Update: Immunotherapy dostarlimab gains FDA approval for treatment of recurrent and advanced endometrial cancer

IN-DEPTH REVIEW OF RESEARCH

Study background

About three percent of women in the US develop endometrial cancer in their lifetimes. Early-stage endometrial cancer is treatable; over 80 percent of those diagnosed with early-stage disease survive more than five years, and 75 percent of those with early-stage endometrial cancer are cured by surgical removal of their tumor. However, some patients survive less than one year after diagnosis and treatment. Few treatment options are available for patients with recurrent or advanced endometrial cancer.

One new promising treatment is dostarlimab, an antibody that blocks the PD-1 protein. This therapy helps the immune system to better recognize and destroy tumor cells.

The safety and effectiveness of dostarlimab were tested during Phase 1 of the GARNET trial. This trial involves patients with various solid tumors, including endometrial tumors, who were treated with dostarlimab. The FDA recently granted accelerated approval of dostarlimab based on the initial results among the participants with endometrial cancer.

Mismatch repair deficient and proficient tumors
Thirty percent of endometrial cancer tumors are mismatch repair deficient (dMMR) tumors that do not perform DNA mismatch repair effectively. Tumors that perform DNA mismatch repair well are called mismatch repair proficient or MMRp tumors. Patients with dMMR and MMRp tumors have similar outcomes.

A later, expanded version of the GARNET trial included two groups with endometrial tumors: patients with dMMR endometrial tumors and patients with MMRp endometrial tumors.

Here we review both the Phase 1 safety and effectiveness findings that led to accelerated FDA approval and the more recent expanded GARNET study that looked at how well patients with dMMR and MMRp tumors responded to dostarlimab.

Researchers of this study wanted to know

Researchers of this study wanted to know whether dostarlimab is useful as a second-line treatment for recurrent or advanced endometrial cancer when patients’ tumors grow after first-line platinum treatment.

Study findings

Phase 1 study on safety and efficacy leads to FDA accelerated approval

The findings of the GARNET trial were presented at the 2020 Society of Gynecological Oncology Annual Meeting and led to FDA accelerated approval for dostarlimab for endometrial cancer in April 2021.

The GARNET trial looked at dostarlimab in patients with several types of solid tumors. In this initial study, patients were treated with dostarlimab only. There was no comparison group for this Phase 1 study.

Phase 1 study population

Eligible participants included those who:

• had cancer that progressed during or after treatment with a platinum therapy, and
• received two or fewer prior lines of therapy for recurrent or advanced disease
• had measurable tumors at the beginning of the study
• had not been previously treated with a PD-1/PD-L1 inhibitor
• were confirmed to have a mismatch repair-deficient (dMMR) tumor
   

Among study participants, 104 patients with endometrial cancer took part in the safety analysis portion of the study.

Among study participants, 71 patients with endometrial cancer took part in the usefulness portion of this study. These patients had dMMR recurrent or advanced endometrial cancer that progressed on or after a platinum-containing regimen.

Phase 1 design:

Each participant was given 500 mg of dostarlimab intravenously (by IV) every three weeks for four doses and then 1,000 mg of dostarlimab by IV every six weeks.

Researchers determined the size of each patient's tumor at various times during and after treatment.

Safety and effectiveness

Initial safety findings

Initial safety analysis showed that patients tolerated  treatment with dostarlimab, although some adverse events were observed:

• Only 5% of patients discontinued dostarlimab due to adverse events.
• No deaths due to treatment were reported.

The most common adverse reactions were:

• fatigue, weakness, lack of energy
• nausea
• diarrhea  
• a low number of red blood cells (anemia)
• constipation

Serious adverse reactions occurred in 34 percent of patients receiving dostarlimab. These included:

• sepsis (widespread inflammation that can damage organs)
• acute kidney injury
• urinary tract infection
• abdominal pain
• fever

The most common severe or potentially life-threatening reactions were:

• a low number of red blood cells (anemia)
• an increase in certain enzymes called transaminases that reflect liver function
• inflammations associated with the lung, colon, liver, kidneys and endocrine system

Initial Phase 1 effectiveness

The objective response rate (ORR)—the percentage of patients whose tumor completely or partially shrank—was 42.3 percent.

• 12.7% of patients had tumors that could no longer be detected.
• 29.6% of patients had tumors that shrank in size.

The researchers were unable to determine the average duration of response because most patients (93 percent) responded more than six months after their treatment.

• At the last assessment, the range of responses seen among patients was between 2.6 and 22.4 months, with many patients continuing to respond to treatment.

Expanded Phase 1 of the GARNET study

In this follow-up to the Phase 1 GARNET study, researchers looked at a larger group of patients that included those whose tumors did not repair DNA mismatch well (mismatch repair-deficient or dMMR tumors) and patients whose tumors had normal DNA mismatch repair (mismatch repair proficient or MMRp tumors). These findings were reported at the 2020 ESMO conference.

Phase 2 study design

Participants were treated with 500 mg of dostarlimab by IV every three weeks for four doses and then 1,000 mg of dostarlimab by IV every six weeks.

The primary study goals were to look at:

• continued safety information about dostarlimab.
• objective response rate (ORR) or how much patients’ tumors shrank in size.
  • An independent review group that did not know which treatment the patient had received determined tumor size. They evaluated tumors using a standardized measure called the RECIST 1.1 criteria.
• duration of response or how long a patient responded to treatment.

Populations looked at in the expanded GARNET study

Two groups of patients were recruited through March 1, 2020:

• 126 patients had mismatch repair-deficient (dMMR) tumors that did not repair DNA mismatch well.
• 145 patients had mismatch repair proficient (MMRp) tumors that had normal DNA mismatch repair.

Researchers looked at adverse events among all participants to continue monitoring the safety of dostarlimab.

For the effectiveness component of the study, researchers looked at only those participants who had at least six months of follow-up during the study and at least one measurable tumor at the beginning of the study. This included:

• 103 patients with dMMR endometrial tumors.
• 142 patients with MMRp endometrial tumors.

Expanded GARNET study findings

Tumors shrank in 46 of the 103 patients (44.7percent) who had dMMR tumors.

Among the 103 patients, after treatment:

• 11 had no detectable tumor (complete response)
• 35 had a smaller tumor (partial response)
• 13 had a tumor that neither grew or shrank (stable disease).
• 39 had tumors that grew or spread in the body.

Tumors shrank in 19 of 142 patients (13.4 percent) who had MMRp tumors.

Among the 142 patients:

• 3 had no detectable tumor (complete response)
• 16 had a smaller tumor (partial response) 
• 31 had a tumor that neither grew nor shrank (stable disease)
• 77 had tumors that grew or spread in the body

Duration of response
Researchers were not able to determine the average duration of response because most patients responded to treatment more than six months after treatment (more than 16 months for the dMMR group and more than 11 months for the MMRp group).

Of patients whose tumors responded to dostarlimab at initial evaluation, most continued to respond to treatment at the time of data cutoff for this report.

• 41 of 46 (89%) of patients with dMMR tumors continued to respond to treatment.
• 12 of 19 (63%) of those with MMRp tumors continued to respond to treatment.

The response among patients with MMR-proficient tumors was lower than among patients with dMMR tumors. However, some patients with MMRp tumors did respond to treatment with dostarlimab.

Modeling showed how likely a patient was to continue responding to treatment.

At 6 months:

            98% of patients with dMMR tumors were estimated to respond to treatment.

            83% of patients with MMRp tumors were estimated to respond to treatment.          

At 12 months:

            91% of patients with dMMR tumors were estimated to respond to treatment.

            61% of patients with MMRp tumors were estimated to respond to treatment.

At 18 months:

            79% of patients with dMMR tumors were estimated to respond to treatment.

            61% of patients with MMRp tumors were estimated to respond to treatment.

Expanded Phase 1 safety findings are similar to initial phase 1 findings

The safety findings in the expanded study mirrored the findings of the initial Phase 1 study.

• Most participants reported some adverse side effects:
  • 80 patients (64%) with dMMR tumors experienced side effects.
  • 104 patients (72%) with MMRp tumors experienced side effects.
  • The 3 most common side effects included: 
    • fatigue
    • diarrhea
    • nausea
• More severe safety issues linked to treatment were less common: 
  • 17 patients (14%) with dMMR tumors had severe side effects.
  • 28 patients (19%) with MMRp tumors had severe side effects.
  • Severe side effects included:
    • low red blood cells numbers (anemia)
    • altered levels of liver enzymes
    • diarrhea
• Serious reported toxicities related to treatment, typically affecting liver function, occurred in some patients:
  • 12 patients (9%) with dMMR tumors had side effects.
  • 13 patients (9%) with MMRp tumors had side effects.
     
• Only 4% of patients in the dMMR group and 7% of patients in the MMRp group discontinued treatment.
   
• No deaths related to study treatment were reported.

Strengths and limitations

Strengths

• This is the first report of dostarlimab in people with endometrial cancer. Few treatments are available for recurrent or advanced endometrial cancer, so this is a promising finding.

Limitations

• Only a small number of participants were included in this study. Additional research with a larger group of patients will likely be needed to fully test the impact of dostarlimab.
• The patient follow-up time after study treatment is relatively short. At the time of the report, most patients were still responding to treatment (an encouraging finding) but the average time of response could not be determined.
• It is unclear whether people with inherited mutations (e.g., Lynch syndrome gene mutations) will benefit from treatment with dostarlimab.
• This single-arm study looked at dostarlimab only for safety and effectiveness. The Phase 1 and expanded Phase 1 studies did not compare dostarlimab to standard-of-care treatment (typically a taxane and platinum chemotherapy drug, e.g. paclitaxel and carboplatin combination). Comparing this treatment to standard of care is an important next step to understand whether this drug improves the benefit to patients.

Context

Few treatments are available for recurrent or advanced endometrial cancer. This newly approved treatment offers a promising approach for those who no longer respond to first-line platinum treatment. This may substantially extend survival for some patients. Other PD-1 antibodies such as pembrolizumab and nivolumab are used to treat endometrial cancer. How these directly compare to treatment with dostarlimab is not yet known.

Conclusions

Dostarlimab is a promising treatment for recurrent or advanced cancer. Initial results indicate that a substantial number of patients respond well to this treatment. Dostralimab is linked to some side effects but these are mild for most people. More research is needed to determine how long patients continue to respond to this treatment on average and the effect on their survival.
 

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posted 5/18/21