ENDOCRINE SOCIETY
OXFORD
Exceptional Response to a Single Dose of Pembrolizumab as Salvage Therapy for Metastatic Adrenocortical Carcinoma
Laurie Branchaud-Croisetière,10 Emma Turcotte,2 Jean-François Castilloux,2 Isabelle Bourdeau,30D Frederic Mercier,4 and Matthieu St-Jean1D
1Division of Endocrinology, Department of Medicine, Research Center, Centre Hospitalier de L’Université de Sherbrooke (CRCHUS),
Sherbrooke, QC, Canada J1H 5H3
2Division of Oncology, Department of Medicine, Research Center, CRCHUS, Sherbrooke, QC, Canada J1H 5H3
3Division of Endocrinology, Department of Medicine, Research Center, Centre Hospitalier de L’Université de Montréal (CRCHUM), Montréal, QC, Canada H2X 0A9
4Division of General Surgery, Department of Surgery, Centre Hospitalier de L’Université de Montréal (CHUM), Montréal, QC, Canada H2X 0C1 Correspondence: Laurie Branchaud-Croisetière, MD, Division of Endocrinology, Department of Medicine, Research Center, Centre Hospitalier de L’Université de Sherbrooke (CRCHUS), 3001 12e avenue Nord, Sherbrooke, QC, Canada J1H 5H3. Email: bral5328@usherbrooke.ca.
Abstract
A 19-year-old woman presented with severe hypertension, hypokalemia, and clinical signs of Cushing syndrome (CS). Computed tomography imaging revealed a large left adrenal mass encasing a major vessel, a left renal lesion, a right ovarian teratoma, and multiple pulmonary micronodules. 18F-fluorodeoxyglucose positron emission tomography (18-FDG-PET) showed hypermetabolism in the adrenal mass, lung nodules, and teratoma. Biochemical work-up confirmed adrenocorticotropin-independent CS and elevated adrenal androgens, consistent with metastatic, unresectable adrenocortical carcinoma. The patient was started on mitotane and metyrapone, followed by 8 cycles of etoposide- doxorubicin-cisplatin plus mitotane. Despite treatment, the disease progressed. Adrenal biopsy revealed high tumor-infiltrating lymphocytes, low tumor mutation burden, low programmed death-ligand 1 expression, and microsatellite stability. Germline testing identified a TP53 pathogenic variant, confirming Li-Fraumeni syndrome. A single dose of pembrolizumab was administered as salvage therapy but led to grade 3 immune-related hepatitis and prolonged hospitalization, requiring cessation of both pembrolizumab and mitotane. Remarkably, a follow-up scan 3 months later showed 60% regression of the adrenal mass, stable renal and ovarian lesions, and resolution of lung nodules. The patient underwent complete surgical resection, achieving full remission. More than 1 year later, she remains disease free.
Key Words: adrenocortical carcinoma, advanced, metastatic, pembrolizumab
Abbreviations: ACC, adrenocortical carcinoma; CR, complete response; CS, Cushing syndrome; CT, computed tomography; EDP-M, etoposide-doxorubicin-cisplatin plus mitotane; F18-FDG-PET, 18F-fluorodeoxyglucose positron emission tomography; ICIs, immune checkpoint inhibitors; irAEs, immune-related adverse events; LS, Lynch syndrome; MSS, microsatellite stability status; NPR, nonprogression rate; OS, overall survival; PD-L1, programmed death-ligand 1; PFS, progression-free survival; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SUV, standardized uptake value; TILs, tumor-infiltrating lymphocytes; TMB, tumor mutation burden.
Introduction
Adrenocortical carcinoma (ACC) is a rare and aggressive ma- lignancy associated with poor prognosis. More than half of patients present with metastatic disease for which there are limited effective treatment options [1]. In the FIRM-ACT trial, median progression-free survival (PFS) and overall survival (OS) for patients treated with etoposide-doxorubicin-cisplatin and mitotane (EDP-M) were only 5.6 and 14.8 months, re- spectively, and the rate of serious adverse events was 58% [2]. To date, no standard second-line therapy has been estab- lished for chemotherapy-refractory cases. The present case study reports an exceptional response to pembrolizumab in a patient with metastatic ACC who had shown disease pro- gression while receiving EDP-M therapy. In addition, a thor- ough review of the available literature was conducted to
identify potential biomarkers that could explain her excep- tional response to pembrolizumab.
Case Presentation
In April 2023, a 19-year-old White female with an unremark- able past medical history presented with severe hypertension and hypokalemia. Her family history included prostate cancer in her maternal grandfather and breast cancer in her maternal great-grandmother.
Diagnostic Assessment
On physical examination, the patient had facial plethora, hir- sutism, increased posterior cervical and supraclavicular fat de- posits, and violaceous striae on her abdomen and thighs. A
thoraco-abdominal-pelvic computed tomography (CT) scan re- vealed a left-sided cluster of confluent adrenal masses (7.3 x 14.4 ×11.4 cm), a left cortical renal lesion (2.8x2×2.1 cm), a right ovarian teratoma (7.9x7.8×7.9 cm), and at least 25 pulmonary micronodules. 18F-fluorodeoxyglucose positron emission tomography (18-FDG-PET) scan showed significant hypermetabolism of the left adrenal lesions (standardized up- take value [SUV] of 18.6), the ovarian teratoma (SUV of 5.5) and the pulmonary micronodules (SUV of 1.1-2). The hyperme- tabolism of the pulmonary micronodules on the 18F-FDG PET scan, in contrast to the absence of hypermetabolism in the renal lesion, suggests that the pulmonary metastasis was probably due to ACC. The initial biochemical evaluation revealed corti- sol excess associated with mild androgen cosecretion (Table 1). Based on all the data obtained from the clinical assessment, bio- chemical analysis, and radiological/nuclear medicine work-up, we concluded that the patient has metastatic ACC associated with cortisol and mild androgen excess, as well as possible renal cell carcinoma and a right ovarian teratoma.
Treatment
Initially, she was deemed unsuitable for debulking surgery due to her tumor location, which surrounded the aorta and the in- ferior and superior mesenteric arteries. After the diagnosis, systemic treatment was initiated, involving a gradual intro- duction of mitotane (up to 8 g) and metyrapone (up to 1.5 g). Hypertension and hypokalemia were treated with a combination of spironolactone (up to 400 mg daily), amlodi- pine (up to 10 mg daily), amiloride (up to 10 mg daily), and irbesartan (up to 300 mg daily). Plasma cortisol levels rapidly decreased from 907 nmol/L (32.92 µg/dL) to 271 nmol/L (9.84 µg/dL) over a period of 3 days. A week later, EDP-M was initiated and after 6 cycles, the disease was considered sta- ble according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria [3]. A consensus was reached to extend EDP-M to 8 cycles. After 8 cycles of EDP-M, the pa- tient’s plasma androgens levels partly improved, and her corti- sol levels were in the normal range (see Table 1). However, subsequent imaging revealed a progression of the adrenal tu- mor (9.2 × 18.2 cm), with stability of the pulmonary micronod- ules. A biopsy of the lesion was performed for therapeutic purposes and showed low programmed-death-ligand 1 (PD-L1) expression (<1%), low tumor mutation burden (TMB) (5.04 mutations/mB), a T-cell score of 3.43 (88th per- centile) (hot immune phenotype), and a microsatellite stability status (MSS) tumor. A TP53 and a CTNNB1 somatic patho- genic variant were also identified in the tumor cells. Germline mutation testing confirmed a heterozygous missense TP53 c.638G>A, p. (Arg213Gln) pathogenic variant (Table 2). Following deliberation by a multidisciplinary tumor board, it was decided that pembrolizumab would be used as second-line therapy. The patient received a single dose of 140 mg in December 2023. Unfortunately, the treatment was complicated by the onset of grade 3 immune-mediated hepatitis, resulting in prolonged hospitalization and the discontinuation of mitotane and pembrolizumab.
Outcome and Follow-up
After pembrolizumab, the patient’s blood pressure returned to normal, but hyperkalemia developed despite antihypertensive medication being stopped. The immune-mediated hepatitis
resolved entirely after 2 months of mycophenolate mofetil and continuous tapering of prednisone. In March 2024, a CT scan showed a 60% reduction of the adrenal mass (4.1 x7.2 cm) and stability of the renal lesion and teratoma. Furthermore, the CT scan showed complete resolution of the pulmonary micronodules (Fig. 1C, 2B, and 3B). Mitotane levels remained within the therapeutic range (15.1 mg/L) six weeks after discontinuation. Mitotane was progressively re-introduced in March 2024 and titrated up to 3 g/day, with no adverse reaction. A subsequent 18-FDG-PET scan confirmed regression of the adrenal mass (3.5 × 5.4×3.3 cm, SUV 18.6) (Fig. 3B), indicating continued response to immunotherapy. Five months after treatment with pembrolizumab, the patient underwent a complete resection of the left adrenal lesion, renal lesion, and teratoma. Pathological analysis confirmed complete resection of the ACC with negative margins (R0), clear cell renal cell carcin- oma, and teratoma. The patient is currently under observa- tion, with no evidence of recurrence shown by imaging or biochemical testing (see Table 1). Images of her most recent 18F-FDG-PET scan performed in July 2025 are shown in Fig. 3C.
Discussion
We describe a unique case of metastatic ACC with an excep- tional response after a single dose of pembrolizumab in a pa- tient diagnosed with Li-Fraumeni syndrome. Immune checkpoints, such as PD-1 and its ligand PD-L1, are the prin- cipal regulators of T-cell responses. The advent of immune checkpoint inhibitors (ICIs) has transformed the landscape of cancer treatment but their role in rare tumors such as ACC is less well established. A phase 2 study evaluated the ef- ficacy and safety of PD-1 blockade as second-line therapy in advanced ACC. This study involved 14 patients, showing an odds ratio (OR) of 14% (95% CI, 2%-43%) at 27 weeks, based on the RECIST v1.1 criteria [7]. Another phase 2 study, which included 39 patients with advanced ACC who had re- ceived any prior line of treatment, showed an OR of 23% (95% CI, 11% to metastatic ACC) and an OS of 24.9 months [8]. In these phase 2 studies, microsatellite instability high and TMB were not significantly associated with response to pem- brolizumab (Table 3) [7, 8].
In the cohort of Raj et al [8], 7 of 9 patients who exhibited a significant response to pembrolizumab had MSS tumors. The median TMB was low and not associated with response to pembrolizumab, consistent with the present patient. These findings indicate that, in selected patients, the efficacy of pem- brolizumab as a treatment option for ACC may be independ- ent of microsatellite status and TMB. However, only a few cases of advanced ACC with complete response (CR) after pembrolizumab as salvage therapy have been reported (see Table 2) [12].
All respondents in the Raj et al [8] cohort also exhibited immunotherapy-related hepatitis, as in our case. A meta- analysis by Zhou et al [13] showed that patients whose cancer responded to PD-1 inhibitors experienced immune-related ad- verse events (irAEs) more frequently. One explanation for these findings is that irAEs reflect a robust immune response to the tumor and healthy tissue. Pembrolizumab-related hepa- titis may have predicted our patient’s exceptional response to immunotherapy. Moreover, Raj and colleagues [8] reported that some patients exhibited a sustained response after only
| Test | Baseline value | After 8 cycles of EDP-M | 12 mo after surgery | Reference range |
|---|---|---|---|---|
| Cortisol | 907 nmol/L (33 µg/dL) | 398 nmol/Lª (14.48 µg/dL) | 29 nmol/Lb (1.06 µg/dL) | 60-625 nmol/L (2-23 µg/dL) |
| 24-h UFC | 3580 nmol/24h (130 µg/24h) | ND | ND | 8-120 nmol/24h (0.3-4.4 µg/24h) |
| LNSC | 15 nmol/L (0.54 µg/dL) | ND | ND | <5 nmol/L (<0.18 µg/dL) |
| ACTH | <1.1 pmol/L (<5 pg/mL) | <1.1 pmol/L (<5 pg/mL) | ND | 0-10 pmol/L (0-45 pg/mL) |
| DHEAS | 4 mol/L (1.5 µg/dL) | 0.4 pmol/L (0.15 µg/dL) | 0.1 µmol/L (0.038 µg/dL) | 1.1-9.2 pmol/L (0.4-3.4 µg/dL) |
| PAC | 399 pmol/L (14.38 ng/dL) | 119 pmol/L (4.29 ng/dL) | <70 pmol/L (<2.52 ng/dL) | 70-660 pmol/L (2.52-23.79 ng/dL) |
| DRC | 91 ng/L (55 mIU/L) | 13.5 ng/L (8.1 mIU/L) | 50 ng/L (30 mIU/L) | 5-55 ng/L (3-33 mIU/L) |
| PAC to DRC ratio | 7 pmol/ng (0.16 ng/dL/mIU/L) | 14.69 pmol/ng (0.32 ng/dL/mIU/L) | <2 pmol/ng (<0.05 ng/dL/mIU/L) | <60 pmol/ng (<1.3 ng/dL/mIU/L) |
| Androstenedione | 4.6 nmol/L (1.32 ng/ml) | 3.1 nmol/L (0.89 ng/ml) | <0.34 nmol/L (<0.1 ng/ml) | 1.7-4.6 nmol/L (0.49-1.32 ng/ml) |
| Total testosterone | 1.2 nmol/L (0.04 ng/dL) | 2.8 nmol/L (0.09 ng/dL) | <0.2 nmol/L (<0.01 ng/dL) | 0.3-2.1 nmol/L (0.01-0.07 ng/dL) |
| SHBG | 16.4 nmol/L (96.76 ng/dL) | 316 nmol/L (1864.4 ng/dL) | 207 nmol/L (1221.3 ng/dL) | 22-104 nmol/L (130-614 ng/dL) |
| Free testosterone | 33 pmol/L (9.5 pg/mL) | 8 pmol/L (2.31 pg/mL) | ND | 0-25 pmol/L (0-7.2 pg/mL) |
| 17-OH-progesterone | 17.19 nmol/L (567.33 ng/ml) | 44.80 nmol/L (1478.55 ng/ml) | ND | 0-6 nmol/L (0-198 ng/ml) |
| Estradiol | <19 pmol/L (<5.2 pg/mL) | ND | ND | ND |
| Sodium | 140 mmol/L | 139 mmol/L | 138 mmol/L | 135-145 mmol/L |
| Potassium | 2.5 mmol/L | 3.7 mmol/L | 4.5 mmol/L | 3.5-5.1 mmol/L |
| Mitotanemia | ND | 16.6 mg/L | 15.4 mg/L | 14-20 mg/L (target range) |
Abbreviations: ACTH, adrenocorticotropin; DHEAS, dehydroepiandrosterone sulfate; DRC, direct renin concentration; EDP-M, etoposide-doxorubicin-cisplatin plus mitotane; LNSC, late-night salivary cortisol; ND, no data; PAC, plasma aldosterone concentration; SHBG, sex hormone-binding globulin; UFC, urinary free cortisol. “On metyrapone and mitotane. Before taking the hydrocortisone pill in the morning.
“On mitotane. Before taking the hydrocortisone pill in the morning.
1 or 2 doses of pembrolizumab, thereby suggesting that con- tinuous dosing may not be necessary in every patient [8].
High PD-L1 expression is another biomarker associated with a favorable response to ICIs in solid tumors [14]. However, the present patient exhibited a notable response to pembrolizumab, despite having a tumor with low PD-L1 expression. This finding is consistent with the results of a re- cent meta-analysis on the safety and efficacy of ICIs in ACC patients that found no correlation between PD-L1 expression and response to immunotherapy [15]. These results under- score the potential efficacity of pembrolizumab in advanced ACC, even in patients with weak PD-L1 expression. “Hot” tu- mors characterized by high levels of tumor-infiltrating lym- phocytes (TILs) have also been linked to a favorable response to immunotherapy in other types of solid tumors [16] but in clinical trials involving ACC patients, the response to immunotherapy was found to be independent of TIL eleva- tion (see Table 3) [15]. A retrospective study of 146 adrenal tissue specimens found an inverse relationship between corti- sol secretion and lymphocyte infiltration, suggesting that cor- ticosteroid synthesis inhibitors may enhance the response to immunotherapy [17]. As the literature shows, there is a link between glucocorticoid excess and a poorer prognosis in ACC patients [18]. Our patient initially had severe hypercor- tisolism that was controlled with metyrapone and mitotane. An adrenal biopsy several months after control of the hyper- cortisolism revealed a hot immune phenotype with an elevated T-cell score. These findings may have led to a stronger immune reaction, which may have contributed to the patient’s re- sponse to pembrolizumab.
Following the transition from EDP-M to pembrolizumab, the decision was made to maintain mitotane due to the
potential for a synergistic effect. Head et al [9] reported in a retrospective case series of 6 patients with advanced ACC who received pembrolizumab and mitotane (PEM-M) a min- imal survival of 16 months. This was also observed in 2 add- itional cases of patients who received combined therapy and exhibited either a CR or partial response (PR) (see Table 3) [5,6].
Our patient was found to have an inactivating germline TP53 and an activating somatic CTNNB1 pathogenic var- iants, both of which have been associated with aggressive ACC and resistance to immunotherapy [15, 19]. In a study by Bedrose et al [11] of 8 patients with advanced ACC treated with pembrolizumab and lenvatinib as salvage therapy, 2 pa- tients had a germline TP53 pathogenic variant, and both pro- gressed. To our knowledge, there are no other reported cases of metastatic ACC with the TP53 pathogenic variant treated with pembrolizumab, nor literature on the use of this drug for the treatment of other solid malignancies in patients with Li-Fraumeni syndrome. Further studies are needed to in- vestigate the role of mutated genes as potential drivers of treat- ment response in ACC patients. To date, germline mutations associated with Lynch syndrome (LS) have been predictive of a favorable response to immunotherapy, and 3 cases of ACC have demonstrated a CR or PR to pembrolizumab (see Table 2) [4, 8].
While some studies have linked older age at diagnosis to poor prognosis in patients with advanced ACC, others have not [20]. Therefore, it remains unclear whether our pa- tient’s young age influenced her response to treatment (see Table 2).
We present the first case of a patient with Li-Fraumeni syn- drome and metastatic ACC who showed a strong response to
| Author | Sex Age, y | Ethnicity | Therapy | Prior systemic therapy | Cortisol producing | last dose of Duration of FU after pembrolizumab, mo | Reason for PEM discontinuation | Genetic findings | Next-generation sequencing findings | End point |
|---|---|---|---|---|---|---|---|---|---|---|
| Mota et al | F 40 | Latin | PEM 100 mg | Left adrenalectomy | NR | 23 | Grade 3 | MSH2-splice site | MSI-H/ | CRR after 5 cycles |
| 2018 [4] | every 3 wk | 2 cycles of | pneumonitis | 1760-2A>G (LS) | MMR-D: | of PEM, | ||||
| (5 cycles) | capecitabine, | ATM-R189K | NR | maintained after | ||||||
| dacarbazine, and | TP53-R213* | TMB (mut/ | 2 y FU | |||||||
| mitotane | -APC-S1465fs* | mB): 32.65 | ||||||||
| Hepatic surgery RFA (liver and pulmonary nodules) Left lung metastasectomy SBRT (45 Gy) on lung and hepatic nodules Curcumin with | DAXX-H620fs*37 KDM5C-L1305fs*5 | TILs: NR PD-L1: 10% | ||||||||
| low-dose cyclophosphamide | ||||||||||
| Alam et al | F 40 | NR | PEM (dose | Left adrenalectomy | No | NR | CR | Somatic mutations identified: | MSS | CRR after |
| 2021 [5] | NR | Mitotane | CCND2, ATRX, FANCC, | TMB (mut/ | 4 cycles of | |||||
| 4 cycles) + | FGF23, FGF6, KDM5A, TP53 | mB): 6 | PEM-M | |||||||
| mitotane | TILs: NR PD-L1: 0% | |||||||||
| Senda et al | M 38 | NR | PEM 200 mg every 3 wk | Left adrenalectomy, | No | 15 | PEM continued on publication | Germline testing declined | MSI-H | PR after |
| 2023 [6] | nephrectomy and | TMB: NR | 15 mo of | |||||||
| for 15 mo + mitotane | thrombectomy | PD-L1: NR | PEM-M | |||||||
| EDP-M every (4 cycles) | ||||||||||
| This study | F 19 | White | PEM 140 mg | EDP-M (8 cycles) | Yes | 16 | Grade 3 hepatitis | Germinal mutation: TP53: | MSI-H/ | ORR RECIST |
| (1 cycle)+ | Mitotane | p.R213Q | MMR-D: | 1.1 70% after | ||||||
| mitotane | Somatic mutations identified: | No TMB (mut/ mB) : 5.04 TIL: 88th percentile PD-L1: 1% | 1 cycle of PEM CRR after surgical resection, maintained at 1-y FU | |||||||
| CTNNB1: p.S45P | ||||||||||
| CNAs: copy-neutral LOH of chr17 (TP53) and chr 3 (CTNNB1) and LOH on chr11 (LRP5) |
Abbreviations: chr, chromosome; CNAs, copy number abnormalities; CRR, complete radiological response; F, female; FU, follow-up; EDP-M, etoposide-doxorubicin-cisplatin plus mitotane; LOH, loss of heterozygosity; LS, Lynch syndrome; M, male; MSI-H, microsatellite instability high; MSS, microsatellite stable; NR, not reported; PD-L1, programmed death-ligand 1; PEM, pembrolizumab; PEM-M, pembrolizumab and mitotane; PR, partial response; RFA, radiofrequency ablation; SBRT, stereotactic body radiation therapy; TIL, tumor-infiltrating lymphocytes; TMB, tumor mutation burden.
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a single dose of pembrolizumab, allowing complete surgical resection. The response was likely due to the patient’s tumor hot immune profile, a synergistic effect between mitotane
and pembrolizumab, and her young age. Further research is needed to identify reliable biomarkers that can predict re- sponse to immunotherapy in ACC patients.
| Study | Study design | Total No. of patients (ACC patients) | Median age (range), y | Female, % | Median FU (range), mo | Therapy | Prior systemic therapy | No. of patients with cortisol- producing tumors | MSI-H/ MMR-D | TMB high (mut/ Mb) | TIL | PD-L1 status | Genetic findings | End points |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Raj et al | Phase 2, | 39 (39) | 62 (19-87) | 61.5 | 17.8 | PEM 200 mg every | 28 patients | NR | 6 | 2.4 mut/Mb | No significant | 7/34 patients | PR in 2 patients with | By RECIST V1.1 |
| 2020 | single-arm | (5.4-34.7) | 3 wk (35 cycles) | (31%≥ 1 prior | (0-31.5) | association with | No significant | LS | ORR: 23% (95% CI, | |||||
| *no mitotane | line) | response | association with | No relation between | 11%-39%) | |||||||||
| response | somatic mutations and response | OS: 24.9 m (95% CI, 4.2 mo) PFS: 2.1 mo (95% CI, 2-10.7) | ||||||||||||
| Head et al | Retrospective | 6 (6) | 45 (24-65) | 100 | NR | PEM 200 mg every | 1 line of systemic | 3 | 1 | NR | NR | NR | -2 patients: MSH2 (LS) | By RECIST V1.1 |
| 2019 [9] | cohort | 3 wk + mitotane | therapy | (PR and SD) | PR:2 (18 and 21 mo) | |||||||||
| SD: 4 (8-19 mo) | ||||||||||||||
| Habra et al | Phase 2, | 16 (16) | 48 (31-78) | 50 | NR | PEM 200 mg every | Median No. of | 7 | 1/14 | NR | No significant | 0/14 | NR | At 27 wk: |
| 2019 | single-arm | 3 wk (35 cycles) | prior lines: 2 | association with | NPR: 36% (95% CI | |||||||||
| *no mitotane | (1-5) | NPR at 27 wk | 13-65%) | |||||||||||
| Mitotane in all | ORR irRECIST: | |||||||||||||
| patients | 14% (95% CI, 2%-43%) | |||||||||||||
| CR: 0 (0) PR: 2 (14) | ||||||||||||||
| SD: 7 (50) | ||||||||||||||
| PD: 5 (36) | ||||||||||||||
| Naing et al | Phase 2 clinical | 127 (15) | 56 (22-84) | 46.5 | NR | PEM 200 mg every | Of 127 patients: | NR | NR | NR | No significant | Mixed | NR | At 27 wk: irRECIST |
| 2020 | trial | 3 wk for 24 mo | 78% ≤ 2 et | association with | CR 0: (0) | |||||||||
| [10] | 49% > 2 | PFS at 27 wk | PR 2: (15) | |||||||||||
| SD: 6 (46) | ||||||||||||||
| PD: 5 (38) | ||||||||||||||
| Bedrose | Retrospective | 8 (8) | 38 (21-49) | 50 | NR | PEM 200 mg every | Median No. of | 3 | 0/7 | NR | NR | NR | #1: PTEN and CDKN2B | ORR RECIST 1.1: |
| et al | case series | 3 wk + lenvatinib | prior | (PR) | 25% | |||||||||
| 2020 | therapies: 4 | #3:TP53 germline (PD) | PFS: 5.5 m | |||||||||||
| [11] | (2-9) | #5: CDK4, MDM2, | (95% CI, 1.8-not | |||||||||||
| CCND3 (SD) | reached) | |||||||||||||
| #6: CTNNB1 and TP53 | PR: 2 (25%) | |||||||||||||
| germline (PD) | SD: 1 12.5%) | |||||||||||||
| #7: CTNNB1, ATRX, | PD: 5 (62.5%) | |||||||||||||
| MUTYH, RB1 (PD) |
Abbreviations: ACC, adrenocortical carcinoma; FU, follow-up; LS, Lynch syndrome; MMR-D, mismatch repair-deficiency; MSI-H, microsatellite instability high; NR, not reported; NPR, nonprogression rate; ORR, overall response rate; PD, progressive disease; PD-L1, programmed death-ligand 1; PEM, pembrolizumab; PFS, progression-free survival; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; TILs, tumor-infiltrating lymphocytes; TMB, tumor mutation burden.
Learning Points
· Pembrolizumab may be effective as a second-line therapy for a selected group of patients with advanced and unre- sectable ACC, irrespective of their PD-L1, TMB, and microsatellite instability status.
· The identification of tumors with a hot immune pheno- type may predict a favorable response to immunotherapy in these patients, but this needs to be confirmed.
· Continuous doses of pembrolizumab may not be neces- sary to achieve a sustained and significant response in pa- tients with advanced ACC.
· The development of improved biomarkers is imperative for the precise selection of patients with advanced ACC who are likely to respond positively to immunotherapy.
Acknowledgments
The authors thank André Begin (Division of General Surgery, Department of Surgery, CRCHUS, Sherbrooke, Quebec, Canada) for initially evaluating the patient to determine her suitability for surgery, and for referring her to a surgeon col- league at the CHUM, and Rabia Themar (Department of Pathology, CRCHUS) for her analysis of the pathological spe- cimen following the biopsy of the adrenal lesion.
Contributors
All authors made individual contributions to authorship. L.B .- C., M.S .- J., E.T., J .- F. C., and I.B. were involved in the diagnosis and management of the patient. F.M. was respon- sible for the patient surgery. L.B .- C. and M.S .- J. were involved in the manuscript submission. All authors reviewed and ap- proved the final draft.
Funding
This work received no public or commercial funding.
Disclosures
M.S .- J. is a research investigator for Spruce Bioscience and a speaker for Recordati Rare Disease and GlaxoSmithKline (GSK). L.B .- C. is a speaker for Recordati Rare Disease, Lilly, and Pfizer. The remaining authors have nothing to disclose.
Informed Patient Consent for Publication
Signed informed consent obtained directly from the patient.
Data Availability Statement
Original data generated and analyzed during this study are in- cluded in this published article.
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