CCA Advance of the Year

This year, ASCO names Progress in Treating Rare Cancers as the Advance of the Year. Rare cancers have been defined as those that account for less than six of 100,000 diagnosed cancers and for 20% of all cancer cases each year in the United States, though definitions and incidence rates differ around the world.4

There is wide variation in the availability and effectiveness of treatment options for rare cancers due to the enormous diversity in clinical presentation and underlying biology. It often takes longer to recruit significant numbers of people to participate in clinical trials that are testing new treatments for rare cancers, and there are unique hurdles to developing and designing specialized therapies.

Recently, however, the decades of research progress in understanding cancer are translating into better treatments for multiple rare cancers. In fact, clinical research this past year identified effective therapies for rare forms of uterine, neuroendocrine, joint, and thyroid cancers, as well as sarcomas, which for decades have been challenging to treat effectively. What follows are some of the more prominent achievements in rare cancers this past year

New Combination of Targeted Therapies Identified for Rare Form of Thyroid Cancer

Anaplastic thyroid carcinomas (ATCs) comprise less than 2% of all thyroid cancers diagnosed in the United States and have a worse prognosis than other more common forms of thyroid cancer.15 Not only do they tend to be aggressive, but also ATCs are usually diagnosed at an advanced stage and have low 1-year survival rates.16

This year, the FDA approved the first treatment of ATCs in almost 50 years,17 a targeted therapy combination of dabrafenib (Tafinlar), a BRAF inhibitor, plus trametinib (Mekinist), a MEK inhibitor, for people with BRAF-mutated ATC.

The approval was based on a 2018 finding from a single-arm phase II trial.18 The federally funded trial assessed 100 patients for eligibility and enrolled 16 patients with BRAF-mutated tumors, all of whom had received prior radiation, surgery, and/or chemotherapy. Of these patients, 69% responded to the drug combination (this study was funded, in part, by NIH). At the time the study was published, seven patients, or nearly half of those enrolled, were experiencing ongoing responses to the therapy. Although overall survival and progression-free survival could not be assessed at the time, clinicians estimated that at least 80% of the patients with tumors that responded would achieve improvements in both outcomes.

Before this study, no chemotherapy treatment for ATC prolonged survival or improved quality of life. This new combination therapy has now become the standard of care for these patients.

Sorafenib Becomes Fiirst Treatment to Improve Progression-Free Survival for Rare Sarcoma

This past year brought the first randomized, global phase III trial, Alliance A091105 ( identifier: NCT02066181)19 for patients with a rare type of sarcoma called a desmoid tumor. Before this federally funded trial, patients with desmoid tumors were often treated with off-label treatments. Designing a trial for desmoid tumors has historically been challenging because there are few patients to study and the tumors are known to periodically regress without systemic treatment. Indeed, approximately 20% of the cancers regressed or did not progress in patients who received a placebo in this trial.

Eighty-seven patients with unresectable progressive desmoid tumors were randomly assigned to receive either the tyrosine kinase inhibitor sorafenib (Nexavar) or a placebo. The trial achieved its primary endpoint, with 87% of those taking sorafenib experiencing improved 1-year progression-free survival compared with 43% of patients on placebo (this study was funded, in part, by NCI).

The study authors attribute part of the success of the trial to the relatively robust patient enrollment for a rare cancer. Enrollment was facilitated by NCI’s National Clinical Trials Network, a collection of organizations, hospitals, and clinicians that coordinates and supports cancer clinical trials.

New Radiolabeled Drug Substantially Lowers the Risk of Progression or Death in Patients With Midgut Neuroendocrine Tumors

Midgut neuroendocrine tumors are rare, estimated to affect fewer than three per 100,000 people annually.20 Patients with advanced midgut neuroendocrine tumors are usually treated with somatostatin, a growth hormone inhibitor, or octreotide, a synthetic form of somatostatin that has a long-acting release.

NETTER-1 ( identifier: NCT01578239), an international phase III trial,21 was the first study to evaluate the safety and efficacy of 177Lu-Dotatate in patients with advanced, somatostatin receptor-positive midgut neuroendocrine tumors. The medicine is composed of the radioisotope 177Lu attached to octreotide. The radionuclide-octreotide analog binds to the neuroendocrine tumor cell, enabling radiation to be directly delivered to the cancer cell, inhibiting tumor growth.

In the trial, 229 people with the disease were randomly assigned to receive either177 Lu-Dotatate or octreotide. The estimated progression-free survival after 20 months was 65.2% in the 177Lu-Dotatate group and 10.8% in the octreotide group. The risk of disease progression or death was 79% lower in people who received 177Lu-Dotatate compared with those who received octreotide. Results of an interim analysis suggest longer overall survival with the new treatment; 14 deaths occurred in the group that received 177Lu-Dotatate compared with 26 deaths in the group that received octreotide.

The FDA approved 177Lu-Dotatate in January 2018 for treatment of adults with this type of tumor in the midgut,  foregut, or hindgut.22 A follow-up study,23 published in September 2018, showed that the new treatment also provided important quality-of-life benefits. Investigators found that in addition to improving survival, 177Lu-Dotatate, compared with octreotide, provided 28.8 v 6.1 months of overall better health and 25.2 v 11.5 months of better physical functioning, respectively.

Trastuzumab Effective for a Rare Form of Endometrial Cancer

Uterine serous carcinoma is a rare and aggressive type of cancer that accounts for 10% of endometrial cancer cases and up to 40% of recurrences and deaths from endometrial cancer.24 The HER2 gene is overexpressed in approximately 30% of uterine serous tumors. This year, researchers demonstrated that trastuzumab (Herceptin), a HER2-targeted treatment used primarily in women with HER2-positive breast cancer, is effective in these tumors.

The phase II trial25 compared a chemotherapy combination of a platinum-based drug, carboplatin, added to paclitaxel with and without trastuzumab among 61 women with stage III or IV HER2-positive uterine serous carcinoma. The median time before disease progression was 12.6 months for women who received trastuzumab compared with 8 months for those who did not. This study is one of the first to demonstrate improved progression-free survival with the addition of a targeted therapy to standard platinum-based chemotherapy in women with this form of uterine cancer.


ASCO’s Targeted Agent and Profiling Utilization Registry (TAPUR; identifier: NCT02693535) Study continues to enroll patients and achieve milestones as patient outcomes are reached. The TAPUR Study evaluates antitumor activity of commercially available, targeted anticancer drugs when used outside of their US Food and Drug Administration–approved indications. It aims to identify new uses for existing, effective treatments that target tumor genomic profiles.

More than 1,600 participants have been registered and more than 1,200 patients treated with a TAPUR Study drug. On the basis of treatment responses in stage I, patient cohorts are either expanded to stage II for additional study or permanently closed. To see the full list of patient cohort updates, go to

First Promising Therapy Identified for Rare Cancer of the Joints That Typically Occurs in Younger Adults

With global collaboration, ENLIVEN ( identifier: NCT02371369)26, a trial studying a novel treatment for tenosynovial giant cell tumors—a rare, debilitating tumor that is generally found in younger, working-age adults—was able to enroll and treat 120 patients. The disease is associated with severe loss of function and morbidity and frequently affects physical ability and job function. There is no current standard of care; two systemic therapies that have been tested in clinical trials to treat these tumors have shown poor overall responses.

Surgery remains the standard initial treatment of tenosynovial giant cell tumors. Some patients undergo multiple synovectomies (surgery to remove the membrane, or synovium, that lines a joint, most typically the knee), and some even need full-joint replacements.

The phase III federally funded trial26 randomly assigned patients with advanced, symptomatic disease to first receive either the CSF-1 inhibitor pexidartinib or a placebo. CSF-1 is a molecule that increases the recruitment of certain tumor-promoting immune cells to the tumor; therefore, an inhibitor of CSF-1 removes these from the milieu. The overall response rate was 39.3% for patients taking pexidartinib compared with 0% for those on placebo. All patients were able to cross over to receive open-label pexidartinib in the second part of the trial. There was a statistically significant improvement in pain scores, range of motion, and physical function in patients who received the study drug (this study was funded, in part, by NIH).

The use of CSF-1 inhibitors holds promise in this disease and continues to be investigated in new clinical trials. CSF-1 inhibitors, including pexidartinib, are not yet recommended for general use as a result of serious liver toxicities that occurred in some trial participants. The toxicity is part of the focus of an ongoing study to clarify safety concerns.

Federal Funding Is Vital to Advancing Progress in Rare Cancers

Progress in rare cancers is being advanced, in part, by ongoing efforts of several major federally funded initiatives:

  • The Cancer Genome Atlas (TCGA) cataloged key genomic changes in 33 types of cancer, of which 10 were rare cancers.
  • In the Molecular Analysis for Therapy Choice (MATCH; identifier: NCT02465060) precision medicine trial, patients receive treatment based on genomic changes in the tumor. More than 60% of enrollees have cancers other than the four most common types.
  • The Dual Anti–Cytotoxic T-Cell Lymphocyte-4 and Anti-PD-1 Blockade in Rare Tumors (DART) immunotherapy trial is studying nivolumab (Opdivo) and ipilimumab (Yervoy) in people with rare types of cancers that are usually ineligible for current immunotherapy trials.

Future funding of these and other similar efforts is vital to accelerating progress in rare cancers.

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