The emerging landscape of immune checkpoint inhibitor based clinical trials in adults with advanced rare tumors

ABSTRACT

“Rare cancers” are a diverse collection of cancers that collectively account for approximately 20% of all adult cancers in the United States. Their rarity has caused an underrepresentation of these cancers in preclinical research and clinical trials, leading to fewer (and often no) treatment options for patients backed by robust clinical evidence. The recent advent of immune checkpoint inhibitors (ICIs) into the oncologist’s armamentarium, while revolutionizing the treatment of many common cancers, has also started to make gradual inroads into the treatment of certain rare cancers. One reason is that the efficacy of ICIs depends more on factors intrinsic to the tumor cells and the tumor microenvironment and less on tumor histology. Recent years have seen ICI approvals in many rare cancers, and many trials are being designed using ICIs as single agents or in combination. In this commentary, we present an overview of the emerging role of ICIs in some rare cancers.

KEYWORDS:

• Rare cancers
• immunotherapy
• anti-PD-1
• tumor microenvironment
• neuroendocrine Tumors
• soft Tissue Sarcoma

Of the approximately 1.7 million annual new cancer cases in the United States, rare cancers, taken together, represent about 20%.^1,2 There are many definitions for what constitutes rare cancer. A widely accepted definition is from the European Union Surveillance of Rare Cancers in Europe (RARECARE), that described the incidence of rare cancers as those with fewer than 6 cases per 100,000 people per year,³ while the United States National Cancer Institute (NCI) defines it as those cancers with an incidence of less than 15 per 100 000 people per year.⁴ Using the NCI definition, all but 11 cancer types would be classified as being rare in American adults, with common cancers being breast, lung, prostate, colon, rectal, uterine endometrial, bladder, melanoma, ovarian, non-Hodgkin lymphoma, and renal malignancies.⁵

When compared to the more common malignancies, the 5-year survival is worse in patients with rare cancers, and this difference is particularly stark amongst adolescents and young adults.¹ Some important factors explaining the poor survival include the lack of well-established treatment guidelines, a paucity of available therapies, and delayed diagnosis. Treatment options for rare cancers are often more limited and less effective than for other types of cancer. This is partly attributed to the fact that due to their rarity and heterogeneity, clinical trials to develop therapies for patients with rare cancers are intrinsically challenging.^1,5,6

In 1983, the Orphan Drug Act provided incentives to pharmaceutical companies for developing agents directed at treating rare diseases. This has had a substantial impact on drug approvals. Despite these improvements, there remains a deficiency in research resource allocation and clinical trials that are specifically focused on rare tumors. Research resources have traditionally been allocated preferentially to the most common tumor types, and therefore, the development of novel agents for rare cancers has fallen behind.¹

For decades, cytotoxic chemotherapy has been the mainstay of systemic cancer therapy. More recently, the increasing understanding of oncogenic molecular aberrations and the ability to target them has led to the expansion of the scope of therapy beyond tumor histology and begun to include molecular targets shared across different histologies.⁷ A similar pattern has been observed in the field of immune-oncology (IO) where the efficacy of agents such as immune checkpoint inhibitors (ICIs) in the more common cancers has spurred the development of many clinical trials exploring their efficacy in different rare tumor histologies as well. Over time this has led to several indications for ICIs across tumor types (including in some rare cancers), with susceptibility to ICIs being based on the innate characteristics of the tumor microenvironment and tumor antigen status.^8,9 An important indicator of this is the efficacy and subsequent histology agnostic approval of the programmed cell death- 1 (PD-1) inhibitor pembrolizumab by the US Food and Drug Administration (FDA) based on DNA mismatch repair deficiency, and more recently on tumor mutational burden (TMB) ≥10 mutations/megabase on targeted next-generation sequencing.^10–12 However, due to the limited efforts directed at biobanking of rare tumor samples compounded by their infrequent occurrence, there is a paucity of data on the immunological drivers, TMB status, or mismatch repair status of these tumors. This makes it important to investigate the efficacy of immunotherapeutic agents, especially ICIs in rare tumors, as an area of unmet need. In this commentary, we provide an overview of some of the recent clinical trial efforts investigating the role of immune checkpoint therapy in rare tumors.

One of the largest and most extensive of these trials is the National Cancer Institute (NCI) sponsored Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART/SWOG1609; NCT02834013). This study is a prospective, multicenter phase II basket trial of ipilimumab and nivolumab across 52 rare tumor cohorts, enrolling patients who have failed standard therapy. The combination of the two ICIs has completed testing in 36 cohorts. Twelve cohorts are still enrolling while as 4 cohorts are temporarily closed for data analysis. While this trial is still accruing participants in some arms, the results of certain cohorts have now been reported with interesting signals. In the non-pancreatic neuroendocrine tumor (NET) cohort, a total of 32 patients were treated, of whom 18 (56%) had high-grade NETs. The objective response rate (ORR) for the entire cohort was 25%, and the 6-month progression-free survival (PFS) was 31%, with a median overall survival (OS) of 11 months. Of note, all the 8 patients with an objective response had a high-grade neuroendocrine carcinoma.¹³ Interestingly, most of the other response rates reported from other cohorts in this study have not been as high and range approximately from 8–12%. For example, the ORR was 8% for the 23 patients with small bowel carcinoma who received the combination ICI therapy, which included 1 complete response (CR) and 1 partial response (PR).¹⁴ The results of 3 salivary gland neoplasm cohorts, (i) major salivary glands, (ii) other sites of origin and (iii) adenoid cystic carcinomas of any site, have been reported together. Twenty-six patients with adenoid cystic salivary gland tumors and 35 patients with other subtypes of salivary gland tumors received treatment. The ORR in patients with adenoid cystic tumors was 4% with only 1 patient achieving a PR, and none achieving a CR. In the remaining subtypes of salivary tumors, the ORR was 9% with 3 PR and no CR.¹⁴ Seventeen eligible metaplastic breast cancer patients received therapy in another cohort of the DART trial achieving an ORR of 12% with amedian OS of 12 months.¹⁵

Moreover, recent results reported at SITC 2020 demonstrated an ORR of 25% in the angiosarcoma cohort especially in patients with cutaneous lesions of the scalp with a 60% response to the combination ICIs.¹⁶ These results are similar to what we have reported earlier from a retrospective case series with a partial response in 6/7 patients with angiosarcoma treated with either anti-PD1 or anti-CTLA-4 based ICIs.¹⁷ So far > 750 patients have been enrolled in the DART trial with a plan to have DNA and RNA sequencing done on tumor and blood to identify the mechanistic basis for response or resistance to ICI in these patients with rare histologies.

The efficacy of ICIs in NETs was again demonstrated in the Australian CA209-538 trial (NCT02923934). This trial is a multicenter, open-label, phase II study of the combination of ipilimumab and nivolumab in patients with advanced rare cancers in 3 separate cohorts, (i) upper gastrointestinal malignancies, (ii) neuroendocrine tumors, and (iii) rare gynecological tumors. Twenty-nine patients with advanced NETs were treated with the ICI combination. Of these patients, 10% had low-grade, 45% intermediate-grade, and 45% had high-grade tumors. The overall ORR was 24% with a median PFS of 4.8 and OS of 14.8 months. Of note, the ORR in high and intermediate-grade NETs was 31% and 24%, respectively, while none of the 4 patients with low-grade NETs had a response.¹⁸ A subgroup analysis of patients with biliary tract cancers (BTC) on the CA209-538 trial demonstrated an ORR of 23% and a disease control rate (DCR) of 44%. The median PFS was 2.9 months, and the OS was 5.7 months. Responses were only seen in patients with intra-hepatic cholangiocarcinoma and gallbladder carcinoma (ORR of 31% in each), while none of those with extra-hepatic cholangiocarcinoma responded. Interestingly, none of the responders had microsatellite instability in their tumors.¹⁹

Naing et al. have recently published the interim results of an open-label, phase 2 trial of single-agent pembrolizumab in patients with advanced rare cancers with progression on standard therapies. A total of 10 cohorts were treated, including 9 tumor-specific cohorts and a tenth cohort to include all other rare tumors.²⁰ One hundred and twenty-seven treated patients were included in the study analysis, and the pre-specified criteria allowing for interim analysis were met in 4 cohorts: squamous cell carcinoma (SCC) of the skin, adrenocortical carcinoma (ACC), carcinoma of unknown primary (CUP), and paraganglioma–pheochromocytoma. Nineteen patients with SCC of the skin were treated with pembrolizumab, of which 16 were evaluable for response. The ORR was 31% (95% CI, 11% to 59%). Four of the 5 patients who achieved a response continued to have an ongoing response at data cutoff at 15 · 9, 17 · 3, 20 · 1, and 23 · 4 months from when treatment was begun. Fifteen patients with ACC received pembrolizumab, of which 13 were evaluable for response. The overall ORR in this cohort was 15%, and of the 2 patients achieving a response, 1 was still receiving treatment 23 · 5 months from initiation. In the CUP cohort, an ORR of 23% was achieved, and all 3 responding patients having a durable response, at 16 · 7, 17 · 6, and 21 · 3 months. In the paraganglioma-pheochromocytoma cohort, a pattern of durable stable disease (≥4 months) in 6 of the 8 patients with no partial or complete responses was seen.

Malignant pleural mesothelioma (MPM) is a rare cancer of the pleural mesothelial cells that is strongly associated with exposure to asbestos and has a poor prognosis. Traditional therapy for unresectable MPM is chemotherapy with or without the VEGF inhibitor bevacizumab.^21,22 Trials of single-agent ICIs have shown some promising benefit in previously treated patients with MPM. These include pembrolizumab (ORR 20%), nivolumab (ORR 26%) and avelumab (ORR 9%).^23–25 The prospective single-arm phase-2 INITIATE trial (NCT03048474) tested the combination of ipilimumab and nivolumab in patients with advanced MPM that had progressed on at least one line of prior therapy. Of the 34 patients evaluable for response, an ORR of 29% was observed, with another 38% achieving SD.²⁶ The multicenter randomized phase-2 IFCT-1501 MAPS2 trial (NCT02716272) enrolled patients with MPM that had progressed on standard chemotherapy. A total of 125 patients were evaluable – 63 receiving nivolumab alone and 62 receiving ipilimumab and nivolumab. An ORR of 19% was observed in the nivolumab only cohort and 28% in the nivolumab plus ipilimumab cohort.²⁷

Merkel cell carcinoma is an exceedingly rare, aggressive skin cancer with an incidence of 0.79 per 100,000 in the United States.²⁸ Durable responses to cytotoxic chemotherapy are infrequent, with a median PFS of approximately 3 months.²⁹ An international phase-2 trial of the PDL-1 inhibitor avelumab showed good responses in patients with metastatic chemotherapy-refractory Merkel cell carcinoma.³⁰ This trial enrolled a total of 88 patients who were evaluable for response. An ORR of 31.8% was achieved, which included 8 CR and 20 PR. An updated follow up of this study showed a PFS at 1-year of 30%, and OS at 1-year of 52%. The median survival for patients on this study was 12.9 months.³¹ Results from this trial led to avelumab receiving accelerated approval from the US FDA in patients with metastatic Merkel cell carcinoma.³² This action has been followed by approvals for the PD-1 inhibitors nivolumab and pembrolizumab as well.³³

In sarcomas, the first trials of ICIs with either pembrolizumab or the combination of nivolumab/ipilimumab reported ORR <20%.^34,35 However, hints of higher ICI efficacy have been seen in specific sarcoma histology’s such as undifferentiated pleomorphic sarcoma (UPS) and alveolar soft part sarcoma (ASPS). In the most recent update of the SARC 028 trial (NCT02301039) of pembrolizumab in advanced sarcomas, which included the two expansion cohorts of UPS and dedifferentiated liposarcoma based on promising activity seen initially. However, the UPS cohort was the only histology that met the primary endpoint with an ORR of 23%.³⁶ Currently, efforts are being directed at understanding the immunologic landscape in STS better to understand windows of opportunity from an IO perspective. Whole-genome microarray assessment of primary resections has shown the nature of highly variable immune-microenvironment characterized by high expression of M2 macrophage markers in some STS subtypes.³⁷ Similar work from the SARC 028 study and The Cancer Genome Atlas (TCGA) samples have attempted to classify STS based on the tumor microenvironment (TME) composition.³⁸ B-cell signatures were identified to be enriched in a subset classified as a high immune subset. More interestingly, the UPS patients that showed a response to pembrolizumab in this trial were seen to be enriched for B-cell signatures along with the presence of tertiary lymphoid structures. The UPS tumors were also noted to be immune high based on CD8 and NK cell gene expression patterns. Despite having a low mutational burden, STS from the SARC 028 study that demonstrated the specific TME signature of having B cells and TLS, had an ORR of 50%. This finding provides an important perspective that other factors within the TME may act as determinants of response to ICIs, especially in tumors that harbor a low mutational burden.³⁹

Alveolar soft part sarcoma (ASPS) is an extremely rare STS. ASPS primarily affects adolescent and young adult patients, often diagnosed in the metastatic setting, and is resistant to standard cytotoxic therapy.⁴⁰ Recent clinical trials have shown compelling evidence of response to ICIs in this disease. A single-center, single-arm, phase 2 trial of the VEGF inhibitor axitinib in combination with the PD-1 inhibitor pembrolizumab aimed to exploit the upregulation of pro-angiogenic factors, including VEGF in the tumor microenvironment, and the contribution of tumor angiogenesis in maintaining an immunosuppressive tumor microenvironment. Thirty-three patients with advanced or metastatic sarcomas were enrolled, of whom 12 (36%) had ASPS. The ORR in the ASPS cohort was > 50%.⁴¹ Similarly, our ongoing NCI sponsored phase-2 study (NCT03141684) of single-agent PD-L1 inhibitor atezolizumab in ASPS has demonstrated an ORR of > 30%.⁴² In this trial using tumor biopsies, one of the working hypotheses that is being evaluated is the role of the ASPCR1-TFE3 fusion protein, a pathognomonic fusion gene product in ASPS, in eliciting responses to ICI by potentially creating neoantigens. Although other sarcomas, such as Ewing sarcoma, are characterized by the presence of conserved fusions, the activity of ICIs has been disappointing with 0 of 13 patients having a response in the SARC 028 study.³² This suggests that other factors related to the TME may influence immunogenicity. In addition, we have recently opened a phase 2 study of atezolizumab in clear cell and chondrosarcoma (NCT04458922), given signs of activity observed in case reports supporting the further evaluation of these sarcomas in a clinical trial setting.

Rare cancers are a disparate group of histologically distinct tumors that, when combined, form a significant proportion of the total cancer burden. Due to their small numbers as individual groups, therapeutic clinical trials have been particularly difficult to undertake. In more recent years, there has been a greater realization about the importance of these cancers on the total disease burden of cancer. This has led to better clinical trial designs such as basket trial-like multiple smaller cohorts which can more realistically be accrued to, while being able to determine if there is any activity of the agent being tested. In alignment with the NCI efforts to expand treatment options for rare tumors, promising combinations are being selected based on available preclinical and/or clinical evidence of anti-tumor activity in rare tumors. The Rapid Analysis and Response Evaluation of Combination Anti-Neoplastic Agents in Rare Tumors: RARE CANCER-1 Nilotinib and Paclitaxel (NCT04449549) is the first trial of this effort that has been opened at the NCI this year. ICI based combinations are planned for future additions as separate subsequent arms. As part of our preplanned correlative studies, tumor and blood sample collection from the RARE CANCER-1 and the subsequent ICI based arms will enable us to evaluate the immunological determinants of response to ICI agents in some of these rare tumors.

Immune checkpoint therapy has created a paradigm shift in cancer therapy and, as demonstrated through ongoing efforts, is gradually making inroads into the treatment of rare tumors. We are gradually learning that the response to these agents relies more on the complex tumor-immune interactions and less on the tumor histology. Admittedly ICIs seem to show higher activity only in a small subset of rare tumors, making it essential to develop an in-depth understanding of the factors that contribute to these differences. We anticipate that the emerging strides being made in the field of integrated omics-related approaches will further facilitate our understanding of the molecular and functional landscape of rare tumors. Data generated from these approaches are likely going to have a strong influence in accelerating drug development, including the use of appropriate immunotherapeutic strategies in patients suffering from some previously untreatable rare cancers.

Disclosure of potential conflicts of interest

The authors report no conflicts of interest.

Additional information

Funding

The authors have no relevant funding to report.