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Home , Cabozantinib, Padeliporfin, Sunitinib

FDA Updates Highlighting the Latest Cancer Treatments

Crizotinib for Children & Young Adults With R/R, notransferase, fatigue, increased blood alkaline phosphatase, increased Systemic Anaplastic Large Cell alanine aminotransferase, diarrhea, hypokalemia, vomiting, constipation, The FDA approved for pediatric patients 1 year of age and increased blood , pyrexia, and alopecia. The prescribing informa- older and young adults with relapsed or refractory (R/R) systemic ana- tion includes a boxed warning to advise health professionals of the risks of plastic large cell lymphoma (ALCL) that is ALK-positive. The safety interstitial lung disease and embryo-fetal toxicity. and efficacy of crizotinib have not been established in older adults The recommended fam- deruxtecan-nxki dose for gastric with R/R systemic ALK-positive ALCL. cancer is 6.4 mg/kg administered as an intravenous infusion once every Efficacy was evaluated in Study ADVL0912 (NCT00939770), a mul- 3 weeks (21-day cycle) until disease progression or unacceptable toxicity. ticenter, single-arm, open-label trial in patients 1 to ≤21 years of age that included 26 patients with R/R systemic ALK-positive ALCL after at least Accelerated Approval of + one systemic treatment. Patients received crizotinib 280 mg/m2 (20 pa- Hyaluronidase for Light Chain Amyloidosis tients) or 165 mg/m2 (6 patients) orally twice daily until disease pro- The FDA granted accelerated approval to daratumumab plus hyal- gression or unacceptable toxicity. Patients were permitted to discontinue uronidase in combination with , , and crizotinib to undergo hematopoietic stem cell transplantation. for newly diagnosed chain (AL) amyloidosis. Efficacy was based on objective response rate (ORR) and duration Efficacy was evaluated in ANDROMEDA (NCT03201965), an open- of response as assessed by an independent review committee. The label, randomized, active-controlled trial in 388 patients with newly di- ORR in the 26 patients was 88 percent (95% CI: 71, 96), with a com- agnosed AL amyloidosis with measurable disease and at least one affected plete remission rate of 81 percent. Of the 23 patients who achieved a organ, according to consensus criteria. Patients were randomized to receive response, 39 percent maintained response for at least 6 months, and bortezomib, cyclophosphamide, and dexamethasone (VCd arm) or with 22 percent maintained response for at least 12 months. daratumumab plus hyaluronidase (D-VCd arm). Ocular toxicity (grade 1 or 2 visual disorders) occurred in 65 percent of The hematologic complete response (HemCR) rate based on estab- patients with ALCL, gastrointestinal toxicity occurred in 92 percent, and seri- lished consensus response criteria as evaluated by an independent re- ous adverse reactions occurred in 35 percent, most often from neutropenia view committee was 42.1 percent for the D-VCd arm and 13.5 percent and infection. The most common adverse reactions (≥35%), excluding labo- for the VCd arm (odds ratio=4.8; 95% CI: 2.9, 8.1; p<0.0001). ratory abnormalities, were diarrhea, vomiting, nausea, vision disorder, head- The prescribing information includes warnings and precautions ache, musculoskeletal pain, stomatitis, fatigue, decreased appetite, pyrexia, that serious or fatal cardiac adverse reactions occurred in patients abdominal pain, cough, and pruritus. Grade 3-4 laboratory abnormalities with AL amyloidosis who received daratumumab plus hyaluronidase (≥15%) were neutropenia, lymphopenia, and thrombocytopenia. in combination with bortezomib, cyclophosphamide, and dexametha- The recommended crizotinib dosage for systemic ALCL is 280 sone. Daratumumab plus hyaluronidase is not indicated and not rec- mg/m2 orally twice daily based on body surface area. Antiemetics are ommended for the treatment of patients with AL amyloidosis who recommended prior to and during treatment with crizotinib in pa- have NYHA Class IIIB or Class IV cardiac disease or Mayo Stage IIIB tients with ALCL. Due to the risk of visual loss, ophthalmologic evalua- outside of controlled clinical trials. tions are recommended at baseline and serially thereafter, coupled with The most common adverse reactions (≥20%) in patients with AL monthly assessments of visual acuity and visual symptoms. amyloidosis who received the D-VCd regimen are upper respiratory tract infection, diarrhea, peripheral edema, constipation, peripheral Fam--Nxki for sensory neuropathy, fatigue, nausea, insomnia, dyspnea, and cough. HER2-Positive Gastric Adenocarcinomas The recommended daratumumab plus hyaluronidase dose is (1,800 Fam-trastuzumab deruxtecan-nxki has been approved by the FDA for mg daratumumab and 30,000 units hyaluronidase) administered sub- adult patients with locally advanced or metastatic HER2-positive gas- cutaneously into the abdomen over approximately 3-5 minutes ac- tric or gastroesophageal (GEJ) adenocarcinoma who have received a cording to recommended schedule in combination with VCd. prior trastuzumab-based regimen. Efficacy was evaluated in a multicenter, open-label, randomized Plus for Advanced trial (DESTINY-Gastric01, NCT03329690) in patients with HER2- positive locally advanced or metastatic gastric or GEJ adenocarci- The combination of nivolumab and cabozantinib as first-line treat- noma who had progressed on at least two prior regimens, including ment for patients with advanced renal cell carcinoma (RCC) has re- trastuzumab, a fluoropyrimidine- and a platinum-containing chemo- ceived FDA approval. therapy. A total of 188 patients were randomized (2:1) to receive fam- Efficacy was evaluated in CHECKMATE-9ER (NCT03141177), a ran- trastuzumab deruxtecan-nxki 6.4 mg/kg intravenously every 3 weeks domized, open-label trial in patients with previously untreated advanced or physician’s choice of either or monotherapy. RCC. Patients were randomized to receive either nivolumab 240 mg over 30 The main efficacy outcome measures were overall survival (OS) and ob- minutes every 2 weeks in combination with cabozantinib 40 mg orally once jective response rate (ORR) assessed by independent central review (RECIST daily (n=323), or 50 mg orally daily for the first 4 weeks of a 6-week 1.1) in the intent-to-treat population. Additional efficacy outcome measures cycle (4 weeks on treatment followed by 2 weeks off) (n=328). were progression-free survival (PFS) and duration of response (DOR). The trial demonstrated a statistically significant improvement in progres- OS was 12.5 months (95% CI: 9.6, 14.3) in the fam-trastuzumab derux- sion-free survival (PFS), overall survival (OS), and confirmed overall response tecan-nxki arm compared with 8.4 months (95% CI: 6.9, 10.7) in the irino- rate (ORR) for patients treated with nivolumab plus cabozantinib compared tecan or paclitaxel arm (HR 0.59; 95% CI: 0.39, 0.88, p=0.0097). Confirmed with those who received sunitinib. Median PFS per blinded independent cen- ORR was 40.5 percent (95% CI: 31.8, 49.6) in the fam-trastuzumab derux- tral review (BICR) was 16.6 months versus 8.3 months; HR 0.51 (95% CI: tecan-nxki arm compared with 11.3 percent (95% CI: 4.7, 21.9) for those 0.41, 0.64). Median OS was not reached in either arm; HR 0.60 (95% CI: 0.40, receiving irinotecan or paclitaxel. Median PFS was 5.6 months (95% CI: 0.89). Confirmed ORR per BICR was 55.7 percent and 27.1 percent in the 4.3, 6.9) in the fam-trastuzumab deruxtecan-nxki arm compared to median nivolumab plus cabozantinib and sunitinib arms, respectively. PFS of 3.5 months (95% CI: 2.0, 4.3) in the irinotecan or paclitaxel arm. The most common adverse reactions (≥ 20%) in patients receiv- Median DOR was 11.3 months (95% CI: 5.6, NR) versus 3.9 months (95% ing the combination of nivolumab and cabozantinib were diarrhea, CI: 3.0, 4.9), respectively. fatigue, hepatotoxicity, palmar-plantar erythrodysesthesia syndrome, The most common (≥ 20%) adverse reactions including laboratory stomatitis, rash, hypertension, , musculoskeletal pain, abnormalities were anemia, leukopenia, neutropenia, lymphocytopenia, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and up- thrombocytopenia, nausea, decreased appetite, increased aspartate ami- per respiratory tract infection.

16 Oncology Times February 20, 2021 The recommended dose is nivolumab 240 mg every 2 weeks Priority Review and assigned a User Fee Act (PDUFA) (30-minute IV infusion) or 480 mg every 4 weeks (30-minute IV infu- goal date of May 20, 2021. sion) in combination with cabozantinib 40 mg orally once daily with- The filing was based on results from the Phase III CheckMate-577 trial, out food until disease progression or unacceptable toxicity. which is the first trial to show positive results in the adjuvant setting in this group of patients. The study met its primary endpoint of disease-free sur- Orphan Drug Designation of PVSRIPO for vival (DFS) in patients with esophageal or GEJ cancer, following neoadju- the Treatment of Advanced Melanoma vant CRT and tumor resection. Results from the CheckMate-577 trial place The FDA granted orphan drug designation for PVSRIPO for the treatment esophageal and GEJ cancer among four tumor types—in addition to mela- of advanced melanoma (stage IIB-IV). It is a novel viral immunotherapy, noma, bladder, and non-small cell lung cancer—for which nivolumab has based on the Sabin type 1 polio vaccine, that activates a patient’s innate and shown a benefit in the early disease setting. The safety profile of nivolumab adaptive immune system to facilitate an anti-tumor response and establish as adjuvant therapy in the CheckMate-577 trial was consistent with that long-term immunologic memory to help prevent the cancer’s return. reported in previous studies. Currently, researchers are recruiting for LUMINOS-102, a Phase II CheckMate-577 is a randomized, multicenter, double-blind study open-label, randomized trial (NCT04577807) in patients with advanced, evaluating nivolumab as an adjuvant therapy in patients with resected unresectable melanoma who previously failed anti-PD1 therapy. This study esophageal or GEJ cancer who have received neoadjuvant CRT and will characterize the safety, tolerability, and initial efficacy of PVSRIPO in- have not achieved a pathological complete response. The primary end- tratumoral injection alone and in combination with a PD-1 inhibitor. The point of the trial is DFS and the secondary endpoint is overall survival first patient is expected to be dosed in the first quarter of 2021. (OS). Following neoadjuvant CRT and complete tumor surgical resec- LUMINOS-102 follows a successful Phase I monotherapy study of tion (also known as trimodality therapy), a total of 794 patients were PVSRIPO in anti-PD1 refractory advanced melanoma in which pa- randomized to receive placebo (n=262) or nivolumab (n=532) 240 tients who received three injections (6/12) had an overall response rate mg by intravenous infusion every 2 weeks for 16 weeks, followed by of 67 percent (4/6). placebo or nivolumab 480 mg every 4 weeks until disease recurrence, PVSRIPO aims to address the significant unmet need in advanced unacceptable toxicity, or withdrawal of consent, with a maximum of 1 melanoma, since most patients are treated with checkpoint inhibitors, year total treatment duration. Follow-up for OS is ongoing. and many do not respond or later become resistant and require other options, which are limited. Fast Track Designation Granted to Orphan drug designation is granted by the FDA Office of Orphan PadeliporfinI mPACT Products Development to drugs or biological products intended for the The FDA granted Fast Track designation to padeliporfin ImPACT for the treatment of rare diseases or conditions that impact fewer than 200,000 treatment of adult patients with low-grade and unifocal high-grade up- people in the U.S. This designation acts as a stimulus for the development per tract urothelial cancer (UTUC). This swiftly follows clearance of the of drugs for rare diseases through several incentives, including eligibility for Investigational New Drug application granted in December 2020, allowing federal grants, research and development tax credits, waiver of filing fees, and initiation of the pivotal Phase III of padeliporfin ImPACT in the potential for a 7-year marketing exclusivity period after FDA approval. patients with low-grade UTUC, expected to begin enrollment in Q1 2021. Padeliporfin ImPACT (immune photo activated cancer therapy) Nivolumab for Resected Esophageal or offers surgery-like efficacy combined with organ preservation. It is an Gastroesophageal Junction Cancer oncology platform comprising the intravenous delivery of an inac- The FDA accepted a supplemental Biologics License Application for tive drug, padeliporfin. Upon activation, the drug rapidly triggers the nivolumab for the treatment of patients with resected esophageal or gas- constriction of the blood supply in the illuminated area only, resulting troesophageal junction (GEJ) cancer in the adjuvant setting, after neoad- in targeted tumor necrosis that activates anti-tumor immunity and juvant chemoradiation therapy (CRT). The FDA granted the application enhances cancer cell eradication. OT

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