March 2019 Edition Vol.12, Issue 3

Rare Cancers Are No Longer Orphans

By Ted Bosworth

New optimism abounds for treatment of rare cancers as shown by the many recent FDA approvals that took place in 2018 for new therapies treating rare cancers. According to news from the TAT 2019 International Congress on Targeted Anticancer Therapies, less common tumor types are receiving an uptick in attention compared with the proportion of early-stage drug trials in the more common cancer types. By 2024, oncology is expected to be the leading orphan drug therapy area and account for about 50% of the total 2024 worldwide market.1

As defined by the National Cancer Institute, rare cancers occur in fewer than 15 out of 100,000 people each year, but the International Rare Cancer Consortium puts that number at less than 6 per 100,000 per year.

In the United States, rare cancer types account for about 20% of all cancers, and adult U.S. men and women with a rare cancer show a poorer five‐year survival rate compared with those diagnosed with a common cancer.2

Since 1983, when the Orphan Drug Act went into effect, 177 drug approvals have been granted to treat rare cancers, representing 36% of all approvals within the United States. The Orphan Drug Act contains incentives for the development of rare disease therapies, including seven years of marketing exclusivity, tax credit for 50% of clinical trial costs, protocol assistance, and an FDA fee waiver.3 These incentives are put in place to help offset the financial cost of developing a drug aimed at a small patient population.

Major advances in genomic sequencing and molecular understanding of tumorigenesis has fast-tracked over the last 10 years and may be the driving force behind the recent burst of rare cancer drug approvals. Consider histology-agnostic studies, often called basket trials, where treatments are given according to molecular profile rather than tumor type. A tumor-agnostic drug treats any kind of cancer in the body as long as the cancer has the specific molecular mutation that the drug targets. Thus, patients in a basket trial have the same genetic mutation no matter where the tumor has originated in the body.

The importance of this is not lost on drug approvals. On November 26, 2018, the drug Vitrakvi (larotrectinib) became the first ever TRK inhibitor to receive FDA approval with a tumor-agnostic indication based on the results of a basket trial.4 Larotrectinib is indicated for adults and children with solid tumors that test positive for NTRK genes. Tumors with this molecular mutation are rare but can be found in various cancers, such as the salivary gland and thyroid, among others.

Tumor-agnostic treatments are representing a new approach on how to treat cancer. Testing the tumor’s genes or other molecular features is not only an essential element but a logical step closer to fulfilling the promise of precision oncology. ASCO has named progress in treating rare cancers the 2019 Advance of the Year, a designation that draws attention to an area where there have been impressive gains in cancer.

The larotrectinib approval is just one of several drugs that were approved in the last year for a rare cancer. Other advancements in rare cancers and approvals are described in the following table.

2018 Rare Cancer Drug Approvals

Of the many reasons for recent progress in treating rare cancers is that several organizations, including the NCI, have ramped up their efforts to pursue treatment targets in rare cancers. The NCI has funded numerous efforts to pursue rare cancer treatments including providing support for research consortiums.

One example is the Experimental Therapeutics Committee for Rare Cancer created by the Alliance for Clinical Trials in Oncology. The Alliance is a large collaborative clinical research network with participating centers across the United States and Canada. Its co-chairman, Gary K. Schwartz, MD, Chief of the Division of Hematology and Oncology, Columbia University School of Medicine and the interim director of the Herbert Irving Comprehensive Cancer Center, New York-Presbyterian Hospital, New York, New York, said the Alliance committee “is solely focused on developing new therapies for patients with rare cancers of all types.”

One of the products of this effort is the phase 3 placebo-controlled trial associating sorafenib, a multikinase inhibitor already approved in the treatment of renal cell carcinoma and hepatocellular carcinoma, with a major progression-free survival (PFS) advantage at two years in desmoid tumors (81% vs. 36%; P<0.001).5 Desmoid tumors, also called aggressive fibromatosis, are diagnosed in about 1000 patients per year in the United States, making collaboration between centers essential.

Although sorafenib has not yet been granted an indication for desmoid tumors, the trial, which enrolled 87 patients, demonstrates that meaningful prospective trials in a rare cancer can be conducted when there is a will for collaboration. Although rare cancers were for years “below the radar screen when compared to the more common cancers,” according to Dr. Schwartz, this has changed.

“There is an increasing awareness of how many patients are, in fact, affected by rare cancers and how difficult many of these cancers are to treat,” Dr. Schwartz said. He indicated that the “resurgence of interest” in this area is real. However, in rare cancers, unlike common cancers, one of the biggest challenges is recruiting enough patients for meaningful clinical studies.

Two recent positive trials in rare cancer provide examples of very different approaches to efforts to inhibit malignant cell proliferation. Although neither has yet generated a new approved indication, one targets a molecular pathway already relevant to other types of cancer and suggests rare cancers do not always have rare molecular pathways. The other targets a new pathway, suggesting the on-going need for novel strategies.

In the first example, trastuzumab [Herceptin; Genentech], improved PFS in uterine serous carcinomas when added to conventional chemotherapy combination of carboplatin and paclitaxel.6 Trastuzumab is a monoclonal antibody that targets the human epidermal growth factor receptor 2 (HER2/neu) and is already a standard adjuvant therapy in HER2-positive breast cancer.

In the other example, pexidartinib (Daiichi Sanyko) demonstrated high rates of response in a phase 3 trial in patients with tenosynovial giant cell tumor (TGCT).7 Based on this activity, the FDA accepted a new drug application in February 2019 under their Priority Review Program. If approved on August 3, 2019, the PDUFA action date, pexidartinib, which selectively inhibits the colony stimulating factor-1 receptor (CSF-1R), will be the first CSF-1R inhibitor to be approved and the first drug of any kind to be approved for TGCT. ASCO has selected pexidartinib as one of five significant advancements in rare disease treatment in its latest Clinical Cancer Advances Report.

The increased pace of drug approvals as outlined in the table may just be the tip of the iceberg in this area as more genomic data are revealed. With that in mind, the FDA has issued a revised draft guidance, “Rare Diseases: Common Issues in Drug Development Guidance for Industry” to assist developers of drug and biological products for the treatment or prevention of rare diseases in conducting more efficient and successful drug development programs. Public comments on the draft are being accepted through mid-March 2019.


  1. Evaluate Pharma. Orphan Drug Report 2018. Accessed March 5, 2019.
  2. DeSantis CE, et al. The burden of rare cancers in the United States. 2017 American Cancer Society. CA Cancer J Clin 2017;67:261–272.
  3. Stockklausner C, Lampert A, Hoffmann GF, Ries M. Novel Treatments for Rare Cancers: The U.S. Orphan Drug Act Is Delivering-A Cross-Sectional Analysis. Oncologist 2016;21:487-93.
  4. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med 2018;378:731-9.
  5. Gounder MM, Mahoney MR, Van Tine BA, et al. Sorafenib for Advanced and Refractory Desmoid Tumors. N Engl J Med 2018;379:2417-28.
  6. Fader AN, Roque DM, Siegel E, et al. Randomized Phase II Trial of Carboplatin-Paclitaxel Versus Carboplatin-Paclitaxel-Trastuzumab in Uterine Serous Carcinomas That Overexpress Human Epidermal Growth Factor Receptor 2/neu. J Clin Oncol 2018;36:2044-51.
  7. Tap WD, Gelderbolm H, S. S, Palmerini E, Ferrari S. Final results of ENLIVEN: a global double-blind, randomized, placebo-controlled, phase 3 study of pexidartinib in advanced tenosynovial giant cell tumor. American Societal of Clinical Oncology Annual Meeting. Chicago 2018.

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