Glandular metastases from renal cell carcinoma show poor clinical responses to immune checkpoint inhibition but durable responses to angiogenesis inhibitors

Abstract

While half of the metastatic clear cell renal cell carcinomas (ccRCCs) involve the lungs, metastatic lesions have been described in various other organs, including glandular tissues such as the pancreas. Recent evidence suggests that ccRCC lesions affecting the pancreas are poorly responsive to immune checkpoint inhibition (ICI) but show superior responses to tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor (VEGF) signalling pathway. However, this has yet to be explored in ccRCC spreading to other glandular tissues. Here we present two cases of ccRCC with glandular metastases, the first to the pancreas and the second to the parotid gland. In both patients, ICI-based immunotherapy offered minimal clinical benefit, but both had durable responses to angiogenesis inhibitors. Given the anatomic similarity between the pancreas and parotid glands, ccRCC with involvement of the parotid gland may also benefit from VEGF-targeting TKIs as opposed to ICIs.

Background

Renal cell carcinoma (RCC) accounts for nearly 90% of all kidney cancers. The overall prognosis for localised renal cancers is excellent, although metastatic disease is associated with poor outcomes and carries a 5-year survival rate of 13%.¹ Metastatic RCC typically involves the lungs, bones or lymph nodes, but metastases have also been observed in many other organ systems.² Metastases affecting the pancreas are extremely rare, accounting for as few as 2% of all pancreatic neoplasms.³ Recent evidence suggests that RCCs involving the pancreas share distinct genomic features, as well as reduced effector T cell activation and enhanced angiogenesis.⁴ Accordingly, pancreatic metastases have shown poor responses to immune checkpoint inhibitors (ICIs) but increased sensitivity to tyrosine kinase inhibitors (TKIs) targeting the VEGF signalling pathway.⁴ Parotid metastases from RCC have also been reported.⁵ The structural, functional and histological similarity of the pancreas and parotid glands are well documented,⁶ but it is unknown whether patients with parotid metastases will also show preferential responses to TKIs targeting VEGF signalling over ICIs.

Case presentation: patient 1

A 75-year-old man was referred to our oncology clinic in June 2017 for recurrent, metastatic clear cell RCC (ccRCC). He was initially diagnosed with stage IIIB ccRCC of the right kidney with inferior vena cava (IVC) invasion and tumour thrombus requiring right nephrectomy, thrombectomy and IVC reconstruction in January 2008. He remained disease free for 9 years but eventually developed epigastric pain, anorexia and a 15-pound unintentional weight loss. His symptoms prompted CT of the chest and MRI of the abdomen and pelvis. MRI showed a T2 hyperintense, peripherally enhancing mass in the distal body of the pancreas measuring 3×2.8 cm (figure 1). Subsequent PET/CT also revealed two ¹⁸F-fluorodeoxyglucose (FDG)-avid masses at the upper and lower poles of the left kidney, the larger of which was 3.3 cm. Endoscopic ultrasound and biopsy of the pancreatic mass confirmed recurrent, now metastatic, ccRCC.

Figure 1.

CT imaging of metastatic RCC involving the body of the pancreas and contralateral kidney. RCC, renal cell carcinoma.

Treatment: patient 1

As resection of the pancreas metastasis was not deemed feasible, he was therefore started on systemic treatment with nivolumab. Nivolumab, although well tolerated, provided stable disease as the best response. After 7 months of treatment, his disease progressed, and therapy was switched to the TKI cabozantinib. Cabozantinib led to a partial response after 4 months of therapy but was discontinued secondary to treatment-related adverse events. Using shared decision making, a treatment holiday was implemented, though imaging showed disease progression after 11 months of surveillance. Subsequent line treatment with the TKI pazopanib has led to continued stable disease to the present day, with another partial response after three 28-day cycles.

Case presentation: patient 2

In 2001, a then 65-year-old man with stage IV ccRCC was referred to our oncology clinic. His primary tumour was in the right kidney, but de novo metastatic disease to T7-T11 was also found at diagnosis. At the time, right nephrectomy and spinal stabilisation were pursued for disease control. He was then treated with high-dose interleukin 2 (IL-2) and achieved remission until November 2008, when he developed a painful, debilitating left iliac bone mass biopsy proven to be recurrent and eventually requiring radiation. Following local treatment, sunitinib was initiated. He had a durable partial response to sunitinib until April 2015, when his disease again progressed on treatment. His ccRCC subsequently progressed through multiple additional lines of therapy, including after only four cycles of nivolumab. In March 2018, he developed a large 4×3 cm pulsatile mass at the left angle of the mandible. The mass was painless but did cause dysphonia and significant left ear lobe oedema. The patient underwent CT imaging, revealing a 3.2 cm × 2.8 cm hyperdense lesion in the left parotid gland (figure 2), highly suspicious for metastasis. Imaging also revealed progression of disease in the liver, lungs and the remaining left kidney. Biopsy of the parotid mass was significant for metastatic ccRCC.

Figure 2.

CT imaging of the patient’s left parotid gland lesion confirmed to be metastatic ccRCC. ccRCC, clear cell renal cell carcinoma.

Treatment: patient 2

The patient was treated with the immunotherapy combination of nivolumab and ipilimumab but had no response and continued growth of the left parotid mass. In November 2018, he was switched to the TKI cabozantinib. He experienced a dramatic reduction in the left parotid mass to 1.3 cm in size with a good response of his visceral disease. His dysphonia has improved significantly, and the left ear lobe oedema has completely resolved. His weight stabilised, and he remained physically active with improved energy and appetite. After 16 months of treatment, cabozantinib was discontinued secondary to a treatment-related adverse event. After 3 months of surveillance, imaging showed progressive disease. Lenvatinib was started at this time and has maintained stable disease without complication for 10 months.

Discussion

Treatment for RCC has advanced in recent years, with many patients deriving long-term benefit from immunotherapy and antiangiogenic therapies.⁷ A recent phase III trial demonstrated that the combination of the ICIs ipilimumab and nivolumab has superior efficacy as first-line therapy compared with sunitinib, a multi-TKI that targets VEGF signalling.⁸ However, recent evidence also suggests that ICI-based immunotherapy is largely ineffective for patients with RCC metastases affecting the pancreas, which generally appear to have a poorly immunogenic tumour microenvironment and increased sensitivity to angiogenesis inhibitors.⁴ This was consistent with observations from our patient with RCC affecting the pancreas, where nivolumab failed to offer any clinical benefit, and the patient was able to achieve stable disease on cabozantinib and subsequently pazopanib.

Though the drug sensitivity of pancreas metastases from RCC is now becoming clear, there are no studies exploring whether RCC metastases affecting other glandular tissues will exhibit similar patterns of drug responses. As discussed, the pancreas and parotid gland share many structural, functional and histological characteristics.⁶ As parotid metastases from RCC are extremely rare, it is currently unknown whether RCC lesions affecting the parotid gland will have shared genetic or pathological features to those affecting the pancreas. Pancreatic metastases from RCC, for example, are associated with an increased rate of PBRM1 mutations, 3p loss, 5q amplification and a lower frequency of BAP1 mutations and loss of 9p, 14q and 4q.⁶ These tumours are also characterised by indolent biology with a comparative increase in angiogenesis and a poorly inflamed tumour stroma, presumably the cause of the increased sensitivity to TKIs targeting the VEGF signalling pathway in these tumours.⁶ Interestingly, our patient with a parotid gland metastasis failed to respond to nivolumab and ipilimumab but instead showing a durable response to TKIs sunitinib, cabozantinib and lenvatinib.

Though only two cases, our data appear to suggest the biochemical niche of these glandular tissues may somehow contribute to immune exclusion and the apparent failure of ICIs, as well as the increased sensitivity to TKIs targeting the VEGF signalling pathway (figure 3). Consistent with this hypothesis, ICIs have yet to show substantial therapeutic efficacy in primary cancers of the salivary or pancreas glands.^{9 10} However, it is important to note that our patient with RCC affecting the parotid gland experienced progression at all disease sites when treated with ICI-based immunotherapy. This suggests that cancers with a metastatic organotropism towards glandular tissues may be inherently immunosuppressive regardless of the secondary disease site. Additionally, the treatment histories of the patients presented in this report differ significantly, with one patient receiving high dose IL-2, potentially contributing to the lack of response to subsequent ICI-based immunotherapy. Hence, further study is warranted into the potential mechanisms of immune suppression in RCC affecting glandular tissues, as well as the comparative efficacy of ICIs and angiogenesis inhibitors in RCC patients with metastases to glands other than the pancreas.

Figure 3.

Schema describing the presumed drug sensitivities of metastatic ccRCC affecting glandular and non-glandular tissues. ccRCC, clear cell renal cell carcinoma; TKIs, tyrosine kinase inhibitors.

Learning points.

• Pancreas metastases from clear cell renal cell carcinoma (ccRCC) respond poorly to immune checkpoint inhibitors (ICIs) and have improved responses to tyrosine kinase inhibitors (TKIs) targeting the VEGF signalling pathway.

• Accordingly, our patient with ccRCC affecting the pancreas progressed on ICI-based immunotherapy but achieved long-term disease control on the multi-TKIs cabozantanib and pazopanib.

• We also present a case of metastatic ccRCC affecting the parotid gland, which has a high degree of structural, functional and histological similarity to the pancreas.

• Similar to observations with pancreas metastases, our patient with metastatic ccRCC to the partoid gland failed to respond to the combination of the ICIs nivolumab and ipilimumab but was able to achieve long-term disease control on cabozantanib followed by lenvatinib.

• Given the anatomic similarity between the pancreas and parotid glands, ccRCC with involvement of the parotid may likewise benefit from TKIs targeting VEGF signalling pathway as opposed to ICIs, and this warrants continued exploration in larger studies.

Ethics statements

Patient consent for publication

Obtained.