Progress in Treating Rare Cancers Named ASCO's Advance of the Year


In recognition of the many advancements that have been made in the past year toward developing new therapies for patients with difficult-to-treat, rare cancers, ASCO has chosen progress in treating rare cancers as its Advance of the Year.

Monica M. Bertagnolli, MD, FACS, FASCO

Monica M. Bertagnolli, MD, FACS, FASCO

In recognition of the many advancements that have been made in the past year toward developing new therapies for patients with difficult-to-treat, rare cancers, ASCO has chosen progress in treating rare cancers as its Advance of the Year.1

ASCO announced its decision as part of theClinical Cancer Advances 2019: ASCO’s Annual Report on Progress Against Cancer,anannual update on oncology treatment that highlights the most impactful clinical research milestones and policy developments that have been achieved over the past year.

Federal investment is critical in furthering the progress made in the cancer space as a whole, especially in rare cancers where there is a great deal of unmet need, said ASCO President Monica M. Bertagnolli, MD, FACS, FASCO, in a press release.

“It’s exciting to see such substantial progress over the course of a single year, particularly against rare cancers,” she said. “With US cancer cases set to rise by roughly a third over the next decade, we must continue to advance research that saves lives…We need to prioritize federal funding of cancer research in the years to come. Americans are counting on it.”

Despite the fact that rare cancers account for approximately 20% of all cancers diagnosed annually in the United States, several achievements have been made within the past year. In January 2018, the FDA approved the radioactive agent Lutathera (lutetium Lu 177 dotatate) for the treatment of patients with somatostatin receptor—positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs). The agency also approved the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) for patients withBRAF-mutated anaplastic thyroid carcinoma—the first treatment in almost 50 years—in May 2018.

Additionally, the TKI sorafenib (Nexavar) was shown to improve progression-free survival (PFS) in patients with desmoid tumors for the first time, trastuzumab (Herceptin) was found to slow the progression of HER2-positive uterine serous carcinoma, and the CSF1R inhibitor pexidartinib became the first agent to produce promising responses in patients with tenosynovial giant cell tumors.

NETTER-1 Trial Leads to Approval in GEP-NETs

Lutathera was granted an approval based on positive results from 2 clinical trials. The first, the phase III NETTER-1 trial, which compared the use of Lutathera plus long-acting octreotide with high-dose long-acting octreotide, and showed that use of the Lutathera led to a 79% reduction in the risk of progression or death.2

For the trial, participants were randomized 1:1 to receive Lutathera at 7.4 GBq (200 mCi) every 8 weeks for up to 4 administrations with a maximum cumulative dose of 29.6 GBq with long-acting octreotide at 30 mg via intramuscular injection every 4 weeks, or high-dose long-acting octreotide at 60 mg via intramuscular injection every 4 weeks. Investigators co-administered Lutathera with an amino acid solution as a renal protectant. Median PFS for Lutathera arm had not been reached versus 8.5 months in the high-dose long-acting octreotide group (HR, 0.21; 95% CI, 0.13-0.32,P<.0001).

Investigators also evaluated the efficacy of Lutathera in a subset of 360 patients with GEP-NETs who were enrolled in the ERASMUS Medical Center (MC) study. Initially, Lutathera was provided as expanded access under a general peptide receptor radionuclide therapy protocol at 1 trial site based in the Netherlands. Patients received the investigational agent at 7.4 GBq (200 mCi) every 6 to 13 weeks for up to 4 doses. The overall response rate (ORR) was 16% (n = 58), which included 3 complete response rates; this was evaluated according to RECIST criteria.

The recommended dose for the radioactive agent is 7.4 GBq (200 mCi) to be delivered intravenously over 30 minutes every 8 weeks for a total of 4 doses.

First Approval for Anaplastic Thyroid Carcinoma in 50 Years

The FDA approval of dabrafenib (Tafinlar) plus trametinib (Mekinist) for the treatment of patients with inoperable or metastatic anaplastic thyroid cancer with aBRAFV600E mutation, was based on positive results from an open-label clinical trial. Among 23 evaluable patients, 57% achieved a partial response and 4% achieved a complete response.3Of the 14 patients who responded to the treatment, 64% (n = 9) were not found to have significant tumor growth for at least 6 months.

In previously published data, 7 in 10 patients with locally advanced or metastaticBRAFV600E—mutated anaplastic thyroid cancer responded to treatment with the combination. In that study, the confirmed ORR was 69% (11 of 16; 95% CI, 41%-89%). Investigators reported that 1 patient achieved a complete response, while 10 had partial responses. A total of 7 patients experienced ongoing responses at the time of analysis.4

Both agents are also approved by the FDA for use alone or in combination to treat patients withBRAFV600 mutation—positive melanoma. The 2 agents are also indicated to be used in combination for the treatment of patients withBRAFV600E mutation—positive, metastatic non&ndash;small cell lung cancer.

Sorafenib as First Treatment to Improve PFS in Desmoid Tumors

In a double-blind phase III trial (NCT02066181), sorafenib demonstrated significantly prolonged PFS and induced durable responses in patients with progressive, refractory, or symptomatic desmoid tumors.

For the trial, investigators randomly assigned 87 patients to receive either oral sorafenib once daily at 400 mg or matching placebo. Patients in the placebo arm of the trial were permitted to crossover to the sorafenib arm upon disease progression.

At a median follow-up of 27.2 months, the 2-year PFS rate in the sorafenib arm was 81% (95% CI, 69%-96%) compared with just 36% (95% CI, 22%-57%) in the placebo arm (HR, 0.13; 95% CI, 0.05-0.31;P<.001). Prior to crossover, the objective response rate in those who received sorafenib was 33% (95% CI, 20%-48%) versus 20% (95% CI, 8%-38%) in those who were given placebo. Further, the median time to an objective response in responders was 9.6 months in the sorafenib arm (interquartile range, 6.6-16.7) compared with 13.3 months (interquartile range, 11.2-31.1) in the placebo arm.5

Sorafenib has been approved by the FDA to treat patients with certain types of advanced kidney, liver, and thyroid cancer; it has not yet been approved for the treatment of this rare form of sarcoma.

Trastuzumab Slows Progression of Aggressive Form of Endometrial Cancer

Results from a small, randomized trial showed that the use of trastuzumab plus chemotherapy resulted in >50% improvement in PFS in patients with HER2-positive uterine serous carcinoma compared with the use of chemotherapy alone.

The median PFS increased to 12.6 months with the addition of trastuzumab to the chemotherapy regimen from 8.0 months with the chemotherapy regimen alone. Further, patients with advanced disease experienced a twofold increase in median PFS—going from 9.3 months with chemotherapy to 17.9 months with the addition of trastuzumab.

A preliminary survival analysis reported at the 2018 SGO Annual Meeting demonstrated a trend in favor of the trastuzumab arm, which seemed to increase for those with more advanced stage disease as well as those who had received the combination as initial systemic therapy.6

Pexidartinib Shows Promise in Tenosynovial Giant Cell Tumor

In results of the phase III ENLIVEN trial, patients with tenosynvial giant cell tumor treated with oral pexidartinib demonstrated a 39% ORR at week 25 based on central review of magnetic resonance imaging scans compared with no tumor response in those who received placebo.

For the trial, patients were randomized 1:1 to receive either pexidartinib or placebo 1000 mg daily for 2 weeks followed by 800 mg daily for 22 weeks. Patients who completed part 1 of the trial had the option to continue into an open-label pexidartinib extension. A total of 120 patients were treated in the trial, of which 61 received pexidartinib while 59 received placebo. ORR by RECIST criteria in the intent-to-treat population was 39.3% in the pexidartinib arm versus 0% in the placebo arm (P<.0001) at the end of part 1.7After a median 6-month follow-up, no responders in the trial progressed.

Hepatic toxicities were seen more often in those who received pexidartinib. A total of 8 patients discontinued treatment with the agent due to adverse events (AEs); 4 patients experienced serious nonfatal AEs with increased bilirubin, with 1 case lasting for around 7 months. Other AEs observed in the pexidartinib arm were changes in hair color, vomiting, fatigue, dysgeusia, and periorbital edema.

The investigators concluded that despite these events, pexidartinib could offer a relevant treatment option for certain patients with this rare cancer of the joints.

In November 2015, FDA granted a breakthrough therapy designation to pexidartinib as a potential therapy for patients with tenosynovial giant cell tumor.

Future Research to Further Progress Against Cancer

For the first time, ASCO has also identified priorities for future research efforts in oncology, including:

  • Identification of approaches to better predict response to immunotherapies in these patients;
  • Determining which patient populations will derive the most benefit from postoperative adjuvant treatment;
  • Translate advances made with cellular therapies into solid tumors;
  • Exploring more precision medicine approaches in pediatric cancers;
  • Improving care for older adults with cancer;
  • Boosting access to cancer clinical trials;
  • Minimizing the long-term consequences of cancer treatment;
  • Reducing obesity and its impact on cancer incidence and patient outcomes;
  • Developing strategies to identify and treat those with premalignant lesions.

&ldquo;These priorities represent our vision for finding the next generation of cancer cures and reducing cancer&rsquo;s impact on patients&rsquo; lives,&rdquo; Richard L. Schilsky, MD, FACP, FSCT, FASCO, senior vice president and chief medical officer of ASCO, said in a press release.


  1. 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 [published online ahead of print].J Clin Oncol. doi: 10.1200/JCO.18.02037.
  2. FDA approves lutetium Lu 177 dotatate for treatment of GEP-NETS [news release]. US Food and Drug Administration. Published January 26, 2018.
  3. FDA approves new uses for two drugs administered together for the treatment of BRAF-positive anaplastic thyroid cancer [news release]. FDA. Published May 4, 2018. Accessed January 31, 2019.
  4. Subbiah V, Kreitman RJ, Wainberg AZ, et al. Dabrafenib and trametinib treatment in patients with locally advanced or metastatic BRAF V600—mutant anaplastic thyroid cancer [published online ahead of print October 26, 2017].J Clin Oncol. doi: 10.1200/JCO.2017.73.6785.
  5. Gounder MM, Mahoney MR, Van Tine BA, et al. Sorafenib for advanced and refractory desmoid tumors.N Engl J Med. 2018;379(25):2417-2428. doi: 10.1056/NEJMoa1805052.
  6. Fader AN, Roque DM, Siegel E, et al. Randomized phase II trial of carboplatin-paclitaxel compared to carboplatin-paclitaxel-trastuzumab in advanced or recurrent uterine serous carcinomas that overexpress Her2/neu.J Clin Oncol. 2018;36(20):2044-2051. doi: 10.1200/JCO.2017.76.5966.
  7. Tap WD, Gelderblom H, Stacchiotti S, et al. Final results of ENLIVEN: a global, double-blind, randomized, placebo-controlled, phase 3 study of pexidartinib in advanced tenosynovial giant cell tumor (TGCT).J Clin Oncol. 2018;36 (suppl; abstr 11502). doi: 10.1200/JCO.2018.36.15_suppl.11502.
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