2018 FDA Approvals of Targeted Therapies

Genetic aberrations across cancer types were the driving force behind drug approvals in 2018. The year saw the first initial approval based on a genetic mutation, rather than a specific tumor type, with larotrectinib (Vitrakvi), which is indicated in solid tumors with an NTRK gene fusion.¹In addition, BRAF and MEK inhibitor combinations were approved for multiple indications in melanoma, and they accounted for the first approval in anaplastic thyroid cancer.^2-4

Olaparib (Lynparza), which has indications in ovarian cancer, including 1 new recent indication, was approved for use in patients with deleterious germlineBRCA-mutated (gBRCAm), HER2-negative metastatic breast cancer following chemotherapy in January.⁵In response to the year’s first approval for a targeted therapy, Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said, “This approval demonstrates the current paradigm of developing drugs that target the underlying genetic causes of a cancer, often across cancer types.”

Standard-of-care therapies in non—small cell lung cancer (NSCLC) saw approvals expanded to include differentEGFRmutations, including the kinase inhibitor afatinib (Gilotrif) which is now approved for patients with metastatic disease whose tumors harbor uncommon EGFR alterations in L861Q, G719X, or S768I.⁶Additionally, osimertinib’s (Tagrisso) approved indications were expanded to include the frontline treatment of EGFR-positive NSCLC with exon 19 deletions or exon 21 L858R mutations.⁷

About half of the new targeted therapy drug approvals occurred in hematologic malignancies, including duvelisib (Copiktra) for the treatment of relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), or follicular lymphoma⁸; ivosidenib (Tibsovo) for the treatment of R/R IDH-positive acute myeloid leukemia (AML), the first agent approved for this patient population⁹; and glasdegib (Daurismo) for the treatment of patients ≥75 years with diagnosed AML who are ineligible for chemotherapy.¹⁰Glasdegib is the first approved therapy targeting the hedgehog-signaling pathway in AML.

JANUARY

The PARP inhibitorolaparibwas approvedon January 12 for the treatment of gBRCAm, HER2-negative metastatic breast cancer based on results from the phase III OlympiAD trial, which showed that the agent reduced the risk of death or disease progression by 42% and improved progression-free survival (PFS) by 2.8 months versus standard chemotherapy.¹¹Selection for treatment with olaparib requires testing using the BRACAnalysis CDx genetic test, which was approved at the same time.⁵

Approval forafatinibwas expandedto included uncommon EGFR alterations in L861Q, G719X, or S768I.⁶

FEBRUARY

Abemaciclib(Verzenio) was approved in combination with an aromatase inhibitor(AI) on February 26 for the treatment of postmenopausal women with HR-positive, HER2- negative advanced or metastatic breast cancer based on the MONARCH 3 trial results.¹²

MARCH

As of March 22,Indications fornilotinib(Tasigna)now include pediatric patients ≥1 year with newly diagnosed Philadelphia chromosome—positive chronic myeloid leukemia in chronic phase or those resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy.⁶

APRIL & MAY

On April 6,the PARP inhibitorrucaparib(Rubraca) was approved for maintenance treatmentof adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.¹³At the same time, the accelerated approval for use in patients with deleteriousBRCAmutation—associated epithelial ovarian cancer was converted to a regular approval.

The approval forosimertinibon April 18 to include patients whose tumors haveEGFRexon 19 deletions or exon 21 L858R mutationswas based on the results of the phase III FLAURA trial, which showed the third-generation EGFR TKI had a median PFS of 18.9 months versus 10.2 months with standard-of-care treatment agents gefitinib (Iressa) or erlotinib (Tarceva).¹⁴

Combination therapy with the BRAF inhibitordabrafenib(Tafinlar) and the MEK inhibitortrametinib(Mekinist) was approvedfor 2 new indications: on April 30 for the adjuvant treatment of patients with melanoma withBRAFV600E or V600K mutations following complete resection and on May 4 for the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer with aBRAFV600E mutation.^2,3The combination now has approvals in 3 cancer types that harbor these mutations.

JUNE

The BCL-2 inhibitorvenetoclax(Venclexta) was granted a regular approvalon June 8 for the treatment of patients with CLL and SLL with or without 17p deletion who have received ≥1 prior line of therapy. The previous accelerated approval was for patients with CLL and SLL who harbored a 17p deletion. Both the regular and accelerated approvals were based on findings from the phase III MURANO trial in which the agent was given in combination with rituximab for an overall response rate (ORR) of 92%, showing superiority over the control group.¹⁵

A novel BRAF/MEK inhibitor combination,encorafenib(Braftovi) plusbinimetinib(Mektovi), was approvedon June 27 in patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. The approval was based on results of the randomized COLUMBUS trial, which showed that the median PFS with the combination was 14.9 versus 7.3 months in patients treated with vemurafenib (Zelboraf) monotherapy, and the ORRs were 63% and 40%, respectively.⁴This was the first approval for both drugs.

JULY

The first targeted inhibitor of the IDH1 enzyme to be approved by the FDA,ivosidenibis now indicated for patients with R/R AML with an IDH1 mutation, which represents approximately 6% to 10% of patients.⁹The agent induced a complete remission rate of 24.7% in 174 patients with the indicated tumor type, and 32.8% of patients achieved either a complete remission or a complete remission with partial hematologic improvement. The approval was granted on July 20.

Indications for the CDK4/6 inhibitorribociclib(Kisqali) were expandedon July 18 to include pre/ perimenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer when used in combination with an AI and postmenopausal women with HR-positive, HER2- negative advanced or metastatic breast cancer when used with fulvestrant.⁶

Enzalutamide’s(Xtandi) indications were expandedon July 13 to include all patients with castration-resistant prostate cancer (CRPC). It was previously approved in patient with metastatic CRPC.⁶

AUGUST

Lenvatinib(Lenvima) was approved for the first-line treatment of patients with unresectable hepatocellular carcinoma(HCC).⁶Prior

to this approval on August 16, the only targeted agent approved for unresectable HCC in the frontline was sorafenib (Nexavar). Lenvatinib also has approvals in thyroid cancer and renal cell carcinoma.

SEPTEMBER

The second-generation EGFR inhibitordacomitinib(Vizimpro) received an initial approvalon September 27 for the frontline treatment of metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations.16 Based on results from the phase III ARCHER 1050 study, dacomitinib is the first second-generation EGFR TKI to show significant improvement over standard- of-care options, specifically gefitinib.¹⁷

The oral inhibitor of phosphoinositide 3-kinase (PI3K), and the first dual inhibitor of PI3K-δ and PI3K-γ,duvelisib(Copiktra) was granted a regular approvalon September 24 for the treatment of adult patients with R/R chronic CLL and SLL after 2 prior therapies and an accelerated approval for R/R FL. The drug comes with a boxed warning for serious or fatal toxicities, including infections, diarrhea or colitis, cutaneous reaction, and pneumonitis.⁸

OCTOBER

The PARP inhibitortalazoparib(Talzenna) was approvedon October 16 for the treatment of patients with gBRCAm HER2-negative locally advanced or metastatic breast cancer.⁶

NOVEMBER

On November 2, the third-generation anaplastic lymphoma kinase (ALK) TKIlorlatinib(Lorbrena) was approved for ALK-positive metastatic NSCLC after disease progression on crizotinib(Xalkori) and 1 other ALK inhibitor in this setting or whose disease has progressed on alectinib (Alecensa) or ceritinib (Zykadia).⁶

The oral thrombopoietin receptor agonisteltrombopag(Promacta) was approvedon November 16 for the first-line treatment of adults and pediatric patients ≥2 years with severe anaplastic anemia in combination with standard immunosuppressive therapy.¹⁸

Glasdegibwas approvedon November 21 in combination with low-dose cytarabine for the treatment of newly diagnosed AML in adult patients ≥75 years who have comorbidities that preclude the use of intensive induction chemotherapy. In the phase III BRIGHT 1003 trial, qualifying comorbidities included severe cardiac disease, baseline ECOG performance status of 2, or baseline serum creatinine >1.3mg/dL. Activation of the hedgehog pathway in adults is thought to contribute to the development and persistence of cancer stem cells; therefore, disruption of the pathway can impair their development.¹⁰

An accelerated approval was granted tolarotrectinibon November 26 for the treatment of solid tumors that have an NTRK gene fusion. This is the first agent to have a tumor-agnostic indication for its initial approval.¹

Approval was based on data from 3 multicenter, open-label, single-arm trials in which efficacy was evaluated in 55 patients with unresectable or metastatic solid tumors harboring an NTRK gene fusion.¹⁹In 12 cancer types, including salivary gland tumors, soft tissue sarcomas, infantile fibrosarcoma, and thyroid cancer, the ORR was 75% (95% CI, 61%-85%), including 22% with complete responses. Response duration was observed to be ≥6 months in 73% and ≥12 months in 39%.

Gilteritinib(Xospata) was approvedNovember 28 for the treatment of patients with R/R AML who harbor a FLT3 mutation and is the first FLT3-targeted therapy for this population to receive FDA approval.⁶

DECEMBER

Olaparibgained a new indicationas a maintenance therapy on December 19 for patients with deleterious or suspected deleterious germline or somatic BRCA-mutated advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to frontline platinum-based chemotherapy. This approval marks the first time a PARP inhibitor has been approved in the first-line maintenance setting.²⁰

The FDA also approved BRACAnalysis CDx to be used to identify patients with advanced ovarian cancer who have a germline BRCA mutation and are eligible for first-line maintenance therapy with olaparib in this setting.

References:

1. FDA approves Vitrakvi (larotrectinib), the first ever TRK inhibitor, for patients with advanced solid tumors harboring an NTRK gene fusion [news release]. Stamford, CT, and Whippany, NJ: Loxo Oncology, Inc.; November 26, 2018. ir.loxooncology.com/press-releases/2378241-Fda-approves-vitrakvi-larotrectinib-the-first-ever-trk-inhibitor-for-patients-with-advanced-solid-tumors-harboring-an-ntrk-gene-fusion12. Accessed December 3, 2018.
2. FDA approves dabrafenib plus trametinib for adjuvant treatment of melanoma with BRAF V600E or V600K mutations [news release]. Silver Springs, MD: FDA; April 30, 2018. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm606165.htm. Accessed December 3, 2018.
3. FDA approves dabrafenib plus trametinib for anapastic thyroid cancer with BRAF V600E mutation [news release]. Silver Springs, MD: FDA; May 4, 2018. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm606708.htm. Accessed December 3, 2018.
4. FDA approved encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations [news release]. Silver Springs, MD: FDA; June 27, 2018. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm611981.htm. Accessed December 3, 2018.
5. FDA approves first treatment for breast cancer with certain inherited genetic mutation [news release]. Silver Springs, MD: FDA; January 12, 2018. www.fda.gov/newsevents/newsroom/pressannouncements/ucm592347.htm. Accessed December 3, 2018.
6. Hematology/oncology (cancer) approvals & safety notifications. FDA website. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm. Accessed December 4, 2018.
7. FDA approves osimertinib for the first-line treatment of metastatic NSCLC with most common EGFR mutations [news release]. Silver Springs, MD: FDA; April 18, 2018. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm605113.htm. December 3, 2018.
8. Verastem Oncology receives FDA approval of Copiktra (duvelisib) capsules [news release]. Boston, MA: Verstem, Inc.; September 24, 2018. investor.verastem.com/phoenix.zhtml?c=250749&p=irol-newsArticle&ID=2368647. Accessed December 3, 2018.
9. FDA grants approval of Tibsovo, the first oral, targeted therapy for adult patients with relapsed/refractory acute myeloid leukemia and an IDH1 mutation [news release]. Cambridge, MA: MarketWatch; July 20, 2018. investor.agios.com/news-releases/news-release-details/fda-grants-approval-tibsovor-first-oral-targeted-therapy-adult. December 4, 2018.
10. 10. US FDA approves daurismo (Glasdegib) for adult patients with newly-diagnosed acute myeloid leukemia (AML) for whom intensive chemotherapy is not an option [news release]. New York, NY: Pfizer, Inc.; November 21, 2018. investors.pfizer.com/investor-news/press-release-details/2018/US-FDA-Approves-DAURISMO-glasdegib-for-Adult-Patients-with-Newly-Diagnosed-Acute-Myeloid-Leukemia-AML-for-Whom-Intensive-Chemotherapy-is-Not-an-Option/default.aspx. Accessed December 3, 2018.
11. Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377(6):523-533 doi: 10.1056/NEJMoa1706450.
12. FDA approves abemaciclib as initial therapy for HR-positive, HER2-negative metastatic breast cancer [news release]. Silver Springs, MD: FDA; February 26, 2018. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm598404.htm. Accessed December 3, 2018.
13. FDA approves rucaparib for maintenance treatment of recurrent ovarian, fallopian tube, or primary peritoneal cancer [news release]. Silver Springs, MD: FDA; April 6, 2018. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm603997.htm. Accessed December 3, 2018.
14. FDA approves osimertinib for the first-line treatment of metastatic NSCLC with most common EGFR mutations [news release]. Silver Springs, MD: FDA; April 18, 2018. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm605113.htm. Accessed December 3, 2018.
15. FDA approves venetoclax for CLL or SLL, with or without 17p deletion, after one prior therapy [news release]. Silver Springs, MD: FDA; June 8, 2018. fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm610308.htm. Accessed December 3, 2018.
16. US FDA approves Vizimpro (dacomitinib) for the first-line treatment of patients with EGFR-mutated metastatic non—small cell lung cancer [news release]. New York, NY: Pfizer Inc.; September 27, 2018. pfizer.com/news/press-release/press-release-detail/u_s_fda_approves_vizimpro_dacomitinib_for_the_first_line_treatment_of_patients_with_egfr_mutated_metastatic_non_small_cell_lung_cancer. Accessed December 4, 2018.
17. Mok TS, Cheng Y, Zhou X, et al. improvement in overall survival in a randomized study that compared dacomitinib with gefitinib in patients with advanced non-small cell lung cancer and EGFR-activating mutations. J Clin Oncol. 2018; 36(22):2244-2250. doi: 10.1200/JCO.2018.78.7994.
18. FDA approves Novartis drug Promacta for first-line SAA and grants breakthrough therapy designation for additional new indication [news release]. East Hanover, NJ: Novartis; November 16, 2018. marketwatch.com/press-release/fda-approves-novartis-drug-promacta-for-first-line-saa-and-grants-breakthrough-therapy-designation-for-additional-new-indication-2018-11-16. Accessed December 4, 2018.
19. 19. FDA approved larotrectinib for solid tumors with NTRK gene fusions [news release]. Silver Springs, MD: FDA; November 26, 2018. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm626720.htm. Accessed December 3, 2018.