Immunotherapy in advanced endometrial cancer

Amr Shafik

Professor of Clinical Oncology

Ain Shams University

Cairo, Egypt

​

Disclosure

RUBY | Dostarlimab + chemotherapy^1,2

18

Phase 3, randomized, double-blind, multicenter study of dostarlimab plus carboplatin-paclitaxel versus placebo plus carboplatin/paclitaxel in patients with primary advanced or recurrent EC

​

​

AUC = area under the plasma or serum concentration-time curve; BICR = blinded independent central review; CTCAE = Common Terminology Criteria for Adverse Events; DCR = disease control rate; dMMR = mismatch repair deficient; DOR = duration of response, EC = endometrial cancer; ECOG PS = Eastern Cooperative Oncology Group performance status; HRQOL = health-related quality of life; IA = investigator assessed; IV = administered intravenously;

MMR = mismatch repair; MSI = microsatellite instability; MSI-H = microsatellite instability-high; ORR = objective response rate; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PFS2 = time to second disease progression or death; PRO = patient-reported outcome; QxW = every x weeks.

On-study imaging assessments are to be performed Q6W (±7 days) from the randomization date until Week 25 (Cycle 8), followed by Q9W (±7 days) until Week 52. Subsequent tumor imaging is to be performed every 12 weeks (±7 days) until radiographic PD is documented by investigator assessment per RECIST v1.1 followed by one additional imaging 4-6 weeks later, or subsequent anticancer therapy is started, whichever occurs first. Thereafter, scans may be performed per standard of care.

^aMixed histology containing at least 10% carcinosarcoma, clear cell, or serous histology. ^bPatients were randomized based on either local or central MMR/MSI testing results. Central testing was used with local results were not available. For local determination of MMR/MSI status, IHC, next generation sequencing, and polymerase chain reaction assays were accepted. For central determination of MMR/MSI status IHC per Ventana MMR RxDx panel was used. ^cTreatment ends after 3 years, PD, toxicity, withdrawal of consent, investigator’s decision, or death, whichever occurs first. Continued treatment with dostarlimab or placebo beyond 3 years may be considered following discussion between the Sponsor and the Investigator. ^dPFS per IA – all patients with recurrent or primary advanced EC (ITT population). ^ePFS by BICR per RECIST v1.1 (not IA) – ITT population and dMMR/MSI-H population. ^fORR by BICR and IA. ^gDOR by BICR and IA, ^hDCR by BICR and IA. ⁱAll AEs assessed for intensity according to CTCAE v4.03.

1. Mirza MR, et al. N Engl J Med 2023. 388:2145-2158. 2. Mirza MR, et al. N Engl J Med 2023. 388:2145-2158 (protocol).

Data cutoff: Sept 28, 2022; Median duration of follow-up: dMMR/MSI-H cohort: 24.8 mo (range, 19.2–36.9 mo), Overall population: 25.4 mo (range, 19.2–37.8 mo)

​

• MMR/MSI status^b
• Prior external pelvic radiotherapy
• Disease status

​

• Histologically/cytologically proven advanced �or recurrent EC
• Stage III/IV disease or first recurrent EC with �low potential for cure by radiation therapy or surgery alone or in combination
• Carcinosarcoma, clear cell, serous, or mixed histology permitted^a
• Naïve to systemic therapy or systemic anticancer therapy and had a recurrence or PD ≥6 months after completing treatment
• ECOG PS 0-1
• Adequate organ function

Demographics and clinical characteristics at baseline

Demographic and clinical characteristics of patients were balanced across treatment arms

BMI = body mass index; dMMR = deficient mismatch mutation repair; MMR = mismatch repair; MSI = microsatellite instability; MSI-H = microsatellite instability-high; MSS = microsatellite stable; pMMR = mismatch repair proficient.

Mirza MR, et al. N Engl J Med 2023. 388:2145-2158.

19

PFS per IA – primary endpoint

dMMR/MSI-H population^1,2

20

Carbo = carboplatin; CI = confidence interval; dMMR = mismatch repair deficient; HR = hazard ratio; mo = months; IA = investigator assessment; MSI-H = microsatellite instability-high; NE = not estimable; No = number; PFS = progression-free survival.

1. Mirza MR, et al. N Engl J Med 2023. 388:2145-2158. 2. Mirza MR et al. Presented at the Society of Gynecologic Oncology Annual Meeting on Women’s Cancer (Oral presentation). March 25-28, 2023, Tampa, FL, US.

No. at Risk

(No. of Events)

HR 0.28 (95% CI, 0.162–0.495)

P<0.001

Dostarlimab + carboplatin/paclitaxel

61.4%

63.5%

Placebo + carboplatin/paclitaxel

24.4%

15.7%

Median duration of follow-up:

24.79 mo (range, 19.15–36.86)

Link to sensitivity analysis results

PFS per IA – primary endpoint

Overall population (dMMR/MSI-H and pMMR/MSS)^1,2

21

Carbo = carboplatin; CI = confidence interval; dMMR = mismatch repair deficient; HR = hazard ratio; IA = investigator assessment; mo = months; MMR = mismatch repair; MSI = microsatellite instability; MSI-H = microsatellite instability-high; MSS = microsatellite stable; No = number; pbo = placebo; PFS = progression-free survival; pMMR = mismatch repair proficient.

1. Mirza MR, et al. N Engl J Med 2023. 388:2145-2158. 2. Mirza MR et al. Presented at the Society of Gynecologic Oncology Annual Meeting on Women’s Cancer (Oral presentation). March 25-28, 2023, Tampa, FL, US.

29.0%

HR 0.64 (95% CI, 0.507–0.800)

P<0.001

Median duration of follow-up:

25.38 mo (range, 19.15–37.75)

Dostarlimab + carboplatin/paclitaxel

Placebo + carboplatin/paclitaxel

Overall survival – primary endpoint

Overall population (dMMR/MSI-H and pMMR/MSS)^1,2

22

^aP≤0.00177 required to declare statistical significance at first interim analysis.

Carbo = carboplatin; CI = confidence interval; HR = hazard ratio; NE = not estimable; dMMR = deficient mismatch mutation repair; MMR = mismatch repair; MSI = microsatellite instability; MSI-H = microsatellite instability-high; MSS = microsatellite stable; No = number; OS = overall survival; pMMR = mismatch repair proficient.

1. Mirza MR, et al. N Engl J Med 2023. 388:2145-2158. 2. Mirza MR et al. Presented at the Society of Gynecologic Oncology Annual Meeting on Women’s Cancer (Oral presentation). March 25-28, 2023, Tampa, FL, US.

HR 0.64 (95% CI, 0.464–0870)

P = 0.0021^a

Median duration of follow-up:

25.38 mo (range, 19.15–37.75)

Dostarlimab + carboplatin/paclitaxel

71.3%

84.6%

Placebo + carboplatin/paclitaxel

81.3%

56.0%

Dostarlimab + carboplatin/paclitaxel

Placebo + carboplatin/paclitaxel

Subsequent use of ICI:

• Dostarlimab + carboplatin/paclitaxel: 34.5% (86/249)
• Placebo + carboplatin/paclitaxel:15.5% (38/245)

Overall survival – prespecified subgroup analysis

dMMR/MSI-H population^1,2

23

Carbo = carboplatin; CI = confidence interval; dMMR = mismatch repair deficient; HR = hazard ratio; mo = months; MSI-H = microsatellite instability-high; NE = not estimable; No = number; OS = overall survival.

1. Mirza MR, et al. N Engl J Med 2023. 388:2145-2158. 2. Mirza MR et al. Presented at the Society of Gynecologic Oncology Annual Meeting on Women’s Cancer (Oral presentation). March 25-28, 2023, Tampa, FL, US.

83.3%

90.1%

79.6%

58.7%

Median duration of follow-up:

24.79 mo (range, 19.15–36.86)

HR 0.30 (95% CI, 0.127–0.699)

Placebo + carboplatin/paclitaxel

Dostarlimab +carboplatin/paclitaxel

Placebo + carboplatin/paclitaxel

Dostarlimab + carboplatin/paclitaxel

No. at Risk

(No. of Events)

Subsequent use of ICI:

• Dostarlimab + carboplatin/paclitaxel: 38.5% (25/65)
• Placebo + carboplatin/paclitaxel:15.1% (8/53)

pMMR/MSS population^1,2

24

Carbo = carboplatin; CI = confidence interval; HR = hazard ratio; IA = investigator assessment; mo = months; MSS = microsatellite stable; No = number; pbo = placebo; PFS = progression-free survival; pMMR = mismatch repair proficient.

1. Mirza MR, et al. N Engl J Med 2023. 388:2145-2158. 2. Mirza MR et al. Presented at the Society of Gynecologic Oncology Annual Meeting on Women’s Cancer (Oral presentation). March 25-28, 2023, Tampa, FL, US.

HR 0.76 (95% CI, 0.592–0.981)

Dostarlimab + carboplatin/paclitaxel

28.4%

43.5%

Placebo + carboplatin/paclitaxel

30.6%

18.8%

No. at Risk

(No. of Events)

PFS per IA – prespecified subgroups

Overall survival – prespecified subgroup analysis

25

Carbo = carboplatin; CI = confidence interval; HR = hazard ratio; MSS = microsatellite stable; mo = month; NE = not estimable; No = number; OS = overall survival; pMMR = mismatch repair proficient.

1. Mirza MR, et al. N Engl J Med 2023. 388:2145-2158. 2. Mirza MR et al. Presented at the Society of Gynecologic Oncology Annual Meeting on Women’s Cancer (Oral presentation). March 25-28, 2023, Tampa, FL, US.

pMMR/MSS population^1,2

No. at Risk

(No. of Events)

HR 0.73 (95% CI, 0.515–1.024)

Dostarlimab +

carboplatin/paclitaxel

67.7%

83.1%

Placebo +

carboplatin/paclitaxel

81.8%

55.1%

Months from Randomization

Dostarlimab +carboplatin/paclitaxel

Placebo + carboplatin/paclitaxel

Thank You