Rucaparib Approved for Ovarian Cancer Anti-CD22 CAR Therapy

Published OnlineFirst January 5, 2017; DOI: 10.1158/2159-8290.CD-NB2016-164 NEWS IN BRIEF “These data will not change the adverse effects after 28 days, on average. a nod to the FoundationFocus CDx- standard of care, but they provide an Only one of the six patients treated at BRCA test on December 19. Marketed enormous opportunity for discovery,” the lowest dose achieved remission, by Foundation Medicine of Cambridge, she said. “We hope to uncover impor- but eight of the 10 participants who MA, the test is the fi rst next-generation tant information about the mecha- received a higher dose experienced sequencing–based companion diagnostic nisms and biomarkers of resistance to remission with no evidence of residual to receive FDA approval. endocrine-based therapy with CD4/6 disease. Six of the nine patients who Rucaparib belongs to a class of inhibitors.” –Janet Colwell ■ achieved remission subsequently anticancer agents called PARP inhibi- relapsed; the other three remain in tors, which induce synthetic lethality Anti-CD22 CAR Therapy remission, with one remission continu- in cancer cells with defective homolo- ing for more than a year, Fry reported. gous repair, such as those harboring Leads to ALL Remissions Most of the patients who relapsed deleterious BRCA mutations. In a fi rst-in-human trial of an anti- experienced decreases in CD22 express- Approval of the drug and the com- CD22 chimeric antigen receptor (CAR) ion, with only one patient experienc- panion diagnostic was based on data T-cell therapy in children and young ing CD22 loss. Fry observed that the from two multicenter, single-arm adults with relapsed/refractory acute opposite seems to occur following trials evaluating their effi cacy and lymphocytic leukemia (ALL), research- anti-CD19 CAR T-cell therapy, with safety. Studies of effi cacy involved 106 ers found that the immunotherapeutic antigen loss, not reduced expression, women with BRCA-mutated advanced approach was not only feasible and safe, more likely. ovarian cancer who had already been but also effective, leading to remissions The primary adverse effect of anti- treated with at least two chemotherapy in most patients. Data from the trial CD22 CAR T-cell therapy was cytokine regimens. At trial enrollment, BRCA were shared last month at the American release syndrome, reported Nirali status was determined with either Society of Hematology’s annual meet- Shah, MD, also from the NCI’s Pediat- local germline test results or a Foun- ing in San Diego, CA. ric Oncology Branch, who shared the dation Medicine clinical trial assay. Although anti-CD19 CAR T-cell fi ndings with meeting attendees. How- Mutation status was later verifi ed by therapy has led to complete remissions ever, Shah said that all cases, which the FoundationFocus CDxBRCA test in 80% to 90% of patients with relapsed/ involved fever and low blood pressure, in 96% of the patients for whom a refractory ALL, “we’re learning now that were mild. One patient died of sepsis, tumor sample was available. one of the limitations of this approach but not until after the cytokine release Among all 106 patients, the objec- is loss of CD19 expression occurring syndrome ended. tive response rate to rucaparib was in, potentially, a substantial number Although researchers continue to 54%, with a median duration of res- of patients,” said Terry Fry, MD, of enroll patients in the trial, they are ponse of 9.2 months. Among patients the Pediatric Oncology Branch, Center already asking new questions about sensitive to platinum-containing for Cancer Research, at the NCI, who how best to use the therapy, Fry com- regimens, the response rate was 66%. presented the trial’s fi ndings at a press mented. For example, he and his team For patients with platinum-resistant conference during the meeting. are wondering whether physicians and platinum-refractory disease, Seeking an alternative target—and should wait for disease relapse follow- the response rates were 25% and 0%, noting the effectiveness of the anti- ing anti-CD19 CAR T-cell therapy respectively. There was no signifi cant body–drug conjugate inotuzumab before starting with anti-CD22 CAR difference in response rates between ozogamicin (Pfi zer), which targets T-cell therapy, or whether remissions patients with a BRCA1 mutation and CD22, an antigen widely expressed would last longer if the therapies were those with a BRCA2 mutation. on B-cell leukemias and lympho- given simultaneously—issues they plan The safety of rucaparib was assessed mas—researchers launched a phase I to investigate. –Suzanne Rose ■ in a trial involving 377 patients. The dose-escalation study of anti-CD22 most common side effects were nausea, CAR T-cell therapy, enrolling 16 chil- Rucaparib Approved for fatigue, vomiting, anemia, abdominal dren and young adults with relapsed/ pain, constipation, decreased appe- refractory CD22-expressing ALL in Ovarian Cancer tite, diarrhea, thrombocytopenia, and the study. Eleven of the 16 patients The FDA greenlighted Boulder, dyspnea. Two cases of acute myeloid had relapsed after previously receiv- CO–based Clovis Oncology’s rucaparib leukemia were reported. ing anti-CD19 CAR T cells. All of the (Rubraca) to treat women with advanced Another PARP inhibitor, olaparib patients had had at least one alloge- ovarian cancer who have already received (Lynparza; AstraZeneca), was approved neic stem cell transplant. at least two chemotherapies and have a in 2014 to treat women with germline Researchers collected T cells from somatic or germline BRCA1 or BRCA2 BRCA-mutated advanced ovarian the patients and modifi ed them to mutation as identifi ed by an approved cancer who had received at least three recognize and bind to CD22. Patients companion diagnostic test. Up to 20% of prior chemotherapies. In the trial then received an infusion of their own high-grade serous ovarian cancers have a that led to its approval, 34% of 137 modifi ed cells at one of three “doses”— deleterious BRCA gene mutation. such patients responded to olaparib. 3 × 105 transduced CAR T cells/kg, To detect the BRCA alterations—and Head-to-head comparisons of PARP 1 × 106 cells/kg, or 3 × 106 cells/kg—and thus determine which patients are eligible inhibitors have not been done, but were evaluated for a response and to receive rucaparib—the agency also gave the effi cacy of olaparib and rucaparib 120 | CANCER DISCOVERYFEBRUARY 2017 www.aacrjournals.org Downloaded from cancerdiscovery.aacrjournals.org on September 30, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst January 5, 2017; DOI: 10.1158/2159-8290.CD-NB2016-164 NEWS IN BRIEF seems comparable based on published to endocrine therapy may improve taking buparlisib,” said study co-author data. outcomes for patients with hormone Ruth O’Regan, MD, of the University In addition, although the toxicities receptor (HR)–positive advanced breast of Wisconsin-Madison, who pre- of PARP inhibitors are generally similar, cancer whose tumors become resistant sented the fi ndings during a press “there will be some innate and unique to mTOR inhibition. However, the drug briefi ng. “It suggests that buparlisib side effects among the different PARP was also associated with dose-limiting may be useful in many cancers that inhibitors,” says Ursula Matulonis, MD, side effects in a signifi cant number of become resistant to mTOR inhibitors.” of Dana-Farber Cancer Institute in patients, investigators said during the However, concerns remain about Boston, MA. For example, she notes that 2016 San Antonio Breast Cancer Sym- toxicities associated with buparlisib, rucaparib is more likely to cause liver posium in Texas, December 6–10. including increased liver enzymes. Also enzyme abnormalities as well as grade 3 In the phase III trial, 432 post- troubling, the drug was associated with anemia, potentially complicating pre- menopausal women who had received severe anxiety and depression, and sev- scribing decisions and making person- a prior aromatase inhibitor and the eral patients attempted suicide during alized treatment plans and follow-up mTOR inhibitors everolimus (Afi ni- the trial, said O’Regan. essential for patients taking the drugs. tor; Novartis) or ridaforolimus (Ariad) These serious adverse events led Because many patients don’t benefi t were assigned to receive buparlisib to medication interruptions or dose from PARP inhibitors, or may not plus fulvestrant or fulvestrant alone. reductions in a higher percentage of benefi t for very long, physicians want Almost 70% had received two or more patients taking buparlisib plus fulves- to test the drugs in combination with lines of endocrine therapy and 90% trant compared with fulvestrant alone, other therapies, such as antiangiogenic experienced disease progression while, researchers reported. agents or PI3K inhibitors. “Can we or after, taking an mTOR inhibitor. “We need to be cautious about [using make the cancer cell more homolo- Patients in the buparlisib group had drugs that cross] the blood–brain bar- gous repair–deficient?” asks Matu- longer progression-free survival (PFS) rier due to the psychiatric effects of lonis. Also, “after there’s evidence of compared with the control group inhibiting PI3K in the brain,” said cancer growth, could we add some- (3.9 vs. 1.8 months) and a higher Carlos Arteaga, MD, of Vanderbilt- thing to a PARP inhibitor to continue 6-month PFS rate (31% vs. 20%). Ingram Cancer Center in Nashville, to make it work? These are good ques- Among those who took buparlisib, TN, who commented on the study. He tions, but they’re not answered yet,” median PFS was higher in patients added that future research should focus she says. –Suzanne Rose ■ whose tumors had mutant, not wild- on developing isoform-specifi c PI3K type, PIK3CA (4.7% vs. 2.8%), and in inhibitors that act on the mutated form Benefit Mixed with patients with nonvisceral disease ver- of the protein while sparing the wild- sus those with metastasis to the liver type version that is essential for normal Caution for Buparlisib or lung (4.2 vs.

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