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original reports
PD-1 Blockade in Advanced Adrenocortical Carcinoma
Nitya Raj, MD1; Youyun Zheng1; Virginia Kelly1; Seth S. Katz, MD, PHD1; Joanne Chou, MPH1; Richard K.G. Do, MD, PhD1; Marinela Capanu, PhD1; Dmitriy Zamarin, MD, PhD1; Leonard B. Saltz, MD1; Charlotte E. Ariyan, MD, PhD1; Brian R. Untch, MD1; Eileen M. O’Reilly, MD1; Anuradha Gopalan, MD1; Michael F. Berger, PhD1; Kelly Olino, MD2; Neil H. Segal, MD, PhD1; and Diane L. Reidy-Lagunes, MD1
abstract
PURPOSE Adrenocortical carcinomas (ACC) are rare and aggressive malignancies with limited treatment options. This study was undertaken to evaluate the immunogenicity of ACC.
PATIENTS AND METHODS Patients with advanced ACC were enrolled in a phase II study to evaluate the clinical activity of pembrolizumab 200 mg every 3 weeks, without restriction on prior therapy. The primary end point was objective response rate. Efficacy was correlated with tumor programmed death-ligand 1 expression, microsatellite-high and/or mismatch repair deficient (MSI-H/MMR-D) status, and somatic and germline ge- nomic correlates.
RESULTS We enrolled 39 patients with advanced ACC and herein report after a median follow-up of 17.8 months (range, 5.4 months to 34.7 months). The objective response rate to pembrolizumab was 23% (nine patients; 95% CI, 11% to 39%), and the disease control rate was 52% (16 patients; 95% CI, 33% to 69%). The median duration of response was not reached (lower 95% CI, 4.1 months). Two of six patients with MSI-H/MMR-D tumors responded. The other seven patients with objective responses had microsatellite stable tumors. The median progression-free survival was 2.1 months (95% CI, 2.0 months to 10.7 months), and the median overall survival was 24.9 months (95% CI, 4.2 months to not reached). Thirteen percent of patients (n = 5) had treatment-related grade 3 or 4 adverse events. Tumor programmed death-ligand 1 expression and MSI-H/MMR- D status were not associated with objective response.
CONCLUSION MSI-H/MMR-D tumors, for which pembrolizumab is a standard therapy, are more common in ACC than has been recognized. In advanced ACC that is microsatellite stable, pembrolizumab provided clinically meaningful and durable antitumor activity with a manageable safety profile.
J Clin Oncol 38:71-80. @ 2019 by American Society of Clinical Oncology
ASSOCIATED CONTENT Appendix Protocol
Author affiliations and support information (if applicable) appear at the end of this article.
Accepted on September 13, 2019 and published at ascopubs.org/journal/ jco on October 23, 2019: DOI https://doi. org/10.1200/JCO.19. 01586
Clinical trial information:
NCT02673333.
INTRODUCTION
Adrenocortical carcinomas (ACC) are rare tumors with poor prognosis. Most patients present with metasta- ses, and for those with localized disease, recurrences are common. 1,2
Mitotane, a derivative of the insecticide dichlor- odiphenyltricholorethane, is the only drug approved for ACC by the US Federal Drug Administration; it is marked by low efficacy and a narrow therapeutic window, often resulting in serious toxicity.3-8 Platinum- based chemotherapy is also considered a treatment on the basis of the results of the FIRM-ACT study (ClinicalTrials.gov identifier: NCT00094497); how- ever, progression-free survival (PFS) and overall sur- vival (OS) were short (5.6 months and 14.8 months, respectively), and the rate of serious adverse events (AEs) was 58%.9
Several clinical trials, including those with anti-angiogenic drugs and insulin-like growth factor receptor 1 inhibitors,
have failed to provide additional treatments for ACC.10-17 To date, no investigated therapy has offered long-term disease control, and no therapy is standard. Evaluation of immunomodulation in ACC was com- pelling on the basis of observations of adrenalitis in patients receiving immune checkpoint blockade, the presence of programmed death-ligand 1 (PD-L1) ex- pression in the tumor cell membrane, and tumor- infiltrating mononuclear cells in surgically treated ACC.18,19 In addition, there have been reports of checkpoint inhibitor activity in ACC.20 To evaluate the immunogenicity of ACC, we conducted a phase II study to evaluate pembrolizumab, an anti-PD-1 monoclonal antibody, in patients with advanced ACC.
PATIENTS AND METHODS
Patients
Patients 18 years of age or older with a patho- logic diagnosis of unresectable or metastatic ACC
ASCO®
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considered incurable and an Eastern Cooperative Oncology Group performance status of 0 or 1 (on a 0 to 5 scale, with lower scores indicating less disability) were eligible.21 All patients had adequate organ function and measurable disease. Key exclusion criteria included a history of im- munodeficiency or receipt of systemic corticosteroids or immunosuppressive therapy within 7 days of the first dose of pembrolizumab (physiologic replacement of corticoste- roids for adrenal and pituitary insufficiency was permitted). Mitotane continuation was not permitted. Complete eligi- bility criteria are in the Protocol.
Study Oversight
The study was reviewed by the Memorial Sloan Kettering Cancer Center Institutional Review Board and was con- ducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. All patients provided written informed consent before study enrollment.
Study Design
This was an investigator-initiated, single-center, phase II study. Enrolled patients were treated intravenously with pembrolizumab 200 mg every 3 weeks (Appendix Fig A1, online only). No dose reduction was permitted, but dose interruption was permitted. Treatment was continued for up to 24 months/35 cycles, or until disease progression, un- acceptable AEs or intercurrent illness, investigator decision to withdraw the patient, or patient withdrawal of consent. Patients could continue treatment beyond progression if they were deriving clinical benefit. Additional guidelines for treatment discontinuation and AE management are in the Protocol.
Study Assessments
The primary end point was objective response rate (ORR), according to RECIST v1.1, by means of blinded radiologic review.22 Response was assessed by computed tomogra- phy and/or magnetic resonance imaging at baseline and every 9 weeks thereafter. Secondary end points were the duration of response, PFS, OS, and safety. OS was moni- tored during therapy and every 3 months after discontin- uation, until death or consent withdrawal. AEs were monitored throughout treatment and for 30 days after treatment end and were graded in severity according to Common Terminology Criteria for Adverse Events version 4.0.
In patients with available archival tissue, tumor PD-L1 expression was evaluated by immunohistochemistry (IHC; QualTek Molecular Laboratories, Newtown, PA). Positive PD-L1 status was defined as a modified proportion score of 1% or more in the tumor or at tumor stromal interface. The tumor-infiltrating lymphocyte (TIL) score was determined by hematoxylin and eosin stain (0: less than one TIL/high power field [HPF; three to five 20x fields]; 1: one to 10 TIL/HPF; 2: 11 to 20 TIL/HPF; 3: > 20 TIL/HPF).
Mismatch repair (MMR) status was evaluated by IHC; MMR deficiency (MMR-D) was defined as any loss of DNA MMR protein expression. Somatic and germline genetic test- ing, as well as evaluation of loss of heterozygosity status, were performed using the Memorial Sloan Kettering- Integrated Mutation Profiling of Actionable Cancer Targets next-generation sequencing (NGS) platform.23-26 Micro- satellite instability (MSI) was assessed from Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets via MSIsensor.27 MSI-high (MSI-H) status was defined as an MSIsensor score ≥ 10 or an MSIsensor score ≥ 3 with tumor mutation burden (TMB) > 10 mutations/megabase (mut/Mb).
Statistical Analysis
A Simon two-stage design was used to test the null hy- pothesis that the true response rate was ≤ 12% versus the alternative hypothesis that the true response rate was at least 29% (type I/II error rates, 10% each). The null hy- pothesis was set at a true response rate of ≤ 12% using data from FIRM-ACT, in which the ORR in the control arm was 9% versus 23% in the experimental arm.9 In FIRM- ACT, mitotane combined with chemotherapy was studied as a first-line treatment in advanced ACC; treatment with mitotane, cisplatin, etoposide, and doxorubicin was asso- ciated with improved response rate and PFS when com- pared with mitotane and streptozocin; however, the PFS benefit was marginal (5.6 months v 2.2 months), serious AE rates were high (58% v 42%), and OS was low (14.8 months v 12.0 months) with no significant difference.9 For that reason, in this study, it was decided that an ORR of ≤ 12% would be unworthy of additional investigation. In stage I, 21 patients were enrolled, with the study expanded to stage II to enroll an additional 18 patients if at least three of the 21 patients had a partial response (PR) or a complete response (CR). It was predetermined that additional in- vestigation with pembrolizumab would be worthwhile if eight or more of 39 objective responses were observed. Accrual time was estimated at 24 months, with the prob- ability of early termination 53%. Patients who enrolled and were deemed ineligible before starting treatment could be replaced.
The Kaplan-Meier method was used to evaluate PFS and OS. For NGS analyses, common recurrent somatic alter- ations were defined as those occurring in five or more patients. A permutation-based log-rank test was used to examine the association between outcomes and somatic alterations. Allele-specific copy number at HLA class I loci was inferred using Loss Of Heterozygosity of Human Leukocytes Antigen (LOHHLA) software.28 Fisher’s exact test was used to examine the association between somatic alterations, HLA zygosity, TIL score, and tumor MSI, MMR, and PD-L1 status and response. The Mann-Whitney test was used to examine the association between TMB and response. Pvalues in the subgroup analyses were two sided (type | error, 5%); P < . 05 was considered statistically
significant. Statistical analyses were performed using SAS Version 9.3 (SAS Institute, Cary, NC) or R Version 3.3.2. The data-lock date was January 11, 2019.
RESULTS
Patients
Thirty-nine patients were enrolled between February 10, 2016, and June 20, 2018, and they received at least one dose of pembrolizumab (Table 1). Forty-four patients had undergone eligibility assessment; five were ineligible. In stage I, three patients had objective responses. The study was expanded to stage II with 18 additional patients
| Characteristic | Patients |
|---|---|
| No. of patients | 39 |
| Sex, male | 15 (38) |
| Age, years, median (range) | 62 (19-87) |
| Time since diagnosis to C1D1, months, median (range) | 15 (1-131) |
| Ethnicity | |
| White | 36 (92) |
| Black/Asian/Other | 3 (8) |
| ECOG PS | |
| 0 | 11 (28) |
| 1 | 28 (72) |
| Current or former smoker | 14 (36) |
| Locally advanced disease at initial presentation | 23 (59) |
| Site of metastases | |
| Lung | 33 (85) |
| Liver | 23 (59) |
| Peritoneum | 10 (26) |
| Lymph nodes | 10 (26) |
| Bone | 5 (13) |
| Soft tissue | 5 (13) |
| Prior Surgery | |
| Adrenalectomy | 27 (69) |
| Debulking of metastatic disease | 2 (5) |
| Regional treatment | 4 (10) |
| Prior systemic therapy | 28 (72) |
| Mitotane | 23 (59) |
| Platinum-based therapy | 17 (44) |
| Germline MMR alteration (Lynch syndrome; n = 33) | 2 (6) |
| MSI-H/MMR-D (n = 38) | 6 (16) |
| PD-L1 expression ≥ 1 (n=34) | 7 (21) |
NOTE. Data are presented as No. (%) unless indicated otherwise.
Abbreviations: C1D1, cycle 1 day 1; ECOG PS, Eastern Cooperative Oncology Group performance status; MMR, mismatch repair; MSI-H/MMR-D, microsatellite instability-high/mismatch repair-deficient; PD-L1, programmed death-ligand 1.
accrued. Seventy-two percent of the enrolled patients had received prior systemic therapy.
Radiographic Response
Nine patients of the 39 treated demonstrated objective responses (nine PRs, no CRs; ORR, 23% [95% CI, 11% to 39%]). Seven additional patients (18%) demonstrated stable disease (SD). The disease control rate (percentage of patients who demonstrated objective response or SD) was 52% (95% CI, 33% to 69%).
Median treatment duration (interval from treatment start to end-of-study date) was 2.3 months (range, 0.3-24.3 months). For the nine PR patients, median time to response was 4.1 months (range, 1.7-10.5 months) and median response duration was not reached (lower 95% CI, 4.1 months). Response characteristics to pembrolizumab are listed in Table 2 and Figure 1.
Two patients had mixed responses; both had reduction in lung metastases but progression in hepatic metastases. In one patient, a complete response was noted in the lung metastases after treatment with pembrolizumab; the pa- tient subsequently underwent hepatic arterial bland em- bolization and currently has no evidence of disease on imaging. Two patients with PRs experienced pseudo- progression (Appendix Fig A2, online only). Data available on seven enrolled patients who went on to receive cytotoxic therapy after treatment with pembrolizumab demonstrated no responses (zero of seven).
Survival Analyses
The median follow-up at the time of data-lock was 17.8 months (range, 5.4-34.7 months). Twenty deaths were observed at analysis. No death was attributed to treatment. Median PFS was 2.1 months (95% CI, 2.0 months to 10.7 months; Fig 1). The 6-month PFS rate was 20% (95% CI, 9% to 42%). Median OS was 24.9 months
TABLE 2. Objective Response According to RECIST v1.1 Criteria Type of Response N = 39
| Complete response, No. (%) | 0 |
| Partial response, No. (%)* | 9 (23) |
| Stable disease, No. (%) | 7 (18) |
| Progressive disease, No. (%) | 15 (38) |
| Could not be evaluated, No. (%)+ | 8 (21) |
| Objective response rate, % (95% CI) | 23 (11 to 39) |
| Disease control rate, % (95% CI) | 52 (33 to 69) |
| Median duration of response, months | Not reached |
| Time to response, months, median (range) | 4.1 (1.7-10.5) |
*All objective responses in this study were classified as partial responses by RECIST v1.1.
tPatients could not be evaluated if they did not undergo a scan at 9 weeks because of clinical progression.
A
C
D
Maximum Decrease From Baseline (%)
100
MSI-H/MMR-D
75
Y
100
100
50
N
Progression-Free Survival (%)
Overall Survival (%)
20
75
75
0
*
50
50
-30
-50
25
25
-75
-100
0
0
0
6
12
18
24
30
36
0
6
12
18
24
30
36
Time Since Immunotherapy (months)
Time Since Immunotherapy (months)
No. at risk:
39
13
7
6
2
0
0
No. at risk:
39
23
15
10
10
4
0
B
Response
Patients With Evidence of Response
PR
Platinum-based chemotherapy
Y
N
Mitotane
Y
N
MSI-H/MMR-D
Y
N
Timeline
Radiographic progression
0
5
10
15
20
25
30
35
Ongoing study treatment
Time Since Treatment Initiation (months)
First response
Time on protocol
> Ongoing response
(95% CI, 4.2 months to not reached; Fig 1). The 2-year OS rate was 50% (95% CI, 36% to 69%).
Three patients had PRs exceeding 24 months of treatment. These patients remain on active surveillance with contin- ued response off therapy (Fig 1).
Safety
Treatment-related AEs (TRAEs) are listed in Table 3; TRAEs of any grade occurred in 23 patients (59%). Grade
3/4 TRAEs occurred in five patients (13%). Thirteen patients (33%) experienced immune-mediated AEs; the most common were liver function test (LFT) elevation (23%), hypothyroidism (8%), and kidney dysfunction (5%). Among patients with immune-mediated AEs, 10 (26%) received systemic corticosteroids, seven (18%) experienced treatment interruption, and two (5%) dis- continued therapy for LFT elevation per investigator discretion; both patients discontinuing treatment had
| Adverse Event | All Grades (1-4),* No. patients (%) | Grades 3-4,* No. patients (%) |
|---|---|---|
| Total No. of patients with treatment- related adverse events | 23 (59) | 5 (13) |
| Laboratory investigations | ||
| Increased AST/ALT+ | 9 (23) | 4 (10) |
| Hypocalcemia | 4 (10) | 1 (3) |
| Increased alkaline phosphatase | 4 (10) | |
| Lymphopenia | 2 (5) | |
| Hypoalbuminemia | 2 (5) | 1 (3) |
| Increased creatininet | 2 (5) | |
| Anemia | 1 (3) | |
| Thrombocytopenia | 1 (3) | |
| Neutropenia | 1 (3) | |
| Hyperglycemiat | 1 (3) | |
| Hypokalemia | 1 (3) | 1 (3) |
| Hypophosphatemia | 1 (3) | 1 (3) |
| Hypomagnesemia | 1 (3) | 1 (3) |
| Hyponatremia | 1 (3) | |
| Increased bilirubint | 1 (3) | |
| General disorders | ||
| Fatigue | 8 (20) | |
| Chills | 2 (5) | |
| Peripheral edema | 1 (3) | |
| Edema limbs | 1 (3) | |
| Pain | 1 (3) | |
| Libido decreased | 1 (3) | |
| Fever | 1 (3) | |
| Malaise | 1 (3) | |
| Other general toxicities | 1 (3) | |
| Endocrine disorders | ||
| Hypothyroidismt | 3 (8) | |
| Hyperthyroidism | 1 (3) | |
| Adrenal insufficiency | 1 (3) | |
| GI disorders | ||
| Nausea | 2 (5) | |
| Anorexia | 1 (3) | |
| Vomiting | 1 (3) | |
| Constipation | 1 (3) | |
| Diarrheat | 1 (3) | |
| Duodenitis | 1 (3) | |
| Skin disorders | ||
| Pruritus | 7 (18) | |
| Rash | 3 (8) | |
| Hyperpigmentationt | 2 (5) | |
| (continued on following page) | ||
PRs that continue on observation. All patients with ob- jective responses to pembrolizumab experienced LFT elevation ≥ grade 2.
Two patients demonstrating PRs developed skin and tongue hyperpigmentation (Fig 2). Both patients had ele- vated adrenocorticotropin hormone (ACTH) levels. One patient underwent pituitary magnetic resonance imaging to evaluate for hypophysitis; imaging demonstrated a normal pituitary.
Two patients demonstrating PRs discontinued therapy before 24 months of treatment per investigator discretion. Patient 1 received a single dose of pembrolizumab and experienced grade 3 LFT elevation; germline testing identified an MSH6 deletion consistent with Lynch syn- drome (LS). Before treatment, the patient’s disease har- bored an aggressive course; imaging 5.5 weeks after receiving pembrolizumab demonstrated response (Fig 2). Because of the early tumor reduction and LFT elevation, the patient did not receive additional pembrolizumab and re- mains off therapy now, more than 2.5 years after the single treatment dose. Patient 2 discontinued therapy when grade 2 LFT elevation was observed after two treatment cycles. The patient was treated with corticosteroids, and imaging at 9 weeks demonstrated tumor reduction; no additional treatment was administered, and the disease continues to respond off therapy almost 1 year after the second pem- brolizumab dose (Fig 2).
Molecular Analyses
Pretreatment, archival tumor tissue and blood normals were collected for correlative testing. Seven of 34 tested tumors (21%) were PD-L1 positive. Response was in- dependent of PD-L1 status (P > .95). ORR in PD- L1-positive tumors was 29% (95% CI, 4% to 71%); ORR in PD-L1-negative tumors was 26% (95% CI, 12% to 47%; Fig 3).
Six of 38 tested tumors (16%) were MSI-H/MMR-D; two patients demonstrated PRs, two demonstrated SD, and two demonstrated rapid progression (prior to radio- graphic assessment). In the two patients with progression, one was heavily pretreated, presenting after 17 months of therapy. This patient expired after one dose of pem- brolizumab (MSIsensor 16.62, MSH2/6 loss by IHC). The second patient’s tumor was MMR proficient by IHC and MSI-H on the basis of MSI-sensor ≥ 3 and TMB > 10. Tumor MSI-H/MMR-D status was not a significant marker predictive of response (P = . 61; Fig 3).
NGS results are listed in Figure 3. There was no relationship between any particular somatic alteration and response (Appendix Table A1, online only). All tested tumors had a TIL score of at least 1. There was no relationship between a TIL score of 1 versus TIL score of 2 or 3 and response (P = . 22). Median TMB was 2.4 mut/Mb (range, 0-31.5 mut/Mb); no significant relationship was observed between TMB and response (P = . 25; Fig 3). A trend of increase in
| Adverse Event | All Grades (1-4),* No. patients (%) | Grades 3-4,* No. patients (%) |
|---|---|---|
| Dry skin | 2 (5) | |
| Alopecia | 1 (3) | |
| Skin and subcutaneous tissue disorder | 1 (3) | |
| Mucositis | 1 (3) | |
| Eye disorders | ||
| Dry eyes | 1 (3) | |
| Conjunctivitis | 1 (3) | |
| CNS disorders | ||
| Dizziness | 1 (3) | |
| Respiratory disorders | ||
| Pneumonitist | 1 (3) | |
| Infusion | ||
| Infusion reaction (hypotensive)t | 1 (3) |
NOTE. Treatment-related adverse events were defined as any adverse event possibly, probably, or definitely related to treatment with pembrolizumab. *A patient who experienced multiple occurrences of an adverse event was counted once at the maximum recorded grade.
tImmune-related adverse events.
homozygosity was seen in nonresponder patients; of the 32 patients analyzed for HLA zygosity, 76% (19 of 25) non- responders and 43% (three of seven) responders had germline homozygosity or somatic loss of heterozygosity in at least one HLA locus (P =. 17). Germline testing identified six likely pathogenic germline alterations; in the patients who did not have LS, no association was noted between germline status and response (Appendix Table A2, online only).
DISCUSSION
Our results demonstrate that pembrolizumab provides noteworthy clinical efficacy with dramatically improved safety profile when compared with other therapies.9 We observed a substantial ORR (23%) and disease control rate (52%) during treatment, associated with a median OS of 24.9 months. Our findings are more favorable than those of a phase I study recently published in metastatic ACC, in which a 6% ORR was observed during treatment with avelumab (with 50% of the treated patients also continuing mitotane), with 42% of patients experiencing SD; these patients all previously received platinum-based chemotherapy (average of two lines of prior systemic therapy; 74% received two or more lines).29 Our study included patients in any treatment line (31% with more than one prior therapy line) and required mitotane dis- continuation and therefore had fewer AEs (59% v82%). A reason for our higher response rate may be that many
patients had received earlier treatment; although our responders had all had at least one prior therapy line, three (33%) had received platinum-based therapy and eight (89%) had received mitotane (Fig 1). In the phase I cohort, ORR was 15% in patients who had received only one prior therapy line.29
Tumor MSI-H/MMR-D status is a known predictive bio- marker of response to immune-based therapies. 30,31 Six patients in this study had MSI-H/MMR-D tumors, and two patients, both with LS, demonstrated PRs. Our findings confirm earlier observations of objective response to immune-based therapies in MSI-H/MMR-D tumors and the observation that ACC can arise in conjunction with LS.32-36 In our treated cohort, we observed a notable MSI-H/MMR-D rate (16%), and our LS rate (6%) is similar to that in other tumors, including colorectal and endometrial cancers; separate investigation in patients with ACC through The Cancer Genome Atlas Research Atlas and others, and via MSIsensor, has demonstrated a notable prevalence of both LS and MSI in this disease. 37-42 Taken together, the findings illustrate that MSI-H/MMR-D screening should be standard practice for patients with advanced ACC, specifically to evaluate for LS. Four MSI-H/ MMR-D ACC tumors did not respond, which may have been in part because of the advanced nature of the disease when pembrolizumab was administered. Notably, most patients with objective responses in this study (78%) did not have LS and had microsatellite-stable (MSS) tumors. Our finding of long-term, highly durable disease control with pembrolizumab is novel and of importance. To date, only one of seven responding patients with MSS tumors later had disease progression. Therefore, the short PFS of the study should be interpreted with caution because those patients who do not respond do so early, affecting the median PFS.
To identify additional biomarkers of response, outcomes were explored by tumor PD-L1 status and genomic correlates. There was no significant association be- tween tumor PD-L1 status, TMB, TIL score, or somatic alterations and response. A trend was noted of an in- crease in homozygosity in nonresponder patients; this has been previously described and warrants additional investigation. 43
This study was based on our understanding that im- munomodulatory drug treatment can result in endocrine- related AEs, including adrenalitis.18 Two enrolled patients, both of whom had PRs, experienced notable hyperpigmentation; to our knowledge, this observation has not been described in patients with response to anti-PD-1 therapies. Bloodwork in these patients dem- onstrated elevated ACTH levels, with hyperpigmentation suspected to be caused by ACTH binding to the mela- nocortin receptor, triggering melanocyte differentiation.44 All patients with objective responses in this study also had immune-related LFT elevation. These observations
A
Week 70 (after one cycle of pembrolizumab)
Baseline
B
Week 17 (after two cycles of pembrolizumab)
Baseline
highlight that in ACC, host-related factors (PD-L1 in- hibition in a presumed immunogenic environment), as described in other cancers, may help inform outcomes during treatment with immunologic drugs.45,46 Some patients in this study received sustained responses with as little as one or two doses of pembrolizumab, suggesting that continuous drug exposure may be unnecessary. All patients with an objective response had low- to moderate-
volume disease, suggesting that these responders may have had a more indolent growth pattern.
Study limitations include the heterogeneity of our pop- ulation, specifically the inclusion of patients in any treat- ment line, varying degrees of aggressiveness of disease, and the absence of a standard-of-care comparator. How- ever, despite these limitations, response to pembrolizumab was seen. The heterogeneity could also explain the
A
B
Response Mutation burden
30
Response
MSI-H/MMR-D
Mutation Burden (mut/Mb)
PR
SD
TIL
20
PD
Response
PD-L1 staining
PR
HLA homozygosity
SD
39
TP53
10
PD
18
CDKN2A/B
Mutation burden
15
APC
30
20
15
ATRX
0
10
0
15
CTNNB1
PR
SD
PD
MSI-H/MMR-D
15
MEN1
Y
15
RB1
N
15
TERT
C
TIL
12
DROSHA
25
MSI-H/MMR-D
3
12
FGFR4
20
Y
2
12
NF1
No. of Patients
N
1
Not available
9
AKT3
15
PD-L1 staining
9
ANKRD11
ARAF
10
Y
9
N
9
AXIN1
5
Not available
9
CDC73
HLA homozygosity
KMT2A
0
9
Y
9
MSH2
PR
SD
PD
N
9
MUTYH
Not available
9
NCOA3
D
9
RBM10
20
9
SDHA
PD-L1 staining
6
MSH6
No. of Patients
15
Y
N
Missense mutation
In-frame mutations
Amplification
Alterations
Truncating mutations
Multiple mutations
Deletion
10
Noncoding mutations
Germline truncating mutation
Germline missense mutation
5
0
PR
SD
PD
Response
absence of correlates of response. Given the rarity of ACC, these limitations are in line with the challenges of con- ducting clinical studies in orphan diseases.
Our findings demonstrate that MSI-H/MMR-D screen- ing should be standard practice for patients with ad- vanced ACC and confirm earlier observations of activity
for pembrolizumab in MSI-H/MMR-D tumors. Most im- portantly, we demonstrate the novel finding of clini- cally meaningful and durable activity in advanced ACC that is MSS. The results demonstrate that pem- brolizumab is an effective treatment option for patients with advanced ACC.
AFFILIATIONS
1Memorial Sloan Kettering Cancer Center, New York, NY
2Yale School of Medicine, New Haven, CT
CORRESPONDING AUTHOR
Nitya Raj, MD, Department of Medicine, Division of Gastrointestinal Medical Oncology, Memorial Sloan Kettering Cancer Center, 300 East 66th St, Room 1007, New York, NY 10065; e-mail: rajn@mskcc.org.
Downloaded from ascopubs.org by National Library of Medicine - US on April 4, 2026 from 130.014.025.182
Copyright @ 2026 American Society of Clinical Oncology. All rights reserved.
Immunotherapy in Adrenocortical Carcinoma
SUPPORT
Supported by Merck & Co., Cycle for Survival, the Drew O’Donoghue Fund, and the National Cancer Institute MSK Cancer Core Grant (P30- CA008748).Presented in part as a poster presentation at the 2019 ASCO Annual Meeting in Chicago, IL, May 31-June 4, 2019.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST AND DATA AVAILABILITY STATEMENT
Disclosures provided by the authors and data availability statement (if applicable) are available with this article at DOI https://doi.org/10.1200/ JCO.19.01586.
AUTHOR CONTRIBUTIONS
Conception and design: Nitya Raj, Leonard B. Saltz, Charlotte E. Ariyan, Kelly Olino, Neil H. Segal, Diane L. Reidy-Lagunes
Financial support: Diane L. Reidy-Lagunes
Administrative support: Virginia Kelly, Diane L. Reidy-Lagunes
Provision of study material or patients: Nitya Raj, Eileen M. O’Reilly, Diane L. Reidy-Lagunes
Collection and assembly of data: Nitya Raj, Virginia Kelly, Seth S. Katz, Richard K.G. Do, Leonard B. Saltz, Eileen M. O’Reilly, Neil H. Segal, Diane L. Reidy-Lagunes
Data analysis and interpretation: Nitya Raj, Youyun Zheng, Joanne Chou, Marinela Capanu, Dmitriy Zamarin, Leonard B. Saltz, Brian R. Untch, Eileen M. O’Reilly, Anuradha Gopalan, Michael F. Berger, Kelly Olino, Neil H. Segal, Diane L. Reidy-Lagunes
Manuscript writing: All authors
Final approval of manuscript: All authors
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AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
PD-1 Blockade in Advanced Adrenocortical Carcinoma
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/journal/jco/site/ifc.
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| Nitya Raj | Charlotte E. Ariyan |
|---|---|
| Research Funding: Novartis (Inst), Xencor (Inst) | Employment: Pfizer (I) |
| Seth S. Katz | Stock and Other Ownership Interests: Pfizer (I) |
| Stock and Other Ownership Interests: Edwards LifeSciences, Editas Medicine, | Speakers' Bureau: Bristol-Myers Squibb |
| Intellia Therapeutics, CRISPR Therapeutics, Sanofi, Quest Diagnostics (I) | Eileen M. O'Reilly |
| Richard K.G. Do | Consulting or Advisory Role: Ipsen, Merck |
| Honoraria: Bayer, ALK (I) | Research Funding: AstraZeneca/MedImmune (Inst) |
| Consulting or Advisory Role: DBV (I) | Michael F. Berger |
| Patents, Royalties, Other Intellectual Property: UptoDate chapters on Food | Consulting or Advisory Role: Roche |
| Allergy (I) | Research Funding: Illumina |
| Dmitriy Zamarin | Neil H. Segal |
| Employment: Acorda Therapeutics (I) | Consulting or Advisory Role: Bristol-Myers Squibb, Pfizer, AstraZeneca/ |
| Consulting or Advisory Role: BioMed Valley Discoveries, Merck, PsiOxus Therapeutics, Synlogic, Western Oncolytics, Tesaro, Agenus, Trieza Therapeutics, ACM Biolabs | MedImmune, Imugene, Roche/Genentech, Pieris Pharmaceuticals, Synlogic, Aduro Biotech, Kyn Therapeutics, Boehringer Ingelheim, Merck, PureTech, Horizon Pharma, EMD Serono, Gritstone Oncology, Chugai Pharma, TRM |
| Research Funding: Merck | Oncology, IFM Therapeutics, PsiOxus Therapeutics, CStone Pharmaceuticals Research Funding: MedImmune, Bristol-Myers Squibb, Pfizer, Roche/ Genentech, Merck, Incyte |
| Patents, Royalties, Other Intellectual Property: I hold a patent regarding the use | |
| of recombinant Newcastle Disease Virus (NDV) for cancer therapy (Inst) | |
| Travel, Accommodations, Expenses: Roche | Diane L. Reidy-Lagunes |
| Leonard B. Saltz | Honoraria: Novartis |
| Consulting or Advisory Role: McNeil PPC (I) | Consulting or Advisory Role: Ipsen, Novartis, Lexicon, AAA |
| Research Funding: Taiho Pharmaceutical | Research Funding: Novartis, Ipsen No other potential conflicts of interest were reported. |
Downloaded from ascopubs.org by National Library of Medicine - US on April 4, 2026 from 130.014.025.182 Copyright @ 2026 American Society of Clinical Oncology. All rights reserved.
Key eligibility criteria
Treatment
Unresectable or metastatic ACC Measurable disease Any line of therapy
Pembrolizumab 200 mg every 3 weeks
Treat until progression or unacceptable toxicity (maximum of 24 months/35 cycles)*
A
B
Week 27 (after 9 cycles of pembrolizumab)
C
Week 99 (after 33 cycles of pembrolizumab)
Baseline
Immunotherapy in Adrenocortical Carcinoma
| Gene | Overall (N = 33) | Objective Responder (n = 9) | Nonresponder (n = 24) | P |
|---|---|---|---|---|
| APC | > .95 | |||
| 0* | 28 (71.8) | 7 (77.8) | 21 (70) | |
| 1 | 5 (12.8) | 1 (11.1) | 4 (13.3) | |
| NA | 6 (15.4) | 1 (11.1) | 5 (16.7) | |
| ATRX | > .302 | |||
| 0 | 28 (71.8) | 8 (88.9) | 20 (66.7) | |
| 1 | 5 (12.8) | 0 (0) | 5 (16.7) | |
| NA | 6 (15.4) | 1 (11.1) | 5 (16.7) | |
| CDKN2A | .652 | |||
| 0 | 26 (66.7) | 7 (77.8) | 19 (63.3) | |
| 1 | 7 (17.9) | 1 (11.1) | 6 (20) | |
| NA | 6 (15.4) | 1 (11.1) | 5 (16.7) | |
| CDKN2B | > .95 | |||
| 0 | 27 (69.2) | 7 (77.8) | 20 (66.7) | |
| 1 | 6 (15.4) | 1 (11.1) | 5 (16.7) | |
| NA | 6 (15.4) | 1 (11.1) | 5 (16.7) | |
| CTNNB1 | > .95 | |||
| 0 | 28 (71.8) | 7 (77.8) | 21 (70) | |
| 1 | 5 (12.8) | 1 (11.1) | 4 (13.3) | |
| NA | 6 (15.4) | 1 (11.1) | 5 (16.7) | |
| MEN1 | .078 | |||
| 0 | 28 (71.8) | 5 (55.6) | 23 (76.7) | |
| 1 | 5 (12.8) | 3 (33.3) | 2 (6.7) | |
| NA | 6 (15.4) | 1 (11.1) | 5 (16.7) | |
| RB1 | .574 | |||
| 0 | 28 (71.8) | 6 (66.7) | 22 (73.3) | |
| 1 | 5 (12.8) | 2 (22.2) | 3 (10) | |
| NA | 6 (15.4) | 1 (11.1) | 5 (16.7) | |
| TERT | .574 | |||
| 0 | 28 (71.8) | 6 (66.7) | 22 (73.3) | |
| 1 | 5 (12.8) | 2 (22.2) | 3 (10) | |
| NA | 6 (15.4) | 1 (11.1) | 5 (16.7) | |
| TP53 | .681 | |||
| 0 | 20 (51.3) | 4 (44.4) | 16 (53.3) | |
| 1 | 13 (33.3) | 4 (44.4) | 9 (30) | |
| NA | 6 (15.4) | 1 (11.1) | 5 (16.7) |
NOTE. Data are presented as No. (%).
Abbreviation: NA, not available.
*0 indicates absence of alteration and 1 indicates presence of alteration.
| Gene | Mutation | HGVSp_Short | No. of Patients | Penetrance and Significance |
|---|---|---|---|---|
| MSH6 | c.3261delC | p.F1088Sfs*2 | 1 | High penetrance |
| SDHC | c.43C>T | p.R15* | 1 | High penetrance |
| MSH2 | c.1906G>C | p.A636P | 1 | High penetrance |
| BARD1 | c.627_628delAA | p.K209Nfs*4 | 1 | Low penetrance |
| MUTYH (Heterozygous) | c.1240C>T | p.Q414* | 1 | Low penetrance |
| MUTYH (Heterozygous) | c.1187G>A | p.G396D | 1 | Low penetrance |
NOTE. Pathogenic or likely pathogenic germline alterations were identified in 6 patients (18%).