CME
Physicians: Maximum of 1.50 AMA PRA Category 1 Credits™
Released: December 13, 2023
Expiration: December 12, 2024
Dostarlimab + CT in Primary Advanced or Recurrent EC (ENGOT-EN6/GOG-3031/RUBY): Study Design
David Scott Miller, MD, FACOG, FACS:
At SGO 2023, Mirza and colleagues1 reported data from the randomized phase III ENGOT-EN6/GOG-3031/RUBY trial evaluating carboplatin and paclitaxel with or without dostarlimab followed by dostarlimab or placebo maintenance, respectively, for 3 years in patients with primary advanced or recurrent endometrial cancer. The coprimary endpoints of the study were progression-free survival (PFS) by investigator and overall survival (OS).
ENGOT-EN6/GOG-3031/RUBY: PFS in Overall Population (Primary Endpoint)
David Scott Miller, MD, FACOG, FACS:
Data presented at SGO 2023 for the RUBY trial showed that the primary endpoint of PFS was met. Addition of dostarlimab to standard-of-care carboplatin and paclitaxel yielded a clinically significant 2-year PFS rate improvement for the dostarlimab arm vs the chemotherapy-alone arm in the overall population (36% vs 18%; HR: 0.64; P <.001).
ENGOT-EN6/GOG-3031/RUBY: PFS in dMMR/MSI-H (Primary Endpoint) and pMMR/MSS
David Scott Miller, MD, FACOG, FACS:
In addition, in the deficient mismatch repair (dMMR)/microsatellite instability–high (MSI-H) population, a robust benefit was noted (HR: 0.28; range: 0.16-0.50; P <.001) and. to a lesser extent, in the proficient mismatch repair (pMMR)/microsatellite stable (MSS) population (HR: 0.76; range: 0.59-0.98). Two-year PFS rates were also improved.
ENGOT-EN6/GOG-3031/RUBY: OS in Overall Population
David Scott Miller, MD, FACOG, FACS:
Data presented for OS also was similarly impressive, with a median OS not reached for the arm containing dostarlimab compared with placebo, with a favorable trend suggesting significant benefit after 2.5 years (HR: 0.64; P <.0021).
ENGOT-EN6/GOG-3031/RUBY: OS in dMMR/MSI-H (Primary Endpoint) and pMMR/MSS
David Scott Miller, MD, FACOG, FACS:
As previously seen with the overall population, we also saw benefit with dostarlimab in the dMMR/MSI-H population (HR: 0.30; range: 0.13-0.70) and in the pMMR/MSS population (HR: 0.73; range: 0.52-1.02) compared with placebo.
Of note, overall response rates (ORR) were also improved in the dostarlimab-containing arm vs the placebo arm (77.6% vs 69.0% in the dMMR/MSI-H population and 68.1% vs 63.4% in the pMMR/MSS population). Median duration of response (DoR) was not evaluable (NE) (95% CI: 10.1-NE) with dostarlimab vs 5.4 months (95% CI: 3.9-8.1) with placebo in the dMMR/MSI-H population, and 8.6 months (95% CI: 6.9-13.1) vs 6.3 months (95% CI: 4.4-6.8) with placebo in the pMMR/MSS population, respectively.
ENGOT-EN6/GOG-3031/RUBY: Safety Summary
David Scott Miller, MD, FACOG, FACS:
All patients experienced treatment-emergent adverse events (AEs) in both arms. As we would expect, immunotherapy-related AEs were more frequent in the dostarlimab-containing arm (39%) than in the placebo arm (15%). In addition, treatment-emergent AEs leading to discontinuation of dostarlimab were seen in 17% of patients compared with 9% of patients discontinuing placebo.
It is important to note that treatment with dostarlimab did not result in a substantially different rate of discontinuation for carboplatin (10% vs 8%) or paclitaxel (10% vs 9%) when compared with placebo.
ENGOT-EN6/GOG-3031/RUBY: TEAEs in ≥20% in Either Arm
David Scott Miller, MD, FACOG, FACS:
Overall, treatment-emergent AEs in 20% of patients or more were very comparable between arms.
ENGOT-EN6/GOG-3031/RUBY: PFS by INV and BICR in dMMR/MSI-H Population
Nicoletta Colombo, MD, PhD:
Later at ASCO 2023, Powell and colleagues2 reported analyses by blinded independent central review and showed that the HRs for PFS mirror those per investigator assessment in the dMMR/MSI-H population (HR: 0.28 vs 0.29) and the overall population (HR: 0.64 vs 0.66), confirming the a consistent benefit of adding dostarlimab to standard frontline platinum-based chemotherapy and/or maintenance for patients with primary advanced or recurrent endometrial cancer.
ENGOT-EN6/GOG-3031/RUBY: HRQoL/PROs
Nicoletta Colombo, MD, PhD:
Also at ASCO, Mirza and colleagues3 reported the quality-of-life assessment among the 494 patients enrolled on the RUBY study.1 The results from European Organization for the Research and Treatment of Cancer Quality of Life Questionnaires (QLQ-C30 and QLQ-EN24) were prespecified secondary endpoints, and the investigators reported the assessment for cycle 7 at the end of chemotherapy and cycle 13 at the end of 1 year of study. Looking at the patient-reported outcomes (PROs), they were similar for dostarlimab plus standard-of-care chemotherapy and placebo plus standard-of-care chemotherapy throughout the chemotherapy treatment period. Moreover, no differences were observed across the 3-year period between the 2 treatment arms.
ENGOT-EN6/GOG-3031/RUBY: PROs on Pain, Fatigue, and Back and Pelvis Pain
Nicoletta Colombo, MD, PhD:
Of importance, significant differences in PROs were seen in favor of dostarlimab compared with chemotherapy at the start of cycle 7 in the dMMR population, with reduction in pain and back and pelvis pain reported by patients. On the other hand, there was deterioration in global quality of life, social functioning, and body image, as well as change in taste, for patients on the placebo plus chemotherapy arm compared with the dostarlimab-containing arm.
Carboplatin + Paclitaxel ± Pembrolizumab as Frontline Treatment for Patients With EC (NRG GY018): Study Design
David Scott Miller, MD, FACOG, FACS:
The NRG GY018 trial presented at SGO 2023 by Eskander and colleagues4 is also an ongoing randomized phase III study evaluating carboplatin and paclitaxel with or without pembrolizumab followed by pembrolizumab or placebo maintenance, respectively, for 2 years in patients with measurable stage III/IVA, stage IVB, or recurrent endometrial cancer (NCT03914612). The primary endpoint is PFS per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by investigator in pMMR and dMMR patient populations.
NRG GY018: PFS (per RECIST v1.1) in dMMR and pMMR Cohorts
David Scott Miller, MD, FACOG, FACS:
Similar to the RUBY trial, in the NRG GY018 trial the primary endpoint of PFS per RECIST v1.1 by the investigator in the pMMR and dMMR population was met.
Here we saw a clinically significant improvement in median PFS for the pembrolizumab-containing arm vs chemotherapy-alone arm for the dMMR cohort (not reached vs 7.6 months; HR: 0.30; P <.001) and the pMMR cohort (13.1 vs 8.7 months; HR: 0.54; P <.001). Of note, the benefit in PFS with the addition of pembrolizumab to carboplatin and paclitaxel was seen across most of the subgroups analyzed in both the dMMR and pMMR cohorts.
NRG GY018: NRG GY018 AEs in ≥15% of Patients
David Scott Miller, MD, FACOG, FACS:
The most common AEs reported in at least 15% of patients included fatigue, peripheral sensory neuropathy, anemia, nausea, constipation, diarrhea, and thrombocytopenia. In all, most of these were comparable between treatment arms.
Although data are not shown here, we saw that the addition of an immunotherapy agent did somewhat increase the rate of grade ≥3 any-grade AEs for approximately 10% to 15%, but it was not prohibitive.
NRG GY018: AEs of Interest in dMMR and pMMR Cohorts
David Scott Miller, MD, FACOG, FACS:
When we look at AEs of special interest within the dMMR and pMMR cohorts, they are very comparable. However, we do see more incidence of immune-related AEs in the arm containing pembrolizumab, for instance there was more grade 1/2 hypothyroidism (12.8% vs 9.4%), hyperthyroidism (9.2% vs 0.9%), colitis (6.4% vs 0%), and pneumonitis (2.8% vs 1.9%) for those in the pembrolizumab-containing arm vs placebo-containing arm and dMMR status. Similar findings were also seen for the pMMR cohort, with grade 1/2 hypothyroidism (13.4% vs 2.6%), hyperthyroidism (5.8% vs 3.6%), and acute kidney injury (1.8% vs 0.4%) and adrenal insufficiency (1.4% vs 0.4%) being the most common.
Takeaways For Studies Adding Immunotherapy to Standard of Care Platinum Chemotherapy in Advanced/Recurrent Endometrial Cancer
Linda Duska, MD, MPH:
Dr Miller, I have a couple of questions for you about these 2 practice-changing results initially presented at SGO 2023.
Do you think we should be changing our practice based on the results presented for the RUBY trial and the NRG GY018 trial?
David Scott Miller, MD, FACOG, FACS:
Yes, I do think so, and a few months after the presentation at SGO 2023 and later updates at ASCO 2023, the FDA approved dostarlimab plus chemotherapy, followed by single-agent dostarlimab for adult with primary advanced or recurrent endometrial cancer that is dMMR, as determined by an FDA-approved test, or MSI-H based on findings from the interim analysis of the first part of RUBY.5
One of the differences between the RUBY trial vs the NRG GY018 trial was the inclusion of patients with carcinosarcoma, which accounted for approximately 10% of patients in RUBY. Patients with serous and clear cell disease were included in both RUBY and NRG GY018 trials. But overall, both studies were positive and met their primary endpoints and I believe they are practice changing.
Linda Duska, MD, MPH:
I agree with you, Dr. Miller. I have a follow-up question for you based on the results from both of these positive studies. How do you think we should proceed in patients with pMMR status?
David Scott Miller, MD, FACOG, FACS:
Well, that is the big question, and we are already trying to address this in my own group: If you have patients who are receiving frontline carboplatin and paclitaxel for advanced pMMR endometrial cancer, do you add PD-1 inhibitor? I can tell you that our main impetus to do that is if we have a patient who is not responding to that initial therapy or has a stable disease. In that scenario, we have been adding pembrolizumab. But I think that with the strength of these new data and publications, we will be able to offer this to more of our patients who qualify for it.
This approach does leave us with a couple of unanswered questions. For example, what are we going to do in that smaller group of patients who experience disease progression? As of December 2023, I do not think we have an answer for that yet.
Linda Duska, MD, MPH:
Indeed. Our second-line therapy for relapsed patients is a single-agent immune checkpoint inhibitor (dostarlimab or pembrolizumab) for those whose disease has dMMR/MSI-H status and pembrolizumab plus lenvatinib in pMMR/MSS. I am curious, as we continue to move checkpoint inhibitors into the frontline setting, what are we going to offer in the second line? Do you have any thoughts on that?
David Scott Miller, MD, FACOG, FACS:
One thing we thought about is that we could use dostarlimab in our first-line therapy, and then if the patient does experience progression, and we want to return to an immune checkpoint inhibitor, we can use a different one, for example, pembrolizumab with or without lenvatinib, depending on the mismatch repair status. But I agree with you. We currently have no data for the use of immune checkpoint therapy in the second line after immune checkpoint therapy in the frontline. In other words, we do not yet know if immune checkpoint therapy will be an effective therapy a second time.
Linda Duska, MD, MPH:
In a patient with dMMR/MSI-H status, how would you choose between the RUBY regimen with dostarlimab and the NRG GY018 with pembrolizumab or other experimental immunotherapies in development?
David Scott Miller, MD, FACOG, FACS:
As previously mentioned, dostarlimab addition to standard-of-care carboplatin and paclitaxel has received FDA approval, and because of these new data in the frontline setting for dMMR/MSI-H, I think we will be able to make some progress and offer this regimen to patients. And as stated before, I would be inclined to start with dostarlimab in anticipation of what might be happening with second-line therapy because we do not have a pembrolizumab plus lenvatinib equivalent with dostarlimab in the second line setting.
Nicoletta Colombo, MD, PhD:
My takeaway from the RUBY results presented at SGO 2023 and later at ASCO 2023 is that the addition of dostarlimab to standard-of-care platinum-based chemotherapy significantly improved PFS while maintaining or improving quality of life, further supporting this regimen as the new standard of care in patients with recurrent and advanced endometrial cancer.
Going forward, affordability and drug access are among the most critical issues to address when it comes to regions with the highest incidence of these cancers. Companies sponsoring these trials should put in place several strategies to help these patients, for example, individual-based timely access programs and clinical trials. I for one think access to these novel therapies remains a major challenge in developing countries.
Data for Locally-Advanced Cervical Cancer Presented at SGO 2023
Linda Duska, MD, MPH:
As in endometrial cancer, there is much interest in evaluating immunotherapy earlier during the course of treatment for patients with locally advanced cervical cancer (LACC). Of importance, there also continues to be an unmet need in this area. We are certainly doing better with the addition of cisplatin to chemoradiotherapy, but we are just not quite there. I think the prevention of cervix cancer is key.
Two of the abstracts presented at SGO 2023 for LACC examined the question of sequencing of immunotherapy with chemoradiation in the upfront setting. We know that in the CALLA trial,6 the combination of the PD-L1 inhibitor durvalumab concurrent with chemoradiation, followed by durvalumab maintenance failed to meet the prespecified endpoint of PFS. It remains unclear to me why that happened. One hypothesis was that maybe adding immunotherapy to the chemoradiation therapy might adversely affect the overall immunogenic outcome.
Of the 2 studies of interest from SGO 2023 for early cervix cancer, the first was presented by Zamarin and colleagues of Memorial Sloan Kettering Cancer Center and I presented the other one.
Phase I NRG-GY017: Atezolizumab Before and/or With Chemoradiotherapy in High-Risk LACC
Linda Duska, MD, MPH:
Zamarin and colleagues7 reported on a phase I NRG GY017 study evaluating 3 total doses of atezolizumab given with chemoradiotherapy (CRT) to patients with high-risk LACC (NCT03738228; n = 36). In arm A, a priming dose was given before and 2 doses given concurrently with CRT, and in arm B, they received the same 3 doses but during CRT. The primary endpoint of the study was identifying biologic parameters that could predict long-term outcomes and determining whether such parameters could help understand the impact of CRT on immune response and immunotherapy plus CRT sequencing.
Phase I NRG-GY017: Pathologic Response and PFS
Linda Duska, MD, MPH:
The PFS rate at 26 months was 79% in arm A and 59% in arm B. It is important to note that this study was not powered to show a difference in PFS or OS. The only thing we can say about this data is that giving the priming dose did not adversely affect these survival outcomes.
Phase I NRG-GY017: T-Cell Clonal Expansion
Linda Duska, MD, MPH:
I think the most interesting outcome from this study was that the priming dose appeared to lead to an early systemic expansion of tumor-associated T-cell clones, which suggests an early systemic tumor-specific immune response. Of note, this was not seen in arm B;, and in arm B, there appeared to be a tumor-associated T-cell clone contraction. Those findings are hypothesis generating and can potentially help us in study design as we continue to explore the idea of moving immunotherapy into the frontline for LACC.
Chemoradiation + Pembrolizumab for Locally Advanced Cervical Cancer: Study Design
Linda Duska, MD, MPH:
At SGO 2023, I presented data from a randomized phase II trial of pembrolizumab during CRT or after CRT in patients with high-risk LACC (NCT02635360; n = 96).8 The primary endpoint for the study was change as a function of intervention in the ratio of CD8-positive T-cells divided by T-regulatory cells. Similar to the NRG GY017 study, we conducted multiple tissue biopsies and multiple blood biopsies. We also included data on PD-L1 staining and looked at PET scan response.
Phase II of CRT + Pembrolizumab: Change Over Time in Tissue CD8+ T-Cell/Treg Ratio (Primary Endpoint)
Linda Duska, MD, MPH:
However, we did see different patterns of change in E7 peptide in peripheral blood, and we saw increases in all of E7 and one E6 response only if pembrolizumab was given during CRT.
Phase II of CRT + Pembrolizumab: Immune Cell Profiling
Linda Duska, MD, MPH:
Similar to the NRG GY017 study, we also saw both sequences altered multiple immune cell populations and ongoing work is continuing to explore that finding.
Takeaways From SGO Studies Adding Immunotherapy to CRT in High-Risk LACC
David Scott Miller, MD, FACOG, FACS:
Your summaries on the immune therapy for cervix cancer were very interesting. I do recall that, a decade or so ago, we used to hear a lot about using neoadjuvant chemotherapy in locally advanced cervix cancer and that eventually did not pan out. Are you a little more optimistic about the addition of immunotherapy?
Linda Duska, MD, MPH:
And I think we need to have a better understanding of the biology. The question is how to make the environment more conducive to immunotherapy success. Whether that is giving the immunotherapy during radiation or after radiation because of concern that radiation is killing-off all the T-cells that you’re trying to stimulate with the immunotherapy, or whether the best idea is to give the immunotherapy upfront. At the time of these presentations, I think we do not fully understand the biology at play, and we need to better design these trials.
Phase II Trial of Letrozole + Ribociclib in Women With Recurrent LGSOC (GOG 3026): Study Design
Linda Duska, MD, MPH:
At SGO 2023, Slomovitz and colleagues presented results from a single-arm, open-label, phase II trial of letrozole and ribociclib in women with advanced and recurrent low-grade serous ovarian cancer (n = 51). This is a rare disease that is in dire need of new therapies. In that study, patients were allowed to have unlimited previous lines of therapy, although no prior letrozole was allowed—most had previous chemotherapy (73%). The primary endpoint was ORR.
Phase II Trial of Letrozole + Ribociclib in Recurrent LGSOC: Response
Linda Duska, MD, MPH:
The ORR was 23%. All responses were partial responses, but the DoR was 19.1 months (range: 4.8-35.8 months).
Phase II Trial of Letrozole + Ribociclib in Recurrent LGSOC: AEs
Linda Duska, MD, MPH:
The most common high-grade AEs were hematologic, and patients did very well while receiving this combination. The most common AEs of any grade with letrozole plus ribociclib were neutrophil count decrease (63%), white blood cell count decrease (46%), anemia and nausea (both 42%). The most common grade ≥3 AEs also were neutrophil count decrease (44%), white blood cell count decrease (8%), anemia (4%), and nausea (2%).
Overall, I think patients did very well while receiving this combination. When we compared this data with alternative therapies, the combination of letrozole and ribociclib has the longest PFS (data not shown) and DoR in this patient population.9 These findings suggest that letrozole plus ribociclib is a viable alternative for these women.
David Scott Miller, MD, FACOG, FACS:
I agree and thank you for those excellent summaries. It is very encouraging to finally see something with actual activity in low-grade serous ovarian cancer.
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