination in patients with pMMR status compared with the standard of care. Do you think that, pending regulatory approval, chemotherapy plus durvalumab followed by durvalumab and olaparib maintenance should become the new standard of care in patients with pMMR status?

Isabelle Ray-Coquard, MD, PhD:
The pMMR status in the DUO-E trial is a stratification factor. Also, pMMR is a negative biomarker, which means your tumor is not dMMR, and within this basket we could have many other variables, including P53 mutated, no specific molecular profile, estrogen receptor positive, or estrogen receptor negative. What we have seen in the phase II GINECO-UTOLA trial evaluating olaparib maintenance in platinum-sensitive advanced endometrial cancer is that P53 status and perhaps homologous recombination deficiency status may be important in the context of olaparib use. Thus, testing for those within the DUO-E trial may better inform what to do with patients who are pMMR in the future, and I am in favor of continuing to explore these variables in the pMMR population in the DUO-E trial.

Ovarian Cancer

Isabelle Ray-Coquard, MD, PhD:
In 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). 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 objective response rate (ORR) by the investigator.

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.

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%. 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.

Cervical Cancer

Ana Oaknin, MD, PhD:
Thank you for your answers, Dr Ray-Coquard. I would like to move on to talk about new key data presented for cervical cancer. 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, locally advanced cervical cancer (N = 1060). 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.

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 ≥1‒positive disease. Of note, the number 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.

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. OS is a coprimary endpoint of the study, and although data are immature at this time, there was a positive trend in favor of the experimental arm.

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 due to immune-related AEs was low for pembrolizumab plus cCRT vs cCRT alone (2.3% vs 0.4%). 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%).

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 cervical cancer (N = 500). The coprimary endpoints were PFS and OS. 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 locally advanced cervical cancer, 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%).

Regarding efficacy outcomes, we can see that the INTERLACE trial met its coprimary endpoint of statistically improving PFS (5-yr PFS: 73% vs 64%; HR: 0.65; P = .013). 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%).

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-yr OS: 80% vs 72%; HR: 0.61; P = .04).

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

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). 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 +/- 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.

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). 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.

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 due to AEs, it was 15% vs 16% in the atezolizumab arm compared with the control arm.

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.

At the 2023 ESMO conference, Professor Ignace Vergote and colleagues 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.

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. 

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. Similarly, when we look at the key secondary endpoint of PFS, it also was significant (HR: 0.67; P = .0001). The ORR rate was 17.8% vs 5.2% with tisotumab vedotin vs chemotherapy.

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.

Isabelle Ray-Coquard, MD, PhD:
Thank you very much for that summary, Dr Oaknin. My first question for you is in the relapse setting in cervical cancer. In Europe, we also have access to cemiplimab for disease that progressed on platinum‑based chemotherapy with or without bevacizumab. How would you sequence the available choices of the second-line treatment for recurrent/metastatic cervical cancer based on innovaTV 301 results?

Ana Oaknin, MD, PhD:
This is a very good question. The phase III EMPOWER-Cervical 1 trial evaluated cemiplimab in the recurrent/metastatic setting in patients who had not received previous immunotherapy. So, if the patient had received previous immunotherapy as part of the standard of care or on a clinical trial, the clear choice is to give tisotumab vedotin after progression. By contrast, in patients who have not received immunotherapy, I may consider cemiplimab because of the estimated long DoR, and then I would pursue tisotumab vedotin. Another consideration for using tisotumab vedotin first will be in those who need a rapid response because—as you know very well—immunotherapy may take longer to achieve that initial response.

Isabelle Ray-Coquard, MD, PhD:
Thank you. My second question to you, in the locally advanced setting, is how do you envision applying the data from both KEYNOTE-A18 and INTERLACE to define the best standard of care in that group of patients?

Ana Oaknin, MD, PhD:
As previously mentioned, INTERLACE had a lower-risk population compared with that of KEYNOTE‑A18. I think we still need more information from what is currently available for INTERLACE so that we can learn more about what happened specifically with the group of patients with positive lymph nodes. And what about those with lymph node‒negative disease, stage II, and stage Ib? These patients were enrolled on both trials, so then we need to see the subgroup results to better assess what the best approach will be.

I think that for daily practice, and pending regulatory approval, we should proceed with the KEYNOTE-A18 regimen until we get more clarity on the INTERLACE results. 

Your Thoughts?
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