Nearly 300 Novel Agents Currently in Development for Rare Cancers

New agents for rare cancers make up approximately 35% of drugs in the pipeline for all rare diseases, according to a report from the Pharmaceutical Research and Manufacturers of America.

New agents for rare cancers make up approximately 35% of drugs in the pipeline for all rare diseases, according to a report from the Pharmaceutical Research and Manufacturers of America (PhRMA).1 Of nearly 800 agents in development for rare diseases, 168 are under investigation for use in patients with solid tumors and 120 are under investigation for use in patients with blood cancers.

There are many definitions of “rare disease,” but the FDA defines this as a rare, or orphan, disease when it affects fewer than 200,000 individuals. The National Cancer Institute defines rare cancers as those that affect fewer than 40,000 people annually. Rare cancers make up 27% of cancer diagnoses and 25% of cancer deaths.2

Already this year, the FDA has moved forward on several agents for rare cancers. For example, on January 24, 2022, Lantern Pharma announced that the agency granted both a rare pediatric disease designation and an orphan drug designation to LP-184 for the treatment of pediatric patients with atypical teratoid rhabdoid tumor (ATRT), which is a rare and very aggressive childhood malignancy that affects the central nervous system.3

The agency grants rare pediatric disease designation for serious and life-threatening diseases that primarily affect children who are aged 18 years or younger and fewer than 200,000 individuals in the United States.

“The gene SMARCB1 was included among several genes whose expression negatively correlated with LP-184 sensitivity in tumors. This in silico correlation was convincingly confirmed by in vitro and in vivo assessments of LP-184 in ATRT. The highest potency of LP-184 in vivo has been seen in ATRT xenografts,” Kishor Bhatia, PhD, chief scientific officer of Lantern Pharma, stated in a news release. “Based on both the in silico and in vivo observations, LP-184 has the potential to become a critical part of the armamentarium of approved treatment options specifically for these patients.”

LP-184 is a small molecule drug candidate and next-generation alkylating agent that preferentially damages DNA in cancer cells that overexpress certain biomarkers or that harbor mutations in DNA repair pathways. The agent is still in the discovery phase for use in ATRT, but LP-184 was found to improve tumor growth inhibition by 106% in 2 subcutaneous xenograft models of glioblastoma multiforme: U87 and M1123. Investigators also determined that LP-184 was associated with extended survival in mice who had an intracranially-implanted tumor model of the disease (U87) vs those that did not receive any drug.4

On January 21, 2022, the agency granted an orphan drug designation to silmitasertib (CX-4945) for use as a potential therapeutic option in patients with biliary tract cancer (BTC), which is a group of rare, diverse, and aggressive cancers that arise from the bile duct system.5 Silmitasertib is a first-in-class molecule drug that targets the CK2 pathway and acts as a CK2 inhibitor.

Preclinical data have demonstrated that CK2 inhibition via silmitasertib prevented DNA repair, induced apoptosis, and improved the antitumor activity achieved with gemcitabine and cisplatin. Moreover, other findings have indicated that the drug is easy to deliver due to its oral formulation, and that it is safe and well tolerated in humans.

As part of the multicenter phase 1b/2 S4-13-001 trial (NCT02128282), the agent was evaluated in combination with gemcitabine/cisplatin as a frontline treatment in patients with locally advanced or metastatic cholangiocarcinoma.6

Investigators conducted dose-escalation, -expansion, and exploratory cohorts evaluating the agent at doses from 200 mg to 1000 mg twice daily for 6 days in the escalation and expansion cohorts, and 10 to 21 days of continuous dosing in the exploratory cohorts. In the phase 2 portion, patients received twice-daily 1000 mg silmitasertib for 10 days in combination with gemcitabine and cisplatin on days 1 and 8 as part of a 21-day cycle, or gemcitabine/cisplatin alone. The primary efficacy outcome measure was PFS.

Investigators established twice-daily 1000 mg silmitasertib as the maximum tolerated dose, which was then used in the expansion and exploratory cohorts.

A total of 88 patients enrolled in the intent-to-treat (ITT) population. Of the 87 who received treatment, 50 did so as part of the phase 1b portion of the research and 37 as part of the phase 2 portion. Fifty-five patients were able to complete at least 1 full cycle of treatment with any dose interruptions or reductions; these patients comprised the modified ITT (mITT) population.

The median age among patients who received treatment was 60 years (range, 38-84), 55% were male, and 50% were Asian, 48% were White, and 2% were another race. Moreover, 51% of patients were from the United States, 35% were from Taiwan, and 14% were from Korea. Most patients had metastatic disease (81.6%), with an intrahepatic primary tumor site (85.0%), and an ECOG performance status of 1 (65.5%).

Interim results showed that among 44 patients who comprised the mITT population, the combination resulted in a median progression-free survival (PFS) of 11.2 months (95% CI, 7.6-14.7), with a 10-month PFS rate of 56.1% (95% CI, 38.8%-70.2%). The median overall survival (OS) with the regimen was 17.4 months (95% CI, 13.4-25.7). Moreover, the objective response rate achieved with this approach was 32.1%, and the disease control rate (DCR) was 79.3%.

Beyond biliary tract cancer, silmitasertib is under evaluation in patients with severe COVID-19 (NCT04668209), in patients with basal cell carcinoma (NCT03897036), and in those with recurrent medulloblastoma who may or may not have undergone surgery (NCT03904862).

On January 5, 2022, the FDA granted a rare pediatric disease designation to IMX-110, the first clinical-stage product within the SMARxT Tissue-Specific Platform, for pediatric patients with life threatening rhabdomyosarcoma.7 IMX-110 will be eligible for priority review designation when a new drug application is submitted.

Investigators are currently assessing IMX-110 in the ongoing phase 1b/2a study (NCT03382340). In preliminary data, 6 of 8 heavily pretreated patients with soft tissue sarcoma experienced tumor shrinkage. The PFS was 4.0 months in this population, with a 100% DCR at 2 months. Additionally, no drug-related toxicities were observed. Patients had received a median of 7 prior lines of treatment (range, 4-14).8

IMX-110 is currently being developed as a monotherapy, with a total of 14 patients having been treated to-date. The phase 2a study will examine the therapy as a first-line treatment for patients with soft tissue sarcoma based on findings from precedent trials in the United States and Europe. Additionally, IMX-110 will be examined as part of a combination regimen with PD-L1 inhibitor tislelizumab (BGB-A317), with 1 trial planned.


  1. Pharmaceutical Research and Manufacturers of America. Medicines in development: rare diseases. December 16, 2021. Accessed January 25, 2022.
  2. National Cancer Institute. About rare cancers. February 27, 2019. Accessed January 25, 2022.
  3. Lantern Pharma receives rare pediatric disease and orphan drug designations for lp-184 for the treatment of atypical teratoid rhabdoid tumor (ATRT) - an aggressive and rapidly growing form of cancer of the central nervous system. News release. Lantern Pharma; January 24, 2022. Accessed January 25, 2022.
  4. Lantern Pharma announces positive preclinical data in glioblastoma (GBM) with drug candidate LP-184 and expands GBM research collaboration. News release. Lantern Pharma; August 19, 2021. Accessed January 25, 2022.
  5. Senhwa’s silmitasertib receives US FDA orphan drug designation for the treatment of biliary tract cancer. News release. Senhwa Biosciences, Inc.; January 20, 2022. Accessed January 25, 2022.
  6. Borad MJ, Bai L-Y, Chen M-H, et al. Silmitasertib (CX-4945) in combination with gemcitabine and cisplatin as first-line treatment for patients with locally advanced or metastatic cholangiocarcinoma: a phase Ib/II study. J Clin Oncol. 2021;39(suppl 3):312. doi:10.1200/JCO.2021.39.3_suppl.312
  7. US Food and Drug Administration approves Immix Biopharma rare pediatric disease designation for IMX-110 as a treatment for life-threatening pediatric cancer in children. News release. Immix Biopharma, Inc.; January 3, 2022. Accessed January 25, 2022.
  8. Immix Biopharma. Novel Tissue-Specific Therapeutics (TSTx) targeting oncology & immuno-dysregulated diseases. Accessed January 25, 2021.