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                        Oncology (Cancer) / Hematologic Malignancies Approval Notifications
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          FDA D.I.S.C.O.: FDA approval of larotrectinib for advanced malignancies with NTRK gene fusionResources for Information | Approved Drugs FDA D.I.S.C.O.: FDA approval of larotrectinib for advanced malignancies with NTRK gene fusion
  
  	
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*FDA medical oncologists discuss the Nov. 26, 2018, accelerated approval of larotrectinib for adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, that are either metastatic or where surgical resection is likely to result in severe morbidity, and who have no satisfactory alternative treatments or whose cancer has progressed following treatment.*

Dr. Sanjeeve Bala: Welcome back to the DISCO, the FDA’s Drug Information Soundcast in Clinical Oncology from the Oncology Center of Excellence. During our soundcasts, we discuss recent FDA approvals of cancer drugs and therapies. We hope this information will help you in better understanding these approvals and how new drugs and therapies are benefitting cancer patients. Today we’ll be discussing the recent approval of larotrectinib for the treatment of select patients with advanced malignancies with NTRK gene fusion. This is the first approval of larotrectinib, marketed as Vitrakvi.

I’m Dr. Sanjeeve Bala, a medical oncologist and clinical team leader at FDA, and I am joined by my colleague Dr. Abhi Nair, also a medical oncologist at the Oncology Center of Excellence here at the FDA.

Dr. Abhi Nair: Hi everyone. Thanks for joining us.

SB: Abhi, this approval happens to have been granted for a very specific subset of patients with advanced malignancies. I think we need to start off by looking at the indication, because it’s pretty complicated.

AN: Yes, that’s true, Sanjeeve. First, patients who are eligible for treatment with larotrectinib are those with metastatic cancer, or cancer for which surgical resection would result in severe morbidity, such as disfigurement.

SB: Right, and eligible patients won’t have other good choices for alternative treatment or will have progressed following treatment.

AN: So, the eligible population has advanced disease and no good alternative treatment options, meaning they’ve already been treated with all standard-of-care treatment options.

SB: That’s about right, but also, to be eligible for treatment, a patient’s tumor should have a very specific genomic abnormality. This is a fusion of the neurotrophic receptor tyrosine kinase, or NTRK, gene. The frequency of this genomic alteration is high in a few rare tumors, like secretory breast cancer and congenital infantile fibrosarcoma, but it’s frequency is fairly low overall, and probably less than one percent according to a recent analysis of over 11,000 pathology specimens by Gatalica and colleagues, published in the journal Molecular Pathology, in August.

AN: And, that NTRK gene cannot have a known acquired mutation that confers resistance to the drug, such as a mutation in the kinase domain. Why don’t you recap the whole indication for us?

SB: Larotrectinib is approved for the treatment of adult and pediatric patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, whose disease is either metastatic or where surgical resection would result in severe morbidity, and who have no satisfactory alternative treatments or whose cancer has progressed following treatment.

AN: But there’s another interesting point. This approval includes treatment of pediatric patients with cancers that meet these criteria.

SB: That’s right, Abhi. And, notably, this is a tissue-agnostic approval, meaning that if a patient’s tumor has the NTRK gene fusion, they may be eligible for treatment with larotrectinib, regardless of where the tumor originated. Most oncology drug approvals include the tissue of origin in the indication, but that’s not the case for this drug. Importantly, there is currently no FDA-approved NTRK gene fusion test available, so testing will be by local laboratory.

AN: This makes it the second tissue-agnostic approval in oncology, and the first approval for the NTRK gene fusion. I’m sure the listeners recall that we discussed the tissue-agnostic approval of pembrolizumab in an earlier Soundcast. We should mention that the dose of larotrectinib is 100 mg orally twice daily for adults, and for children its 100 mg/m2 twice a day (with a maximum of 100 mg twice a day) and there are oral capsule and solution formulations. Sanjeeve, tell us about the clinical trial that led to the approval.

SB: This approval is based on data from three single-arm clinical trials of larotrectinib, which enrolled patients who had NTRK gene fusions identified by a local test using next-generation sequencing or FISH. This included three pediatric patients with infantile fibrosarcoma, who had NTRK fusions inferred. Efficacy was evaluated in the first 55 patients, all of whom had progressed following systemic therapy for their disease, if such a therapy was available, or would have required surgery with significant morbidity. Twelve patients were less than 18 years old, and 12 cancer types were represented. These included salivary gland tumors, which represented 22% of the patients, soft tissue sarcoma for 20% of the patients, infantile fibrosarcoma for 13% of the patients, and thyroid cancer for 9% of the patients. Other tumor types with responses include lung cancer, melanoma, colon cancer, and gastrointestinal stromal tumors or GIST.

AN: Go ahead and now tell us about the outcome.

SB: The trial evaluated the objective response rate by RECIST criteria as determined by a blinded central review. The ORR was 75%, including 22% complete responses and 53% partial responses, and at the time of database lock, median duration of response had not yet been reached.

AN: That’s a robust ORR. It sounds like the responses lasted at least 12 months for 39% of the patients who responded, and there were an additional 10 responders who had been followed for less than 12 months and that supported the approval as well.

SB: Abhi, this was an accelerated approval, and as we’ve discussed during other Soundcasts, that means it used a surrogate endpoint, which in this case is objective response rate. ORR is reasonably likely to predict clinical benefit, but that benefit must be confirmed in subsequent studies using endpoints that are direct measures of clinical benefit, like overall survival or progression-free survival.

AN: Right, and some of those confirmatory studies are open and ongoing. What about the safety findings?

SB: The safety database included 176 patients, including 44 pediatric patients. The most common adverse reactions were fatigue, nausea, dizziness, vomiting, cough, constipation, and diarrhea. Also, neurologic adverse reactions occurred in 53% of patients, with grade 3 neurologic adverse reactions in 6% and grade 4 in 0.6%. Most of these occurred within the first three months of treatment, but there was a case that occurred 2.2 years into treatment. Examples of grade 3 neurotoxicity include delirium, dysarthria, gait disturbance, and a grade 4 encephalopathy occurred in one patient. So, the prescribing information contains information to prescribers to warn patients not to drive while taking larotrectinib if they are experiencing neurologic adverse reactions, or to stop the drug if the symptoms are severe and modify the dose. Also, around 45% of the patients had hepatotoxicity based on increased transaminases, with grade 3 elevations in 6% of patients. One patient had a grade 4 ALT increase. Dose modifications followed AST increases in 4% of patients, and ALT increases in 6% of patients.

AN: So, the prescribing information contains a warning about driving if neurologic adverse reactions have been observed, as well as a warning to monitor liver enzymes every two weeks for the first month of treatment and then monthly thereafter, or as clinically indicated.

SB: Detailed safety information is available in the product label.

AN: Thanks, Sanjeeve. Why don’t you give us the three take-aways for this D.I.S.C.O.

SB: Sure, Abhi. 1) larotrectinib is the second drug that has received FDA approval for what’s called a tissue-agnostic indication, and the first based on the presence of an NTRK gene fusion; 2) patients should be selected for treatment based on the presence of an NTRK gene fusion, but an FDA-approved test for NTRK fusion is not currently available; and 3) treatment may be associated with certain neurologic and hepatic safety findings that require vigilance.

SB: You can find more detailed prescribing and safety information in the approved prescribing information, also available on the web at Drugs@FDA. For a transcript of this Soundcast, visit the FDA Oncology Center of Excellence D.I.S.C.O. website at www.fda.gov/DISCO.

AN: Thank you Sanjeeve. Are there other FDA oncology drug approvals that you would like to hear about? Leave us your questions and comments on Twitter @FDAOncology and as always, we welcome your feedback at our email address, FDAOncology@fda.hhs.gov. I’m Abhi Nair, thank you for tuning in to D.I.S.C.O. today.

SB: And until next time at the D.I.S.C.O., I’m Sanjeeve Bala.

Acknowledgements

This Drug Information Soundcast in Clinical Oncology was developed by Sanjeeve Bala, Abhilasha Nair, Leigh Marcus, Kirsten B. Goldberg, and Richard Pazdur, of the Oncology Center of Excellence and the Office of Hematology and Oncology Products. Steven Jackson of the Division of Drug Information was the sound producer.

                                                                                  Content current as of:
      12/13/2018
              
              
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						  OncologyResources for Information | Approved Drugs

          
                        Oncology (Cancer) / Hematologic Malignancies Approval Notifications
          Ongoing | Cancer Accelerated Approvals
          Verified Clinical Benefit | Cancer Accelerated Approvals
          Withdrawn | Cancer Accelerated Approvals
          Other | Cancer Accelerated Approvals


                        Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) Short Description
 
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