Journal for ImmunoTherapy of Cancer
Combined lenvatinib and pembrolizumab as salvage therapy in advanced adrenal cortical carcinoma
Sara Bedrose 1,1,2 Kevin Charles Miller,3 Lina Altameemi,1 Mohamed S Ali,4 Sameh Nassar,5 Naveen Garg,5 Marilyne Daher,1 Keith D Eaton,6 Jeffrey Thomas Yorio,7 Davey B Daniel,8 Matthew Campbell,9 Keith C Bible, 10 Mabel Ryder,1º Ashish V Chintakuntlawar,10 Mouhammed Amir Habra 1 1
To cite: Bedrose S, Miller KC, Altameemi L, et al. Combined lenvatinib and pembrolizumab as salvage therapy in advanced adrenal cortical carcinoma. Journal for ImmunoTherapy of Cancer 2020;8:e001009. doi:10.1136/jitc-2020-001009
SB and KCM contributed equally. SB and KCM are joint first authors.
Accepted 18 June 2020
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@ Author(s) (or their employer(s) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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Correspondence to
Mouhammed Amir Habra; mahabra@mdanderson.org
ABSTRACT
Background There is no effective systemic therapy for metastatic adrenal cortical carcinoma (ACC) after failure of platinum-based chemotherapy. The efficacies of single- agent oral multikinase inhibitors (MKIs) or salvage immune checkpoint inhibitors (CPIs) have been very limited. It is unknown whether combining CPIs, such as pembrolizumab (PEM), with other therapies, such as MKIs, could yield higher response rates in ACC, yet this combination has shown promise in other cancers. Herein, we describe the first case series using PEM in combination with the MKI lenvatinib (LEN) in patients with progressive, metastatic ACC.
Methods A retrospective case series describing the use of LEN/PEM as salvage therapy in patients with progressive/ metastatic ACC.
Results Eight patients were treated with the LEN/PEM combination therapy. Half were female, and the median age at time of diagnosis was 38 years (range 21-49). Three (37.5%) patients had hormonally active ACC. The median number of prior lines of systemic therapy was 4 (range 2-9). Six (75%) patients had had disease progression on prior CPIs and five (62.5%) patients had progressed on prior MKI therapy. The median progression- free survival was 5.5 months (95% CI 1.8-not reached) and median duration of therapy was 8.5 months (range 2-22). Two (25%) patients had a partial response, one (12.5%) patient had stable disease, and five (62.5%) patients had progressive disease. None of the eight patients stopped therapy because of adverse events. Conclusions In our small cohort of heavily pretreated patients with ACC, the combination of LEN/PEM was associated with objective responses in a subset of patients without significant toxicity. This combination should be formally investigated in phase II clinical trial with robust correlative studies to identify predictors for response.
BACKGROUND
Adrenal cortical carcinoma (ACC) is an aggressive malignancy that recurs in the vast majority of patients with a very high mortality rate. Both the rarity and aggressiveness of ACC have contributed to a lack of effective therapies to date. For recurrent/metastatic ACC, the combination of etoposide, doxorubicin, and
cisplatin (EDP), with or without mitotane, is considered the first-line treatment based on the First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carci- noma Treatment (FIRM-ACT) trial.1 However, this regimen (EDP+mitotane) has limited efficacy, as evidenced by an overall response rate of 23% and a median progression-free survival (PFS) of 5 months.2 Salvage thera- pies for patients who progress after treatment with mitotane or cytotoxic chemotherapy are desperately needed.
Multiple trials have investigated the efficacy of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors in ACC, including sorafenib, axitinib, and sunitinib.3 4 However, these agents showed very limited effi- cacy as single-agent therapies for advanced ACC. Additionally, immune checkpoint inhibi- tors (CPIs) are an attractive option to investigate in ACC because of their efficacy in numerous solid malignancies. However, emerging data have shown limited efficacy for single-agent CPIs in ACC, with durable responses limited to a small subset of patients.5-
The combination of multikinase inhibi- tors (MKIs) with CPIs has shown promising data in multiple cancers.8-11 In particular, the MKI lenvatinib (LEN), which inhibits Vascular Endothelial Growth Factor Receptor 1-3 (VEGFR 1-3), Fibroblast Growth Factor Receptor 1-4 (FGFR 1-4), Platellet Derived Growth Factor Receptor-« (PDGFR-«), RET, and KIT, has been combined with the anti-PD-1 monoclonal antibody pembrolizumab (PEM) in phase I/II trials. Synergy between LEN and PEM is putatively due to LEN creating a more therapeutically advantageous tumor-immune microenvironment,12 in part through blockade of immunosuppressive VEGFR signaling. This combination was approved by the United States Food and Drug Administration (FDA)
for advanced endometrial carcinoma in 2019,9 and is currently being studied as a salvage therapy for thyroid cancer,10 renal cell carcinoma,11 head and neck cancer, and other solid tumors.8
There are no published data on use of the LEN/PEM combination in ACC. Herein, we report the clinical course of eight patients with recurrent/metastatic ACC who were treated with LEN/PEM, representing the first reported case series. The majority of the patients in our cohort progressed through several lines of therapy prior to LEN/ PEM, including several who had previous disease progres- sion while receiving single-agent CPIs and/or MKIs.
METHODS
Eight patients with recurrent and/or metastatic ACC were treated with combination LEN/PEM after disease progres- sion on prior lines of therapy. After obtaining the Institu- tional Review Board approval, electronic medical records were reviewed. All pathologic diagnoses of ACC were confirmed on referral to MD Anderson and Mayo Clinic. The European Network for the Study of Adrenal Tumors staging system was used to define stage13 at the time of diagnosis. LEN and PEM were obtained through insurance or via patient assistance programs. LEN was administered orally at a starting dose of 24mg (n=3), 20mg (n=2), 18mg (n=1), and 10mg (n=2) according to clinicians’ judgment about each patient’s tolerability. PEM was administered intravenously at a dose of 200mg every 3 weeks.
We used Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 criteria to evaluate objective response to prior lines of therapy and the LEN/PEM combination.14 PFS was defined as the time from the start of LEN/PEM combination therapy until either disease progression as defined by RECIST V.1.1 or death, whichever occurred first. Patients who remained alive and progression free were censored at the time of last follow-up, as of December 31, 2019. Median PFS, with 95% CIs, was estimated using
the Kaplan-Meier method. Adverse events (AEs) were evaluated using Common Terminology Criteria for Adverse Events (CTCAE) V.4.03.
RESULTS Patient characteristics
Eight patients with ACC (four women, four men) were treated with LEN/PEM for recurrent/metastatic ACC. Their baseline characteristics and tumor genetics are summarized in table 1. The median age at the time of diagnosis was 38 years (range 21-49). At diagnosis, three (37.5%) patients had stage IV ACC, while the remaining five (62.5%) patients developed metastases after their initial diagnosis with stage II (n=2) or III (n=3) ACC. Three (37.5%) patients had hormonally active ACC. Seven of the eight patients had somatic mutation testing for microsatellite instability or deficiency in mismatch repair genes and were found to be negative. The median number of prior lines of systemic therapy was four (range 2-9). Median time in months between initial ACC diag- nosis and initiation of combination therapy was 42.5 months (range 5-86 months). Six (75%) patients had had disease progression while receiving prior CPIs, and five (62.5%) patients had progressed on prior MKI therapy (sorafenib, cabozantinib, and LEN, n=1; cabozan- tinib, n=2; single-agent LEN, n=2). No patients were on mitotane at the time of initiation of LEN/PEM therapy. Details of the individual patients’ prior treatment modal- ities received are described in table 2. All eight patients had progressive distant metastatic lesions on radiological staging scans prior to initiation of LEN/PEM combina- tion therapy.
Efficacy of combined LEN and PEM
Objective responses are summarized in table 3 as well as figure 1. The median duration of LEN/PEM therapy
| Table 1 Baseline characteristics | ||||||
|---|---|---|---|---|---|---|
| Sex | Age at diagnosis (years) | Hormonal function | Stage at diagnosis | Sites of metastatic disease at initiation of LEN/PEM | Genetic findings | |
| 1 | M | 37 | No | IV | Lungs, liver, bone | PTEN and CDKN2B mutations |
| 2 | F | 22 | No | III | Lung | No mutations |
| 3 | F | 21 | Yes | II | Lung, liver, adrenal bed | TP53 mutation (germline) |
| 4 | M | 39 | No | IV | Liver, lung, retroperitoneum, and bone | No mutations |
| 5 | M | 44 | Yes | IV | Lung | CDK4, MDM2, and CCND3 mutations |
| 6 | M | 34 | Yes | II | Lung, abdomen, and liver | CTNNB1 and TP53 mutation (germline) |
| 7 | F | 41 | No | III | Lung, abdomen, pelvis, and liver | CTNNB1, ATRX, MUTYH, and RB1 mutations |
| 8 | F | 49 | No | II | Lung, abdomen, and liver | No mutations |
LEN, lenvatinib; PEM, pembrolizumab.
a
| Patient | Lines PEM | of therapy prior to LEN/ | PFS | Time since diagnosis till initiation of LEN/PEM therapy in months |
|---|---|---|---|---|
| 1 | 1. | Sorafenib | 2 months | 56 months |
| 2. | Mitotane, etoposide, | 6 months | ||
| doxorubicin, and cisplatin | ||||
| 3. | PD-1 inhibitor (nivolumab) and radiotherapy | 4 months | ||
| 4. | ACAT inhibitor | 3 months | ||
| 5. | Wee-1 inhibitor | 4 months | ||
| 6. | Cabozantinib | 2 months | ||
| 7. | PD-1 inhibitor (PEM) and LAG- 3 inhibitor | 4 months | ||
| 8. | Gemcitabine and capecitabine | 4 months | ||
| 9. | LEN (single-agent) | 12 months | ||
| 2 | 1. | Mitotane | 7 months | 66 months |
| 2. | PD-1 inhibitor (nivolumab) | 5 months | ||
| 3. | CSF-1R inhibitor and PD-1 | 2 months | ||
| inhibitor (PEM) | ||||
| 4. | Etoposide, doxorubicin, and | 2 months | ||
| cisplatin | ||||
| 3 | 1. | Mitotane | 36 months | 68 months |
| 2. | Etoposide, doxorubicin, and cisplatin | 1 month | ||
| 3. | Ipilimumab and PD-1 inhibitor | 2 months | ||
| (nivolumab) | ||||
| 4. | LEN (single-agent) | 6 months | ||
| 4 | 1. | Mitotane and adjuvant radiotherapy | 18 months | 86 months |
| 2. | Mitotane, etoposide, | 13 months | ||
| doxorubicin, and cisplatin | ||||
| 3. | PD-1 inhibitor (PEM) | 6 months | ||
| 4. | Carboplatin, etoposide, and | 13 months | ||
| mitotane | ||||
| 5. | Cabozantinib | 6 months | ||
| 5 | 1. | Mitotane, etoposide, | 7 months | 29 months |
| doxorubicin, and cisplatin | ||||
| 2. | Mitotane (single-agent) | 5 months | ||
| 3. | PI3K inhibitor and PD-1 | 4 months | ||
| inhibitor (nivolumab) | ||||
| 4. | Cabozantinib | 2 months | ||
| 6 | 1. | Etoposide, doxorubicin, and cisplatin | 6 months | 24 months |
| 2. | Etoposide | 3 months | ||
| 3. | Gemcitabine and docetaxel | 1 month | ||
| 4. | Cyclophosphamide, | 2 months | ||
| vincristine, and dacarbazine | ||||
| 5. | PD-1 inhibitor (PEM) | 1 month | ||
| 7 | 1. | Etoposide, doxorubicin, and | 1 month | 5 months |
| cisplatin | ||||
| 2. | Gemcitabine and docetaxel | 1 month | ||
| 8 | 1. | Mitotane and adjuvant radiotherapy | 4 months | 10.5 months |
| 2. | Mitotane, etoposide, | 1 month | ||
| doxorubicin, and cisplatin | ||||
| 3. | Gemcitabine and docetaxel | 3 months | ||
| 4. | LEN (single-agent) | 1 month |
LEN, lenvatinib; PEM, pembrolizumab; PFS, progression-free survival.
was 8.5 months (range 2-22). Two (25%) patients had a partial response (PR) to the combination therapy: one patient had a maximum 90% reduction in tumor burden
at 19 months after initiating the combination therapy (figure 2); the other had 33% reduction in tumor burden at 9 months. One (12.5%) patient had stable disease (SD) with the LEN/PEM combination, lasting 8 months. Five (62.5%) patients developed progressive disease while receiving the combination therapy. The median PFS from the time of initiation of LEN/PEM for all eight patients was 5.5 months (95% CI 1.8-not reached, figure 3). Median duration of therapy was 8.5 months from the time of initiation of LEN/PEM therapy until either cessation of combination therapy (n=6) or last follow-up (n=2).
Adverse events
LEN/PEM combination therapy was well tolerated in our cohort of patients, and there were no severe AEs (CTCAE grade ≥3) during therapy. Grade 1-2 AEs were hand and foot syndrome (n=4), fatigue (n=4), hypertension (n=4), diarrhea (n=1), and acneiform rash (n=1). AEs detected by clinical laboratory testing were mild microcytic anemia (n=2), thyroid-stimulating hormone elevation (n=1), and transaminitis (n=1). None of the eight patients stopped LEN/PEM because of AEs.
DISCUSSION
To our knowledge, this is the first reported case series describing the use of MKIs in combination with Immune Checkpoint Inhibitor (ICPs) as salvage therapy in recur- rent/metastatic ACC. The clinical benefit rate from the combination therapy in our case series was 37.5%, with two patients achieving PR and one patient achieving SD lasting 8 months at the time of last follow-up. Observed responses occurred with LEN/PEM despite progression on multiple lines of prior therapy, including single-agent MKIs or CPIs.
VEGFR tyrosine kinase inhibitors have minimal single- agent efficacy in recurrent/metastatic ACC, with phase I/II trials of sorafenib plus metronomic paclitaxel,3 suni- tinib,15 and axitinib4 showing no objective responses in a total of 61 patients. One putative contributor to this lack of efficacy is that mitotane, which is often employed with chemotherapy in ACC, significantly interferes with the pharmacokinetics due to marked cytochrome P450- 3A4 induction. Another reason is that multiple tyrosine kinases are important for the malignant properties of ACC,16-18 including cMET and FGFR4. Thus, cabozan- tinib (a MKI that targets cMET, as well as VEGFR, AXL, and RET, and that is FDA approved in several solid tumor types) is now undergoing two parallel phase II studies (NCT03370718 and NCT03612232) in ACC. LEN targets FGFR 1-4 as well as VEGFR 1-3, PDGFR-a, RET, and KIT, but there are currently no ongoing clinical trials with single-agent LEN in ACC.
Meanwhile, several recent clinical trials have investi- gated using CPIs as a salvage therapy in ACC, although with limited efficacy. Le Tourneau et al reported the results of a study in which 50 patients with advanced ACC were treated with avelumab; the objective response rate
o
| Table 3 Duration and outcomes of LEN/PEM combination therapy | ||||
|---|---|---|---|---|
| Patient | Duration of LEN/PEM therapy | PFS | Status at time of last follow-up* | Patient on treatment at time of data cut-off |
| 1 | 22 months | 19 months | AWD | Yes |
| 2 | 10 months | 6 months | AWD | Yes |
| 3 | 2 months | 2 months | AWD | No |
| 4 | 10 months | 5 months | AWD | Yes |
| 5 | 8 months | 8 months | AWD | Yes |
| 6 | 3 months | 2 months | DOD | No |
| 7 | 3 months | 3 months | DOD | No |
| 8 | 9 months | 9 months | AWD | Yes |
*Date of data cut-off: December 31, 2019.
AWD, alive with disease; DOD, died of disease; LEN, lenvatinib; PEM, pembrolizumab; PFS, progression-free survival.
was 6%, with a median PFS of just 2.6 months.6 Another trial where 10 patients were treated with nivolumab had similar results, with no confirmed objective responses and a median PFS of 1.8 months.19 Interestingly, Raj et al recently reported the results of treating 39 patients with single-agent PEM, with an objective response rate of 23%, and a small subset of patients achieving durable responses despite a median PFS of just 2.1 months.7 The investigators were unable to confirm any biomarkers that predicted for response, including PD-L1 staining, tumor-infiltrating lymphocyte score, or tumor mutational burden, but the findings did suggest that microsatellite- high and/or mismatch repair-deficient tumors were enriched for responses.
It is unknown whether combining CPIs with other therapies could yield higher response rates in ACC-the subject of this report. A small case series of six patients suggested that mitotane might augment the effect of CPIs, which was postulated to occur via immune micro- environment modulation.20 In point of fact, the possible synergistic effect of the LEN/PEM combination might alternatively be in part due to the effect of LEN on the tumor microenvironment.12 21-23 Interestingly, LEN/PEM combination therapy has demonstrated promising anti- tumor activity in multiple cancers, including endometrial carcinoma9 and renal cell carcinoma.11
This report demonstrates the ability of the LEN/ PEM combination to produce objective responses in few
Individual patient responses since starting treatment
110
100
90
3
Percentage of Change from Baseline
80
70
Progressive disease
60
50
40
Patient 1
30
6
4
Patient 2
20
10
7
2
Stable disease
Patient 3
5
0
Patient 4
-10
4
6
8
10
12
14
16
18
20
22
14
Patient 5
-20
Patient 6
-30
-40
8
Patient 7
-50
Patient 8
-60
-70
Partial response
1
-80
-90
-100
Months since starting LEN/PEM combination
a
R
R
patients with heavily pretreated ACC. However, the lack of objective responses in six (75%) of the eight patients in our cohort suggests that the plurality of resistance mechanisms mitigating the activity of single-agent MKIs and CPIs are likely present in the context of combination therapy as well.
It is important to notice that none of the eight patients in our cohort had to discontinue LEN/PEM because of toxicity, and generally AEs were managed with dose modi- fications of LEN. Given the poor prognosis of ACC, partic- ular attention should be paid to quality of life of patients being treated with these therapies in future prospective trials.
The limitations of our report include the potential for selection bias given that patients were referred to tertiary care centers, selecting for patients with greater baseline healthcare access, and possibly more indolent tumor biology. Further, our small sample size precludes the ability to make conclusions about the broader safety or efficacy of this combination. In addition, we did not have consistent genomic analysis of the tumor samples.
1.0
Progression-Free Survival
0.8
Probability
0.6
Median PFS 5.5 months (95% CI, 1.8 - not reached)
0.4
0.2
0.0
N=8
0
5
10
15
Time from LEN/PEM initiation (months)
Number at risk
8
5
1
1
Interestingly, two of the patients with the shortest PFS were cortisol producing which are patient 3 and patient 6 (PFS of 2 months for each) which raises the question if cortisol production may be associated with worse response to the therapy. However, Patient 5 who had SD with a PFS of 8 months was also cortisol producing; thus cortisol produc- tion status was not one of the predictors of poor response to LEN/PEM combination therapy in this particular case. Also, it should be noted that patients 3 and 6 had germ- line T53 mutation. It is unclear if T53 mutation is associ- ated with worse response to combination therapy. Finally, we could not make conclusions regarding predictors of response to therapy, given the small sample size and rela- tively low rate of objective response.
In summary, ACC is a devastating malignancy with a paucity of effective therapies. The combination of LEN/ PEM represents a salvage strategy for a subset of patients but should be formally investigated in phase II clinical trials with robust correlative studies to identify predictors for response.
Author affiliations
1Department of Endocrine Neoplasia and Hormonal Disorders, Unit 1461, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
2Section of Endocrinology, Diabetes and Metabolism, Baylor College of Medicine, Houston, Texas, USA
3School of Medicine, Mayo Clinic, Rochester, Minnesota, USA
4Section of Endocrinology, Diabetes and Metabolism, University of Texas Health Science Center at Houston, Houston, Texas, USA
5Department of Abdominal Imaging, University of Texas MD Anderson Cancer
Center, Houston, Texas, USA
6Department of Medical Oncology, University of Washington, Seattle, Washington, USA
7Texas Oncology Austin Central, Austin, Texas, USA
8Tennessee Oncology, Chattanooga, Tennessee, USA
9Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
10Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA
Twitter Jeffrey Thomas Yorio @jeffyoriomd
Acknowledgements Editorial assistance was provided by Sunita Patterson, Scientific Publications Services, Research Medical Library, MD Anderson Cancer Center, Houston, Texas, USA.
Contributors SB and KCM contributed equally as joint co-first authors. All authors have contributed to literature review, manuscript writing, creating figures and tables and have agreed to the final version of the manuscript.
Funding Supported in part by the National Institutes of Health/National Cancer Institute under award number P30CA016672 (used the Clinical Trials Office).
Competing interests KDE has received research funding from Mirati Therapeutics. MAH has received research funding from Exelixis. AVC received funding from Eisai Inc and Merck Inc for clinical trial unrelated to this work (both institutional grants).
Patient consent for publication Not required.
Ethics approval Two IRB-approved protocols were obtained to conduct this retrospective study (protocol PA12-0933 at The University of Texas MD Anderson Cancer Center and protocol 18-010500 at Mayo Clinic).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.
Open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is
O
properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.
ORCID iDs Sara Bedrose http://orcid.org/0000-0003-1396-6384 Mouhammed Amir Habra http://orcid.org/0000-0002-4148-9637
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