CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: August 03, 2023
Expiration: August 02, 2024
Conference to Clinic: Gynecologic Cancer
Lauren Prescott, MD, MPH:
I would like to start by highlighting a couple of key studies that were presented at the 2023 ASCO Annual Meeting for endometrial cancer. There were 2 abstracts of interest, both relating to the ongoing phase III ENGOT-EN6-NSGO/GOG-3031/RUBY study with outcomes by BICR and patient-reported outcomes (PROs).1,2
Outcomes by BICR With Addition of Dostarlimab to CP in Advanced/Recurrent EC (RUBY): Study Design
Lauren Prescott, MD, MPH:
As our readers may recall, the phase III RUBY study is evaluating the combination of standard of care platinum-based chemotherapy with or without dostarlimab followed by dostarlimab or placebo maintenance for 3 years in patients with primary advanced/recurrent stage III/IV endometrial cancer (N = 494). The coprimary endpoints of the study are PFS by investigator and OS. The coprimary endpoints were previously presented at the Society of Gynecologic Oncology (SGO) annual meeting in Tampa, Florida, and were subsequently published in the New England Journal of Medicine.2,3 Data presented at SGO showed the primary endpoint of PFS was met with a clinically significant 2-year PFS improvement for the dostarlimab-containing arm vs the chemotherapy-alone arm in the overall population (36% vs 18%; HR: 0.64; P <.001), dMMR/ MSI-H population (HR: 0.28; range: 0.16-0.50; P <.001), and proficient mismatch repair (pMMR)/microsatellite stable (MSS) population (HR: 0.76; range: 0.59-0.98).
At the ASCO annual meeting, Dr Mathew Powell and colleagues reported the secondary endpoints of PFS by BICR. In addition, we saw response and safety data for RUBY.
Ritu Salani, MD, MBA:
We should also mention that a similar ongoing study is evaluating pembrolizumab in an equivalent patient population. The NRG-GY018 trial is a randomized phase III study of carboplatin and paclitaxel with or without pembrolizumab followed by pembrolizumab or placebo maintenance for 2 years in stage III/IVA, stage IVB, or recurrent endometrial cancer (NCT03914612).4 Similar to the RUBY trial, the primary endpoint of PFS per RECIST v1.1 by investigator in the pMMR and dMMR population was met. Data presented at SGO 2023 showed a clinically significant improvement in median PFS for the pembrolizumab-containing arm vs chemotherapy-alone arm in the dMMR cohort (not reached vs 7.6 months; HR: 0.30; P <.001) and pMMR cohort (13.1 vs 8.7 months; HR: 0.54; P <.001).
I would say a key distinction between NRG-GY018 and the RUBY trial design is that with RUBY we have longer follow-up (25.0 vs 12.0 months) and OS is a coprimary endpoint. At this point, we have much more mature outcomes with RUBY which makes this data very exciting.
ENGOT-EN6/GOG-3031/RUBY: PFS by INV and BICR in Overall Population
Lauren Prescott, MD, MPH:
In the analyses presented at ASCO, we saw that the hazard ratios for PFS by BICR in the overall population were almost identical to those previously presented for investigator assessment (HR: 0.66 vs 0.64) and confirmed the benefit of adding dostarlimab to standard of care platinum-based chemotherapy in the frontline setting. Of note, the percent PFS maturity by BICR was lower than per investigator assessment (52.2% vs 63.2%) at the ASCO 2023 presentation.
ENGOT-EN6/GOG-3031/RUBY: PFS by INV and BICR in dMMR/MSI-H Population
Lauren Prescott, MD, MPH:
We also saw that PFS by BICR in the dMMR/MSI-H population showed strong concordance of hazard ratios when compared to that by trial investigator assessment (HR: 0.29 vs 0.28). Again, here also the percent PFS maturity by BICR was lower than per investigator assessment (44.9% vs 55.9%).
ENGOT-EN6/GOG-3031/RUBY: Response by INV and BICR
Lauren Prescott, MD, MPH:
We saw a remarkable overall response rate (ORR) for the dostarlimab-containing arm vs the standard platinum-based chemotherapy arm, and this was true for both the overall population (70.3% vs 64.8%) and in the dMMR/MSI-H population (77.6% vs 69.0%). These results were very similar in the BICR assessment overall population (68.2% vs 59.4%) and in the dMMR/MSI-H population (77.1% vs 63.3%), which is very reassuring.
ENGOT-EN6/GOG-3031/RUBY: Safety Summary
Lauren Prescott, MD, MPH:
Although adverse events (AEs) were relatively common in both treatment arms, it is worth noting that the addition of dostarlimab to standard-of-care platinum-based chemotherapy did not result in substantially higher toxicity. Any grade ≥3 treatment-emergent AEs were seen in approximately 70% of patients in the dostarlimab arm vs 60% in the chemotherapy arm. Serious AEs were reported in approximately 38% of patients in the dostarlimab arm vs 28% in the chemotherapy arm. Similarly, treatment-emergent AEs leading to carboplatin or paclitaxel discontinuation were comparable in both treatment arms and ranged from 8% to 10%.
There were 5 total deaths reported in the dostarlimab arm vs 0 with placebo (2.1% vs 0%). In total, 3 deaths were deemed not related to dostarlimab use (eg, opioid overdose, COVID-19, and general physical health deterioration) and 2 were considered by investigators to be related to dostarlimab use (myelosuppression or hypovolemic shock).
Ritu Salani, MD, MBA:
I agree. I do not think the toxicities with the addition of dostarlimab to standard-of-care platinum-based chemotherapy are prohibitive.
RUBY Outcomes by BICR: Takeaways
Lauren Prescott, MD, MPH:
The RUBY trial outcomes by BICR confirmed improvements in PFS, ORR, and safety profile we had seen previously reported.
Ritu Salani, MD, MBA:
I agree. The BICR analyses from RUBY are reassuring, but do not significantly add to the already impressive results reported for this study.2 I also agree with you that the data presented at ASCO reaffirms that the primary endpoint was met and there was no difference between investigator and BICR assessed endpoints with a very favorable safety profile.
ENGOT-EN6/GOG-3031/RUBY PROs: Study Design
Lauren Prescott, MD, MPH:
The second abstract that was presented for the RUBY study was looking at the PROs. This abstract had an emphasis on quality of life (QoL) assessment and was presented Dr Manzoor Mirza, from Copenhagen, Denmark.
The RUBY study was designed to have QoL assessments completed prior to treatment on Day 1 of each treatment cycle, at end of treatment, and at safety and survival follow-ups:
The main metrics used were the European Organisation for Research and Treatment of Cancer (EORTC-C) 30 global health status/QoL functional scales (physical, role, emotional, cognitive, social) and symptoms scales (including fatigue, pain, nausea, insomnia), the EORTC QoL questionnaire (QLQ)-EN24 functional scales (sexual interest, sexual activity, sexual enjoyment) and symptoms scale (including GI, lymphoedema, pain in back and pelvis, hair loss). Of importance, completion rates for QLQ-C30 and QLQ-EN24 were similar between treatment arms at each time point (94%-99% at baseline and during treatment, and 76%-82% at end of treatment), which is highly important.
ENGOT-EN6/GOG-3031/RUBY: Global Health Score/QoL, Functional Scales at Start of Monotherapy (Cycle 7)
Lauren Prescott, MD, MPH:
The difference in overall health related QoL is summarized in the table. In the patients with dMMR/MSI-H disease, we saw a significant improvement from baseline for the metrics of global health score/QoL, physical functioning, and role functioning in the dostarlimab-containing arm compared with the standard of care of platinum-based chemotherapy plus placebo (all P <.05) by Cycle 7. In other words, we saw faster deterioration in the QoL of patients who received frontline standard of care without immunotherapy presumably due to disease progression.
ENGOT-EN6/GOG-3031/RUBY: PROs on Pain, Fatigue, and Back and Pelvis Pain
Lauren Prescott, MD, MPH:
The PROs of pain and back and pelvis pain were significantly improved in the dMMR/MSI-H cohort of the dostarlimab-containing arm vs the placebo-containing arm at the start of Cycle 7 (P value of .01 and .03, respectively). Although a numerical trend for improvement in pain and back and pelvis pain measures was also seen in the overall population, these were not statistically significant (P >.05).
I believe these improvements are likely a result of a reduction in tumor burden, including a significant reduction in tumor size based on the ORR and PFS analyses reported previously for RUBY.1,2
ENGOT-EN6/GOG-3031/RUBY: Global Health Score/QoL, Functional Scales at Start of Yr 2 (Cycle 13)
Lauren Prescott, MD, MPH:
The table shows the PROs at the start of year 2, or Cycle 13, for dMMR/MSI-H and the overall population, respectively. We saw numerical improvements in QoL earlier during treatment, both in the dMMR/MSI-H and the overall population receiving treatment in the dostarlimab compared with the standard-of-care platinum-based chemotherapy alone arm, but this was not seen at Cycle 13.2
Ritu Salani, MD, MBA:
I think what we can take away from the PROs analyses of RUBY is that we now have data to show and explain to patients that they do very well with the addition of dostarlimab to the standard of care in the front-line setting, both regarding survival and response outcomes, as well as improved QoL with a noticeable reduction in pain and back and pelvis pain at Cycle 7 but not at Cycle 13.
RUBY Outcomes by BICR and PRs: Clinical Implications
Lauren Prescott, MD, MPH:
My take home messages from the 2 abstracts presented for the RUBY study are that the addition of dostarlimab to platinum-based chemotherapy in the frontline setting for patients with primary advanced or recurrent endometrial cancer has a favorable benefit and safety profile when compared to platinum-based chemotherapy alone.
Ritu Salani, MD, MBA:
For me, the results of the RUBY trial are impressive. Checkpoint inhibitors are now part of guideline recommendations in the frontline setting in the United States. Whether clinicians will be using dostarlimab or pembrolizumab in the frontline setting will initially depend on familiarity with the agent, and which one is already part of the formularies that they use in their practice. For the dMMR/MSI-H population, I have not yet had a patient who meets that criteria as in the RUBY trial but I would definitely use the RUBY regimen of dostarlimab plus standard-of-care platinum-based chemotherapy for that patient.
If you were to ask me whether the RUBY or NRG-GY018 regimen could be offered to patients with pMMR/MSS status, I would say we do not yet have strong data regarding OS in that patient population. Even if the FDA grants approval in this group, there might be poor uptake because OS is not an endpoint in NRG-GY018, and this question remains unanswered.
My take-home from the safety profile that we saw with RUBY was that adding immunotherapy was not prohibitive and together with additional health-related QoL data presented by Dr Mirza at SGO 2023 is very encouraging.2 I do believe this data because we saw in the graphs that lines were not perfect for either arm, so they likely represent how patients are doing on these treatments. Together, these 2 analyses presented at ASCO affirm that the patients are reporting QoL improvement, which we would not necessarily expect and where often we see no difference at all.
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