A Phase II Study of Durvalumab in Combination with Tremelimumab in Patients with Rare Cancers

Abstract

Lessons Learned

• Disease control with signals of response were demonstrated, which should lead to future validating clinical trials using checkpoint inhibitors in this underserved rare malignancy population.

• Although the study of single types of rare cancers is practically challenging, clinical trial designs that aggregate such patients into cohorts treated similarly are feasible, even in the community setting.

Background

Patients with rare cancers are an underserved population with limited access to clinical trials aside from phase I trials in the refractory setting. Treatment of these patients is often based on collections of anecdotes and small denominator review articles. Despite broad evidence of efficacy of combined immune checkpoint blockade across multiple tumor types, patients with rare tumors have not been afforded the opportunity for these therapies.

Methods

A phase II, investigator‐initiated, single institution trial using durvalumab (1,500 mg every [Q]4 weeks × 13) and tremelimumab (75 mg Q4 weeks × 7, then Q12 weeks × 2) is reported. The population included 50 patients with advanced rare solid tumors (incidence <6/100,000 per year). The phase II dose and safety profile were defined in prior phase I trials. All patients had exhausted standard therapy options and all had received at least one prior line of systemic therapy (n = 49) unless a standard treatment option did not exist (n = 1).

Results

A complete response was demonstrated in one patient with anal cancer. Striking partial responses were seen in four patients. Prolonged disease stability was noted in 18 patients. Thirteen patients experienced disease progression. Patients were considered unevaluable if unable to initiate therapy (n = 6) or unable to complete two cycles of therapy (n = 8). In all cases, patients were unevaluable because of clinical deterioration. The toxicity profile paralleled prior published studies. Toxicities were manageable and without new signals. There were two events of grade 4 immune‐mediated hepatitis and one death from pneumonitis.

Conclusion

This single‐cohort basket trial demonstrated clinical activity from combined checkpoint blockade in 23 of the 36 evaluable patients. Patients with rare cancers, not eligible for immunotherapy via conventional clinical trial mechanisms, should be considered for this therapy through compassionate use, further clinical trials, and national registry programs.

Discussion

Patients with rare cancers, as defined in this study, encounter multiple challenges regarding optimal management of their malignancy. Lack of familiarity by physicians [1], poorly defined natural history, less frequent mutational characterization [2, 3], and lack of consistent clinical trial availability [4] all hamper the development of care algorithms. In this single institution basket trial, patients with rare cancers (Table 1) were offered combined checkpoint blockade as a means to facilitate exposure to therapy which would otherwise have been unavailable. At the time this study was implemented, the national DART trial (NCT02834013) using mechanistically identical therapy in rare cancers was not yet open for enrollment.

Table 1.

Rare tumor diagnosis

Histology	n (%)
Adenocarcinoma of the bladder	1 (2)
Adrenocortical carcinoma	2 (4)
Anal cancer	2 (4)
Anaplastic thyroid carcinoma	4 (8)
Appendiceal carcinoma	4 (8)
Cervical adenocarcinoma	1 (2)
Cholangiocarcinoma	12 (24)
Clear cell salivary gland tumor	1 (2)
Ex pleomorphic salivary gland tumor	1 (2)
Fallopian tube carcinoma	1 (2)
Gallbladder carcinoma	1 (2)
Fibrolamellar hepatocellular carcinoma	1 (2)
Mesothelioma	4 (8)
Metaplastic breast cancer	1 (2)
Mixed Mullerian	5 (10)
Metastatic basal cell	1 (2)
Salivary adenoid cystic carcinoma	4 (8)
Sertoli‐Leydig cell tumor	1 (2)
Small bowel carcinoma	1 (2)
Urachal carcinoma	1 (2)
Vulvar carcinoma	1 (2)

Despite the community setting of this trial, we were able to accrue patients at a rate of approximately 1.5 per month, suggesting that this is feasible to accomplish outside of the major referral centers. Moreover, the successful completion of this first cohort provides the framework for a potential national registry of patients with rare cancers that are treated with immunotherapy because randomized clinical trials are unlikely in this setting.

No new toxicities were identified during the course of the trial. Despite careful surveillance, one patient still succumbed to pneumonitis as a consequence of treatment. Other toxicities were manageable with prompt initiation of corticosteroids and/or other response modifying agents.

Because of the design of the trial, there can be no statistical description of the results. Nonetheless, 23 of 36 evaluable patients experienced a response or disease stability. Translational research into the cohort may result in the identification of biomarkers that are predictive of benefit; this work is ongoing. PD‐L1 expression and microsatellite stability status were not predictive of benefit in this cohort of patients.

Several groups within the cohort of 50 deserve specific mention. Cholangiocarcinoma (n = 12) represented 24% of the enrolled patients and, despite their designation, appear not to be as rare as expected. This group of patients had two partial responders and four with disease stability. These findings are consistent with Klein et al. [5] and perhaps suggest an expanded role of checkpoint blockade in the management of biliary malignancy. In contrast, malignant mixed Mullerian tumors (5 enrolled) did not appear to respond to protocol directed therapy. We await the mixed Mullerian cohort report from the DART trial to confirm these findings but would be hesitant to offer enrollment to patients going forward.

Finally, one of the most profound and rapid responses was seen in a patient with metastatic salivary gland adenoid cystic carcinoma. This tumor, generally regarded as poorly responsive to immunotherapy because of the suppressive tumor microenvironment [6], regressed dramatically with combined checkpoint blockade with a durable response lasting well over 1 year. Of the other patients enrolled, several demonstrated prolonged disease stability, admittedly difficult to interpret in light of the indolent disease trajectory of many such patients.

Trial Information

Disease	Advanced cancer/solid tumor only
Stage of Disease/Treatment	Metastatic/advanced
Prior Therapy	No designated number of regimens
Type of Study	Phase II, single arm
Primary Endpoint	Overall response rate
Additional Details of Endpoints or Study Design (Materials and Methods)
Study Population
Fifty patients with advanced rare cancers defined by the European Union and project Surveillance of Rare Tumors in Europe (RARECARE) as fewer than 6 cases per 100,000 per year [7], were recruited prospectively. A full appendix of these tumors was created by the RARECARE working group [8] and used to determine eligibility for enrollment in the trial. The dose‐exploration phase, conducted across a range of tumor types, had been completed. Because the industry sponsored dose‐expansion phase was ongoing at the start of this trial and included certain soft tissue sarcomas, neuroendocrine tumors, and thymic carcinoma, subjects diagnosed with any of those rare tumors were excluded. The tumor types represented and patient characteristics are shown in Tables 1 and 2.
Eligible patients must have experienced disease progression or been ineligible to receive standard treatment options if available, have at least one measurable lesion per RECIST v1.1 [9 ], be amenable to biopsy of a tumor site or have recent (≤2 years) archival material available, have ECOG performance status of 0 to 2, life expectancy ≥3 months, have adequate organ and marrow function, and provide informed consent. Patient were excluded if they had received previous treatment with any checkpoint inhibitor (including anti‐CTLA‐4, anti‐PD‐1, and anti‐PD‐L1) or had untreated central nervous system disease, active or documented autoimmune disease within previous 2 years, uncontrolled psoriasis, chemotherapy within 28 days or radiation within 14 days, or steroid exposure within 28 days of treatment. Intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, not to exceed 10 mg per day of prednisone or an equivalent corticosteroid, were allowed.
Trial Design
Given the safety and tolerability data in the previous and ongoing studies at that time, a fixed dose schedule was selected. All patients received durvalumab 1,500 mg intravenously (IV) Q4 weeks for 13 doses and tremelimumab 75 mg IV Q4 weeks for 7 doses, followed by an additional 2 doses at 12‐week intervals based on the phase I safety data and maximum tolerated dose. Formal disease assessment was performed every eight weeks and reported per immune‐related RECIST v1.1 [9].
Clinical Activity
The primary study objective was to evaluate the antitumor activity of durvalumab in combination with tremelimumab based on RECIST v1.1 and described as best overall response: complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Disease control rate was defined as CR + PR + SD.
Safety
The National Cancer Institute Common Terminology Criteria for Adverse Events (Version 4.03) [10 ] was used as the standardized grading system for study related adverse events (AEs) (Table 3). AEs were reported by degree of relatedness (not related, possibly related, likely related, or related to the study drug or study therapy). The safety analysis included all patients who received at least one dose of study drug.
Statistical Analysis
Descriptive statistics were used to summarize the data and for assessment of emerging patterns in this exploratory study.
Results
Fifty patients were enrolled between December 2016 and January 2020, representing 23 rare tumor diagnoses (Table 1). Patients were considered unevaluable (n = 14) if they did not complete two cycles of therapy. The majority of unevaluable patients had a rapid clinical decline and were unable to complete two cycles of therapy.
Investigator's Analysis	Active and should be pursued further

Table 2.

Patient demographics

Characteristics	n (%)
Gender
Male	22 (44)
Female	28 (56)
Race
Asian	1 (2)
Biracial/multiracial	1 (2)
Black/African American	7 (14)
White/Caucasian	41 (82)
Performance status
0	20 (40)
1	29 (58)
2	1 (2)
Age, median (range)	62 (26–78)

Table 3.

Adverse events summary (n = 44)

Adverse event term	Any grade (%)	Grade ≥ 3 (%)
Fatigue	15 (34)	1 (2)
Diarrhea	11 (25)	2 (5)
Rash	7 (16)	1 (2)
Anemia	6 (14)	0 (0)
Dyspnea	6 (14)	0 (0)
Cough	4 (9)	0 (0)
Itching	4 (9)	0 (0)
Myalgias	4 (9)	0 (0)
Hepatitis: immune mediated	2 (5)	2 (5)
Adrenal insufficiency	1 (2)	0 (0)
Noncardiac chest pain	1 (2)	0 (0)
Pneumonitis: immune mediated	1 (2)	1 (2)

All events graded using CTCAE Version 5. Although 50 patients were enrolled, 6 patients did not initiate therapy because of clinical decline.

Drug Information: Durvalumab and Tremelimumab Combination

Durvalumab
Generic Name	Durvalumab
Drug Type	Antibody
Drug Class	Immune therapy
Dose	1,500 mg per flat dose
Route	IV
Schedule of Administration	Every 4 weeks for 13 doses
Tremelimumab
Generic Name	Tremelimumab
Drug Type	Antibody
Drug Class	Immune therapy
Dose	75 mg per flat dose
Route	IV
Schedule of Administration	Every 4 weeks for 7 doses followed by an additional 2 doses at 12‐week intervals

Patient Characteristics

Number of Patients, Male	22
Number of Patients, Female	28
Age	Median (range): 62 years (26–78 yrs)
Number of Prior Systemic Therapies	Median (range): null
Performance Status: ECOG	0 — 20 1 — 29 2 — 1 3 — 0 Unknown — 0
Other	See also Tables 1 and 2.

Primary Assessment Method

Title	Overall response rate
Number of Patients Screened	70
Number of Patients Enrolled	50
Number of Patients Evaluable for Toxicity	44
Number of Patients Evaluated for Efficacy	36
Evaluation Method	RECIST 1.1
Response Assessment CR	n = 1 (2.8%)
Response Assessment PR	n = 4 (11.1%)
Response Assessment SD	n = 18 (50%)
Response Assessment PD	n = 13 (36.1%)
(Median) Duration Assessments TTP	159.5 days
Waterfall plot: see Figure1.
Outcome Notes
Of the 36 evaluable patients, a complete response was observed in one patient with anal cancer. Partial responses were seen in one patient with adenoid cystic carcinoma, one patient with adrenocortical carcinoma, and two patients with cholangiocarcinoma. Eighteen patients had prolonged disease stability with a median time to progression of 159.5 days (range, 106–678 days). Progression of disease occurred in 13 patients. The disease control rate was 63.8%.

Figure 1.

Waterfall plot of response (n = 34) by RECIST v1.1. Four patients not represented in the waterfall plot had disease progression (3 with new lesions and 1 with clinical progression).

Adverse Events

All Cycles
Name	NC/NA	1	2	3	4	5	All grades
Fatigue	0%	87%	7%	7%	0%	0%	100%
Diarrhea	0%	36%	45%	18%	0%	0%	100%
Rash maculo‐papular	0%	71%	14%	14%	0%	0%	100%
Anemia	0%	83%	17%	0%	0%	0%	100%
Dyspnea	0%	83%	17%	0%	0%	0%	100%
Cough	0%	100%	0%	0%	0%	0%	100%
Pruritus	0%	75%	25%	0%	0%	0%	100%
Myalgia	0%	100%	0%	0%	0%	0%	100%
Autoimmune hepatitis	0%	0%	0%	0%	100%	0%	100%
Adrenal insufficiency	0%	0%	100%	0%	0%	0%	100%
Noncardiac chest pain	0%	0%	100%	0%	0%	0%	100%
Pneumonitis	0%	0%	0%	0%	0%	100%	100%

Adverse Events Legend

Overall, the toxicity profile paralleled prior reports with most toxicity easily manageable and no new signals identified.

Abbreviation: NC/NA, no change from baseline/no adverse event.

Serious Adverse Events

Name	Grade	Attribution
Autoimmune hepatitis	4	Definite
Pneumonitis	5	Definite
Autoimmune hepatitis	4	Definite
Colitis	3	Definite
Colitis	3	Definite

Serious Adverse Events Legend

There were five study‐related SAEs, including two patients who developed grade 4 autoimmune hepatitis resulting in permanent discontinuation of treatment but which resolved with corticosteroid therapy; one patient who developed immune‐mediated pneumonitis, which resulted in death; and two events of colitis requiring hospitalization.

Pharmacokinetics/Pharmacodynamics for Phase II Combination

Of the 29 patients (out of 35) with adequate tumor tissue, 23 patients had PD‐L1 expression <1%, 2 had PD‐L1 expression 1%–5%, and 4 had PD‐L1 expression >5%. All patients were microsatellite instability (MSI) stable. Specimens were available to assess for interferon‐γ signatures. Of interest, both patients with anaplastic thyroid cancer had PD‐L1 expression of 50% or greater.

Assessment, Analysis, and Discussion

Completion	Study completed
Investigator's Assessment	Active and should be pursued further

Of particular interest were three patients diagnosed with salivary adenoid cystic carcinoma, adrenocortical carcinoma, and Sertoli‐Leydig cell tumor. These patient cases are described in the following vignettes.

Case 1 Salivary Adenoid Cystic Carcinoma

A 51‐year‐old woman with parotid adenoma stable for over 20 years presented with 5 months of painful neck swelling. Computed tomography (CT) neck demonstrated a 33‐mm mass extending into dermis. Fine needle aspiration confirmed an adenoid cystic carcinoma. Preoperative positron emission tomography/CT scan revealed a solitary fluorodeoxyglucose avid lung nodule. Parotidectomy confirmed a grade 3 adenoid cystic carcinoma, clear margins, perineural invasion, 0 of 9 lymph nodes, PD‐L1 0%, microsatellite (MS)‐stable, tumor mutation burden (TMB)‐low, and next‐generation sequencing (NGS) without actionable mutations. Postoperative radiation therapy and metastatectomy were planned. However, CT scan 4 weeks postradiation revealed interval development of multiple pulmonary nodules. In the absence of effective therapy, she enrolled on the rare tumor protocol and received durvalumab and tremelimumab. She had rapid regression of all pulmonary disease except a single left upper lobe lesion (Fig. 2). This residual lesion was resected and found to be consistent with the primary. She completed immunotherapy and remained in complete remission for 17 months before relapse was found at the primary site, with confirmed high‐grade transformation. She was rechallenged with the same immunotherapy with 6 months stable disease. At relapse, radiation was given to the primary site followed by oral lenvatinib. At 11 months of therapy, the tumor continues to respond.

Figure 2.

Salivary adenoid cystic carcinoma with diffuse pulmonary metastases response following two cycles of immunotherapy. Contrast enhanced axial and coronal computed tomography chest.

Case 2 Adrenocortical Carcinoma

A 54‐year‐old man was found to have an elevation in alkaline phosphatase. Imaging revealed a 22‐cm mass arising from the left adrenal gland. Adrenalectomy confirmed adrenocortical carcinoma. He was followed without additional therapy over the next 18 months when imaging revealed liver lesions consistent with biopsy‐proven metastatic disease, PD‐L1 of 1%, MS‐stable, TMB‐low, and NGS without actionable mutations. He underwent six cycles of cisplatin, doxorubicin, and etoposide therapy with resultant neuropathy and subsequently transitioned to mitotane. Progression on mitotane prompted referral for the Rare Tumor trial and treatment with durvalumab and tremelimumab. Liver lesions rapidly became cystic in appearance and eventually regressed (Fig. 3). More than 18 months since completion of therapy, no new disease has emerged. Toxicity from treatment included asymptomatic, transient serum lipase elevation, and the development of adrenal insufficiency requiring corticosteroid replacement therapy.

Figure 3.

Adrenocortical carcinoma with hepatic metastases response following two cycles of immunotherapy.Contrast enhanced axial and coronal computed tomography abdomen.

Case 3 Sertoli‐Leydig Cell Tumor

A 45‐year‐old women presented with abdominal pain and a 3‐cm solid‐appearing lesion of her right ovary. woman history was significant for removal of a Sertoli‐Leydig cell tumor 3 years prior. Short‐term follow‐up demonstrated interval growth of the tumor, and surgery was recommended. Debulking surgery to include small bowel resection revealed recurrent Sertoli‐Leydig cell tumor, PD‐L1 0%, MS‐stable, TMB unable to be performed, and NGS without actionable mutations. Adjuvant therapy with bleomycin, etoposide, and cisplatin was complicated by peripheral neuropathy. Subsequent progression of disease and the lack of other cytotoxic options prompted referral for the Rare Tumor protocol, and she received durvalumab and tremelimumab. After two cycles of therapy, four of five target lesions had regressed (Fig. 4). Unfortunately, she developed immune‐mediated enteritis requiring steroids and infliximab and was removed from the study because of toxicity.

Figure 4.

Sertoli‐Leydig cell tumor with reduction in peritoneal implants following two cycles of immunotherapy. Contrast enhanced axial and coronal computed tomography abdomen.

Conclusion

The rare tumor patient population represents a group characterized by unmet medical needs due to limited standard therapies, minimal durable responses to prior therapy, and poor prognoses. Advanced rare tumors are clinically challenging because of the lack of evidence‐based data and clinical trials to guide the optimal approach. Although rare, when pooled as a conglomerate group, these cases represent more than 20% of all malignancies [11].

Agents targeting the immune checkpoint have demonstrated clinical benefit with U.S. Food and Drug Administration approval in many solid malignancies. An active search for positive laboratory surrogates of clinical response to check point inhibitors has identified PD‐1 and MSI‐high status but is far from complete. Preclinical as well as clinical evidence suggests synergistic clinical activity of combining anti‐PD‐1 and anti‐CTLA‐4 agents [12].

The DART trial (NCT02834013) includes 53 cohorts of rare tumors treated with ipilimumab plus nivolumab and has enrolled 94% of goal through March 31, 2021. Preliminary results include an overall response rate of 4% in adenoid cystic carcinoma [13], 8% in small bowel tumors [14], and 44% in nonpancreatic high‐grade neuroendocrine carcinoma [15].

Current clinical trial data involving durvalumab, a PD‐L1 inhibitor, and tremelimumab, an anti‐CTLA‐4 agent, in solid tumor trials identified potential optimal doses of each agent, balancing toxicity and clinical benefit [16].

A larger expedited study of a tumor agnostic, universally effective therapy without confirmed surrogates for response should be performed in this underserved rare malignancy population, which represents a large numerical fraction of the cancer patient population. Disease control with signals of response were demonstrated, which should lead to future validating clinical trials. Although the study of single types of rare cancers is practically challenging, clinical trial designs that aggregate such patients into cohorts treated similarly are feasible, even in the community setting. Conducting this study as an investigator‐initiated trial allowed greater flexibility in overall study assessments. The predefined toxicity profile and dosing schedule minimized clinic visits and allowed us to recruit patients regionally. This study suggests that combining multiple large cohort trials might serve as the basis for defining new treatment options for patients with rare diseases who are not well served by clinical trials.

Disclosures

William Jeffery Edenfield: Chimerix Corp. (C/A); Heather Bowers: Incyte, Pfizer, Astellas (H). The other authors indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board