Efficacy and safety of dostarlimab in elderly patients with multiple comorbidities and allergic diathesis: case report

Introduction

The most frequent gynecological cancer in women in developed world is endometrial cancer (EC) (1). In 2013, the old histology classification of EC was replaced by the classification based on the molecular profile proposed by The Cancer Genome Atlas (TGCA). The molecular subgroups were associated with a more or less favorable prognosis. There molecular classification identifies four subgroups: (I) ultramutated DNA polymerase epsilon (POLE), characterized by high mutagenicity and favorable outcome; (II) hypermutated microsatellite instability (MSI), characterized by secondary MSI, high mutagenicity, with an intermediate prognosis; (III) low copy number; (IV) high copy number. Hypermutated MSI represented about 30% of EC; immunohistochemistry allows identification of deficient mismatch repair (dMMR; loss of expression of proteins such as MLH1, MSH2, MSH6 and PMS2), while MSI-high (MSI-H) can be assessed by polymerase chain reaction (PCR). dMMR/MSI in EC patients has a diagnostic value (Lynch syndrome) and predictive of response to therapy with immune checkpoint inhibitors (ICIs) (2). In 2017, pembrolizumab (ICI) was the first drug-agnostic approved by the Food and Drug Administration (FDA) for the treatment of dMMR/MSI-H solid tumors (including EC). Later in 2021, the results of the GARNET trial allowed the FDA to approve dostarlimab monotherapy in dMMR/MSI-H EC patients after platinum therapy (3). These drugs introduced immunotherapy into the treatment of EC. The only therapeutic option for these patients before the introduction of immunotherapy was chemotherapy, which was less effective and worse tolerated. Immunotherapy currently allows dMMR/MSI-H EC patients to have excellent responses, improving survival data and their quality of life. The Ruby trial (ENGOT-EN6-NSGO/GOG3031), phase III, reported an improvement in progression-free survival (PFS) from the addition of dostarlimab to platinum-based chemotherapy, furthermore the interim analyzes offer promising data in overall survival (OS). Immunotherapy and platinum-based therapy are the new standard of care in advanced or metastatic dMMR/MSI-H EC (4). We described a single case of our real-practice experience showing the safety of dostarlimab administration in elderly patients with multiple comorbidities and multiple allergies with metastatic and recurrent EC with MSI-H. We present this case in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-24-239/rc).

Case presentation

In April 2022, a 75-year-old woman in poor general condition [Eastern Cooperative Oncology Group (ECOG) performance status 1/2] went to the emergency room of Garibaldi Hospital of Catania due to anemia, metrorrhagia and cough not responsive to antibiotic therapy. She performed a whole-body computed tomography (CT) which showed “heterologous lesion occupying the uterine lodge invading parameters bilaterally, the cervix, incorporating the distal part of both the ureters, in the absence of a cleavage plane with the posterior wall of the bladder. Abdominal-pelvic colliquated adenopathy. Bilateral lung lesions. Lytic lesion on D12”. The patient underwent hysteroscopy. The histological examination highlighted “epithelial neoplasm with morpho phenotypic characteristics compatible with endometrioid adenocarcinoma, G3, p53 aberration, focal lymph-vascular space invasion (LVSI), MSI-H”. The patient’s medical history was positive for arterial hypertension, autoimmune thrombocytopenia and allergy to amoxicillin and levofloxacin. Markers at diagnosis were carcinoembryonic antigen (CEA) 42 ng/mL and cancer antigen 125 (CA 125) 485 U/mL. Genetic counseling and blood sampling were required to search for the genes responsible for Lynch syndrome (negative result). Given the stage of the disease [International Federation of Gynecology and Obstetrics (FIGO) IVa], the patient was a candidate for first-line treatment according to carboplatin plus paclitaxel regimen. The blood tests, in anticipation of the first infusion of antiblastic treatment, showed a marked increase in creatinine values and hyperkalemia. Ultrasound of the urinary tract was performed which highlighted III–IV-degree hydronephrosis, so we placed bilateral nephrostomies with the resolution of the picture of hyperkalemia, acute renal insufficiency (IRA) and metabolic acidosis. In May 2022, she started treatment with carboplatin and paclitaxel. With occasional steroid support the patient was able to recycle at an almost correct rate, no transfusions of platelet concentrates were necessary. The CT scan in August 2022 showed stable disease and with a reduction in markers serum values (CEA 32 ng/mL; CA 125 283 U/mL), so the patient received further 3 cycles of the same regimen of polychemotherapy. On November 2022, a new CT scan performed upon completion of the sixth cycle of carboplatin and paclitaxel, showed an “increase in size of the uterine mass, pelvic lymphadenopathy and lung lesions in number and size”. On December 2022, the patient started a second line treatment with dostarlimab. During the first administration she presented with itchy maculopapular erythema for which the infusion was suspended and chlorphenamine was administered. An hour after the infusion reaction, symptoms were resolved and the therapy was resumed with doubled infusion time. The patient completed administration without other complications. On January 2023, the administration of dostarlimab was delayed for approximately 10 days, due to pain related a D12 metastasis requiring radiotherapy [volumetric modulated arc therapy (VMAT) 8 Gy]. In February 2023, the patient resumed therapy with dostarlimab with doubled administration time in the absence of infusion reactions. After 4 administrations (3 weeks) she underwent a CT-scan which showed a partial response to the treatment with reduction of the uterine mass, of pulmonary secondaries (Figure 1A,1B and Figure 2A,2B) and normalization of tumor markers (CEA 4 ng/mL; CA 125 15.2 U /mL). In May 2023, she started a maintenance therapy with dostarlimab (1,000 mg dose every 6 weeks), the platelets remain at values of approximately 90,000 microL so the patient continues therapy in the absence of steroid support. As of May 2024, maintenance is continuing with clinical benefit and disease stability documented on CT. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Figure 1 Reduction of the pulmonary nodule from computed tomography November 2022 (A) to computed tomography March 2023 (B).

Figure 2 Reduction of endometrial mass from November 2022 computed tomography (A) to March 2023 computed tomography (B). The red line marks the size of the tumor.

Discussion

Immunotherapy is an important therapeutic strategy for the treatment of cancer, especially for advanced or metastatic disease. It is able to slow down the progression of disease. In the context of gynecological cancers, immunotherapy has demonstrated a major improvement in PFS and quality of life, with a more tolerable toxicity profile compared to chemotherapy in advanced EC. The Ruby study, phase III, showed benefit in PFS for patients with stage III–IV EC, both dMMR/MSI-H and mismatch repair proficient/microsatellite stable (pMMR/MSS), treated in the first line with chemotherapy in combination with dostarlimab (4). Even earlier, the GARNET trial, which enrolled patients with advanced or relapsed EC with dMMR and/or MSI progressing on prior platinum therapy to receive dostarlimab, reported overall response rate (ORR) of 43.5% with a manageable safety profile (3). We described the case of locally advanced endometrioid carcinoma of the endometrium in an elderly patient with many comorbidities. Dostarlimab was effective and safe in our patient. She showed a clinical improvement after the second administration of dostarlimab. No toxicities related to autoimmune thrombocytopenia occurred. The grade 2 infusion reaction was resolved with the suspension of the drug, with premedication (antihistamine) and the resumption of the infusion by doubled the administration time. In the gynecological oncology setting, several studies have demonstrated the efficacy and safety of dostarlimab. Bartoletti et al. described a case report of a patient treated with dostarlimab with platinum-refractory EC with a high disease burden and dMMR (5). After three months of therapy the patient with pulmonary and hepatic localizations showed a complete pulmonary response and a partial response on the liver. Ducceschi et al. collected a multicenter case series of patients with advanced EC and advanced ECOG PS treated with dostarlimab, showing exceptionally rapid clinical/radiological responses (6). ICIs had changed the landscape of solid tumors (melanoma, lung, genitourinary, breast). The safety profile of anti-programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) drugs makes them usable in particular population subgroups, such as elderly patients with multiple comorbidities and drug allergies. Elderly patients with multiple pathologies are usually excluded from clinical trials, even if several studies demonstrated the effectiveness and safety of ICI in solid tumors (7,8). Although we have described a single case, our real-practice experience showed that it is safe to administer dostarlimab in elderly patients with multiple comorbidities and multiple allergies with metastatic and recurrent EC with high dMMR/MSI and that the administration of immunotherapy in this subset of patients may lead to long-lasting remissions.

Conclusions

Elderly patients with many diseases are frail and therefore more difficult for clinicians to manage. Thyroid disease, diarrhea, pneumonitis, colitis and immune-related adverse reactions can develop seriously in patients with comorbidities and the elderly. Clinicians must be alert to detect symptoms early. Treatment-related adverse events (TRAEs) grade 3–4 [Common Terminology Criteria for Adverse Events (CTCAE)] require immediate treatment with high-dose intravenous cortisone. If symptoms do not resolve within 48 hours of high-dose cortisone therapy, it is necessary to start specific therapies (infliximab, mycophenolate, intravenous immunoglobulin). In our case, dostarlimab was proven to be a safe and effective drug in elderly, allergic patient with autoimmune thrombocytopenia.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-24-239/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-24-239/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-24-239/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Concin N, Matias-Guiu X, Vergote I, et al. ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma. Int J Gynecol Cancer 2021;31:12-39. [Crossref] [PubMed]
2. Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature 2013;497:67-73. [Crossref] [PubMed]
3. Oaknin A, Gilbert L, Tinker AV, et al. Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET-a phase I, single-arm study. J Immunother Cancer 2022;10:e003777. [Crossref] [PubMed]
4. Mirza MR, Chase DM, Slomovitz BM, et al. Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer. N Engl J Med 2023;388:2145-58. [Crossref] [PubMed]
5. Bartoletti M, Giorda G, Viel A, et al. An Exceptional Response to Dostarlimab in Mismatch Repair Deficient, Microsatellite Instability-High and Platinum Refractory Endometrial Cancer. Curr Oncol 2022;29:5209-12. [Crossref] [PubMed]
6. Ducceschi M, Polignano M, Bini M, et al. The Revolution of Immunotherapy in Gynecological Cancers: The Lazarus Effect in Endometrial Cancer. J Clin Med 2023;12:5540. [Crossref] [PubMed]
7. Paderi A, Fancelli S, Caliman E, et al. Safety of Immune Checkpoint Inhibitors in Elderly Patients: An Observational Study. Curr Oncol 2021;28:3259-67. [Crossref] [PubMed]
8. Bartoletti M, Montico M, Lorusso D, et al. Incorporation of anti-PD1 or anti PD-L1 agents to platinum-based chemotherapy for the primary treatment of advanced or recurrent endometrial cancer. A meta-analysis. Cancer Treat Rev 2024;125:102701. [Crossref] [PubMed]