Innovation Fuels Breakthroughs for Rare Cancers

Oncology Live®Vol. 22/No. 11
Volume 22
Issue 11
Pages: 26

Innovative strategies are vital for patients diagnosed with rare cancers, who are frequently at a disadvantage compared with those who have more common malignancies, experts say.

Jaydira Del Rivero, MD

Jaydira Del Rivero, MD

Although there are only approximately 10,000 people in the United States living with von Hippel-Lindau (VHL) syndrome, nearly 3 dozen cancer institutes and hospitals throughout the nation have joined a network of specialized clinical centers for diagnosis and treatment of patients with the rare genetic condition.1,2 In March 2021, the FDA granted a priority review for belzutifan (MK-6482) as a potential treatment for patients with VHL-associated renal cell carcinoma (RCC) that does not require immediate surgery; if approved, the novel agent would be the first pharmacologic treatment option for VHL.3

These developments in the VHL field are emblematic of advancements that are unfolding throughout the rare cancer arena, where teamwork, innovation, and molecular analyses are paving the way for progress against malignancies that affect relatively small patient populations.

Such strategies are vital for patients diagnosed with rare cancers, who are frequently at a disadvantage compared with those who have more common malignancies, experts say. Diagnoses are often delayed, clinical research is challenging, and clinical management can be complex and available only at specialized centers. Moreover, patients with rare cancers often have limited social support and advocacy networks and can feel isolated.

Collaboration among investigators, clinicians, basic scientists, and patients is invaluable, according to Jaydira Del Rivero, MD, a physician scientist in the Developmental Therapeutics Branch of the National Cancer Institute (NCI) who studies neuroendocrine neoplasms and adrenocortical cancers. Furthermore, it is vital for medical professionals to understand the course of disease from the patient’s perspective.

“We need to bring advocacy groups together in order to understand more about what [patients’] needs are,” Del Rivero said in an interview with OncologyLive®. “I’m hoping that I’m able to bring researchers, physicians, advocacy groups, and patients together because I think that’s important to advance the science in any rare tumor. We need to understand from the patient side what the needs are, how we can help them.”


The NCI defines rare cancers as those with an incidence of fewer than 15 cases per 100,000 people per year.4 By contrast, the rate of new cases of prostate and breast cancer, the most prevalent malignancies in men and women, was 111.3 per 100,000 men and 129.1 per 100,000 women, respectively, according to the most recent estimates from the NCI’s Surveillance, Epidemiology, and End Results Program.5,6 Childhood cancers are considered rare, with only about 15,000 cases diagnosed annually in patients younger than 20 years.7

However, although the incidence of individual malignancies classified as rare cancers is a fraction of that of the leading cancer types, the aggregate impact is significant. Overall, rare cancers represent 27% of all malignancies and account for 25% of cancer deaths, according to the NCI.8

Investigators from RARECANCERnet, a European Union (EU) consortium that uses a more selective definition of rare cancers as fewer than 6 cases per 100,000 people per year, found that 24% of all cancers diagnosed in the EU from 1999 to 2007 could be classified as rare, a category comprising approximately 200 malignancies, according to results of a 2017 study.8 Using the EU definition, the American Cancer Society estimated that approximately 13% of cancer diagnoses—1 in 8—in adults aged 20 and older would be considered rare.4

For many patients with a rare cancer, outcomes may be less favorable than they are for those with more common malignancies. The 5-year relative overall survival (OS) rate for all rare cancers was 48.5% (95% CI, 48.4%-48.6%) compared with 63.4% (95% CI, 63.3%-63.4%) for all common cancers from 1999 to 2007, according to the RARECANCERnet study. Although the OS data improved during the later years of the study period (2007-2009) for those with rare cancers, the gains were not as great as they were for patients with common cancers.8

Although investment in studying rare cancers historically was limited, research attention has increased during the last decade, partly through collaborations such as RARECANCERnet and several US initiatives4 such as the NCI’s My Pediatric and Adult Rare Tumor Network (MyPART).

The number of clinical trials focused on rare cancers has grown significantly since 2010, the IQVIA Institute for Human Data Science reported in May 2021. Studies for rare oncology indications represented 63% of all cancer trials launched in 2020 and 64% of all rare disease studies, the report said.9

Moreover, the rare cancer field shared in what turned out to be a robust year for oncology trial launches despite the COVID-19 pandemic, with more than 1600 studies initiated across all indications. Overall, approximately 500 products were in late-stage development for rare cancers, representing half of all therapies in the oncology pipeline.9

The research focus on rare cancers has helped fuel advancements. Among the initiatives that have aided in this progress is The Cancer Genome Atlas, which has led to the characterization of cell signaling networks and enabled the identification of targeted therapies, according to the American Society of Clinical Oncology (ASCO). In 2019, ASCO investigators named progress in treating rare malignancies as the Advance of the Year, citing 5 particularly notable developments10:

  • FDA approval for the combination of dabrafenib (Tafinlar) plus trametinib (Mekinist) for treating patients with BRAF-mutated anaplastic thyroid cancer
  • Findings showing that sorafenib (Nexavar) improves progression-free survival (PFS) for patients with desmoid tumors
  • Improved PFS results with lutetium Lu 177 dotatate (Lutathera) for patients with somatostatin receptor–positive midgut neuroendocrine tumors
  • New data showing that the combination of carboplatin, paclitaxel, and trastuzumab (Herceptin) improved survival for women with uterine serous carcinoma
  • Results leading to FDA approval for pexidartinib (Turalio), a colony-stimulating factor-1 inhibitor, in patients with symptomatic tenosynovial giant cell tumor

Since then, FDA approvals for rare diseases, including cancers, have continued to grow. In 2020, oncology approvals for rare cancers included these new drugs for patients with certain tumor types: naxitamab-gqgk (Danyelza) for neuroblastoma; avapritinib (Ayvakit) and ripretinib (Qinlock) for gastrointestinal stromal tumors; tazemetostat (Tazverik) for epithelioid sarcoma; pemigatinib (Pemazyre) for cholangiocarcinoma; and selumetinib (Koselugo) for neurofibromatosis type 1.11


VHL syndrome is an example of a rare disorder in which improvements have flowed from an expanded understanding of its molecular underpinnings. In 2019, William G. Kaelin Jr, MD, of Dana-Farber Cancer Institute, Sir Peter J. Ratcliffe of the University of Oxford, and Gregg L. Semenza, MD, PhD, of Johns Hopkins University School of Medicine shared the Nobel Prize in Physiology or Medicine for their discoveries showing that VHL proteins can degrade the hypoxia- inducible factor (HIF)-1α and HIF-2α and for describing the pathways downstream of HIF (FIGURE). These findings may lead to therapies that treat a variety of diseases including RCC, breast cancer, and anemia.12

Cellular Oxygen Sensing and Adaption by HIFα

FIGURE. Cellular Oxygen Sensing and Adaption by HIFα

Specifically, VHL syndrome is an autosomal dominant condition resulting from a germline deletion or mutation in the VHL gene that predisposes carriers to tumors and/or cysts in up to 10 body areas, including the kidneys, pancreas, adrenal glands, reproductive tract, liver, and lung.1 Although the tumors are often benign, patients with aberrations in the VHL gene have an increased risk of RCC, central nervous system and retinal hemangioblastomas, pancreatic neuroendocrine tumors, and other lesions.13 Approximately 70% of patients with the condition will develop clear cell RCC (ccRCC) by the age of 60 years and it is a leading cause of death among patients with VHL.14 Moreover, 90% of patients with sporadic ccRCC have defects in VHL proteins.

In the past several years, investigators have shown success in targeting HIF-2α, a transcription factor thought to be undruggable as recently as the 1990s. The FDA granted a priority review for belzutifan, an HIF-2α inhibitor, for patients with VHL-associated RCC not requiring immediate surgery based on data from the phase 2 study 6482004 (NCT03401788), and the agency is scheduled to make a decision by September 15, 2021.3

Investigators reported a confirmed objective response rate (ORR) with belzutifan monotherapy of 36.1% (95% CI, 24.2%-49.4%) in a cohort of 61 patients with VHL diseaseassociated RCC during the 2021 Genitourinary Cancer Symposium. All patients had partial responses. Overall, 91.8% saw a reduction in the size of the target ccRCC lesions. The median time to response was 31.1 weeks (range, 11.6-61.0) and the median duration of response was not reached (range, 11.9-62.3). The 1-year PFS rate was 98.3%.13

Investigators also reported responses in trial participants who had pancreatic lesions (n = 61) and central nervous system hemangioblastomas (n = 50), with ORRs of 63.9% (95% CI, 50.6%75.8%) and 32.0% (95% CI, 19.5%-46.7%), respectively. The corresponding rates of complete response were 6.6% and 2.0%.13

Eric Jonasch, MD, a professor of genitourinary medical oncology at The University of Texas MD Anderson Cancer Center in Houston, has investigated novel treatments for cancers associated with VHL disease, including belzutifan, and is excited about the potential for the therapy.

Findings that Ramaprasad Srinivasan, MD, PhD, and colleagues are scheduled to present at the 2021 ASCO Annual Meeting show that belzutifan induced an ORR of 30% in nervous system hemangioblastomas and ORRs of 70% to 90% in the pancreas, according to Jonasch. Investigators also observed responses in patients with retinal hemangioblastomas. They have recorded a confirmed ORR of 49% in patients with RCC, plus another 6% unconf irmed partial response rate.

“Having worked with patients with VHL disease for close to 20 years now and having this type of therapy potentially available in the near future is incredibly encouraging and exciting,” Jonasch said. “VHL disease is a disease affecting many different organs and what you really want is a therapy that’s going to manage all organ-specific manifestations and it looks like belzutifan is doing that,” he said. “In that regard, this drug really is a game changer for patients with VHL disease.”


Understanding the broader significance of rare cancers such as VHL syndrome is the key to raising awareness and attracting research funding to investigate these malignancies, Jonasch said.

“Mutations in the VHL gene, which regulates HIF, are obviously very important for patients with VHL,” Jonasch explained. “But HIF dysregulation is something that’s frequently seen in many other cancers, and so by understanding VHL disease more precisely, we will learn much more about other diseases. The Nobel Prize [in Physiology or] Medicine was awarded to those who discovered the function of the VHL gene in more detail. I think that speaks to the significance of VHL [syndrome] for the broader cancer community as well as the noncancer community.”

Belzutifan, for instance, already is being studied in a broader context in ccRCC. A multicenter phase 3 trial (NCT04586231) is evaluating the efficacy and safety of belzutifan plus lenvatinib (Lenvima) versus cabozantinib (Cabometyx) in patients with advanced ccRCC who have progressed on prior anti–PD-1/PD-L1 therapy.

Investigators note that HIF-2α also activates VEGFA gene expression and plays a role in resistance to anti-VEGF therapy. As such, combining belzutifan with a VEGF tyrosine kinase inhibitor such as lenvatinib may have a synergistic effect in the advanced RCC setting.15 Investigators plan to recruit a total of 708 patients in Australia, Europe, and North and South America. The primary end points are progression-free survival and OS.

When it comes to studying rare cancers, Jonasch said that difficulty in enrolling patients into clinical trials can be overcome with a hub-based approach in which those with rare cancers travel to a central study location.

He cited work conducted by Srinivasan and W. Marston Linehan, MD, both with the NCI’s Urologic Oncology Branch, which helped to elucidate the genetic and metabolic bases of kidney cancer, as a successful example of such an approach.

“Now we’re getting more of a decentralized approach where we’re starting to treat more and more individuals at their local site or local hospital,” Jonasch said. This method causes less disruption to the patient’s life and is less expensive but requires extensive data sharing between institutions.

“We need to have informatics solutions here,” he added. “Then you can actually start improving care for those individuals without them having to travel as much. We haven’t reached that point yet—that’s an aspirational goal.”

One innovative trial design is the MASTER KEY Project, a multicenter platform study initiated in Japan in May 2017. The project consists of a prospective registry study and multiple simultaneous clinical trials targeting patients with advanced rare cancers, cancers of unknown primary origin, or rare tissue subtypes of common cancers.

The registry study accumulates consecutive data that can be used for future drug development. The clinical trials target either a specific biomarker or a rare tumor type of interest, with multiple trials ongoing. Of 560 patients recruited from May 2017 to April 2019, 69% underwent next-generation sequencing. Forty-eight percent of those tested (176 of 364 patients) had an actionable alteration. In all, 13% of patients in the study enrolled in a clinical trial.16

Similarly, studies that leverage precision medicine include rare as well as common tumor types. Roche is planning to update progress on 4 such studies at the 2021 ASCO Annual Meeting:

  • ALpha-T (NCT04644315)—evaluating alectinib (Alecensa) in ALK-positive malignancies confirmed through next-generation sequencing for solid tumors other than lung cancer and in cancers of unknown primary origin
  • ARROW (NCT03037385)—testing pralsetinib (Gavreto) in RET-altered solid tumors;
  • TAPISTRY (NCT04589845)—a platform study evaluating several drugs in solid tumors harboring ALK, ROS1, or NTRK1/2/3 fusions, a high tumor mutational burden, or AKT1/2/3 mutations; and
  • MyTACTIC (NCT04632992)—matching therapies to help patients with solid tumors with ROS1 fusions, PIK3CA mutations, ALK rearrangement, AKT1/2/3 mutation, or PTEN loss of function.17

At the NCI, Del Rivero is taking a long-term approach to unraveling the mechanisms of rare cancers. She is serving as principal investigator for the NCI’s Natural History Study of Rare Solid Tumors (NCT03739827), the Natural History Study of Children and Adults With Adrenocortical Cancer (NCT04447014), and the Natural History Study of Children and Adults With Neuroendocrine Neoplasms (NCT04488263).

Del Rivero and colleagues are studying patients longitudinally and comprehensively over time and obtaining clinical information and biospecimen collection to further understand the biology and pathophysiology of these rare cancers.

Adrenocortical cancer (ACC) is a rare, heterogeneous, and aggressive disease. At least 50% of patients present with metastatic disease and the only treatment to demonstrate broad efficacy is repeated surgical resection. The only FDA-approved systemic option is mitotane, which has low efficacy and a controversial risk to benefit ratio.18

“To our knowledge, there are not robust preclinical models for neuroendocrine tumors such as ACC, gastroenteropancreatic neuroendocrine tumors, or pheochromocytomas or paragangliomas,” she said. “And without those preclinical models, drug testing and understanding the tumor biology to develop effective therapies is quite challenging.”

Del Rivero is working closely with basic scientists to develop preclinical models for neuroendocrine tumors to be used to screen and identify new drugs with the goal of personalized treatments for patients with these rare cancers.

“Most of the studies for neuroendocrine tumors depend on only a few cell lines that do not resemble the patients’ tumor biology,” she said. “Only a few therapies are FDA approved. More recently, the FDA approved Lutathera [lutetium Lu 177 dotatate] in 2018, which is a peptide receptor radionuclide therapy that basically binds to a somatostatin receptor. We know Lutathera is increasing survival in those patients, but we need to increase its efficacy and current research efforts [seek] to understand how we can enhance its efficacy and develop further treatments with better outcomes and quality of life.”

Del Rivero is working on several clinical trials to study targeted therapies for neuroendocrine tumors. These include a phase 1/2 study (NCT04086485) in cooperation with other investigators at the NCI examining the combination of lutetium Lu 177 plus olaparib (Lynparza) in patients with inoperable gastroenteropancreatic neuroendocrine tumors. Lutetium Lu 177 monotherapy is being tested in a phase 2 study (NCT03206060) in patients with inoperable pheochromocytoma and paraganglioma. Del Rivero also is co-chairing a prospective, multi-institutional phase 2 National Clinical Trials Network study (NCT04394858) evaluating the combination of olaparib plus temozolomide for patients with advanced or metastatic pheochromocytoma and paraganglioma.


For patients with rare cancers, creating support networks that can respond to the particular needs of an individual patient is key to both treating disease and improving patient well-being, Jonasch said. He added that physicians need to understand the implications of living with such a disease. Further, they should be able to recognize the signs of distress and provide patients with the necessary support.

Organizations such as the VHL Alliance, the largest organization serving the needs of patients with VHL disease, provide important assistance, including coordinating treatment through the VHL Clinical Care Centers network.2 “The VHL Alliance is very much at the forefront of creating those resources for individuals with VHL disease,” said Jonasch, who is a member of the alliance’s clinical advisory council.

“This is not just a physiological disease, but also the physiological impact of the disease has a huge impact on people’s lives, on their livelihood, on their emotional state,” Jonasch said. “Being able to help individuals living with VHL disease and other rare diseases by creating support networks, by creating infrastructure that can really help them in all aspects of their care, is really important and should be a focus for rare diseaserelated research.

“The bottom line is that physical health and mental health are inextricably intertwined,” he added. “You need to address both and only by addressing both can you improve physical health.”


  1. Von Hippel-Lindau disease. National Organization for Rare Disorders. Accessed May 12, 2021.
  2. Clinical Care Centers Directory. VHL Alliance. Updated May 3, 2021. Accessed May 18, 2021.
  3. Merck receives priority review from FDA for new drug application for HIF-2α inhibitor belzutifan (MK-6482). News release. Merck. March 16, 2021. Accessed May 18, 2021.
  4. American Cancer Society. Cancer facts & figures 2017 - special section: rare cancers in adults. 2017. Accessed May 18, 2021.
  5. Cancer stat facts: prostate cancer. Surveillance, Epidemiology, and End Results Program. National Cancer Institute. Accessed May 18, 2021.
  6. Cancer stat facts: female breast cancer. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Accessed May 18, 2021.
  7. Rare cancers of childhood treatment (PDQ)-health professional version. National Cancer Institute. Updated February 10, 2021. Accessed May 18, 2021.
  8. Gatta G, Capocaccia R, Botta L, et al; RARECAREnet working group. Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet―a population-based study. Lancet Oncol. 2017;18(8):1022-1039. doi:10.1016/S1470-2045(17)30445-X
  9. Global Trends in R&D. Overview through 2020. IQVIA Institute for Human Data Science. Published May 19, 2021. Accessed May 21, 2021.
  10. Pal SK, Miller MJ, Agarwal N, et al. Clinical cancer advances 2019: annual report on progress against cancer from the American Society of Clinical Oncology. J Clin Oncol. 2019;37(10):834-849. doi:10.1200/JCO.18.02037
  11. New drug approvals for 2020. FDA. Updated January 13, 2021. Accessed May 19, 2021. 
  12. What is von Hippel-Lindau syndrome? Dana-Farber Cancer Institute. December 6, 2019. Accessed May 18, 2021.
  13. Iliopoulos O, Jonasch E, Donskov F, et al. Phase II study of the oral hypoxia-inducible factor 2a (HIF-2α) inhibitor MK-6482 for Von Hippel-Lindau (VHL) disease-associated clear cell renal cell carcinoma (ccRCC). J Clin Oncol. 2021;39(suppl 6):333. doi:10.1200/JCO.2021.39.6_suppl.333
  14. van Leeuwaarde RS, Ahmad S, Links TP, Giles RH. Von Hippel-Lindau Syndrome. GeneReviews. University of Washington, Seattle; 2015. Updated September 6, 2018. Accessed May 18, 2021.
  15. Motzer RJ, Liu Y, Perini RF, Zhang Y, Heng DYC. Phase III study evaluating efficacy and safety of MK-6482 + lenvatinib versus cabozantinib for second- or third-line therapy in patients with advanced renal cell carcinoma (RCC) who progressed after prior anti-PD-1/L1 therapy. J Clin Oncol. 2021;39(suppl 6):TPS372. doi:10.1200/JCO.2021.39.6_suppl.TPS372
  16. Okuma HS, Yonemori K, Narita SN, et al. MASTER KEY project: powering clinical development for rare cancers through a platform trial. Clin Pharmacol Ther. 2020;108(3):596-605. doi:10.1002/cpt.1817
  17. Roche to present data from one of the most comprehensive oncology portfolios at the 2021 ASCO Annual Meeting showcasing advancements for people living with cancer. News release. Roche. May 11, 2021. Accessed May 19, 2021. 
  18. Mauda-Havakuk M, Levin E, Levy EB, et al. Long-term outcomes in patients with advanced adrenocortical carcinoma after image-guided locoregional ablation or embolization. Cancer Med. 2021;10(7):2259-2267. doi:10.1002/cam4.3740
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