The novel coronavirus (COVID-19) spreading across the world represents a distinct challenge for all physicians, especially oncologists who commonly treat patients who have compromised immune systems. The spread of the virus was discussed by Scott Gottlieb, MD, during the keynote address at the 

At this point, the number of new confirmed cases of coronavirus infection seems to change every day, with more than 100,000 infections reported worldwide. When looking at epidemiology data, Gottlieb noted a distinct spike in reported respiratory illnesses across the United States. He partially credited this to additional hospital visits due to worry over the virus. However, given a lack of widespread testing, he added that it could also be from wider spread of the virus than estimated.

“I think we’re facing some difficult months ahead of this,” said Gottlieb. “Seeing what’s happening in some of the cities, there’s some speculation on just how bad this disease is. I think most of the modeling we’ve seen coming out, looking at South Korea, Italy, and certain parts of China, suggests the mortality rate will be about 1%, which is significantly more than the seasonal flu, which is about 0.1%.”

Gottlieb noted that each country seems to be handling the coronavirus outbreak differently. In China, he said there has been some success in containing the virus, but at significant social and human costs. On the opposite end of the spectrum, however, there seems to be very little effort on the part of Iran to slow the virus, allowing it to “burn through their population,” he said.

“We’re going to have to figure out what our American approach is to this and how we’re going to take more aggressive mitigation steps. We’re losing a pretty narrow window to step in,” Gottlieb said. “We really haven’t stepped in with the kind of mitigation step and social distancing in these hot spots that you’d want to see to break the chain of transmission. I think this week is going to be critical.”

Effective and widespread testing has represented another challenge facing the prevention of coronavirus spread. The initial step in the process, which was creation of a diagnostic by the Centers for Disease Control and Prevention (CDC), went as planned, he said; however, there was a shipment delay for reagents to public health labs, slowing down use of this test. Additionally, there was inadequate communication between the CDC and other testing organizations, such as LabCorp and Quest Diagnostics.

“In an ideal world, we would be doing what the Netherlands is doing. They’re testing their indeterminate cases of the flu. If someone shows up with the flu, gets swabbed, and shows up negative for the flu but still has a significant respiratory disease they’ll then get tested for the coronavirus,” said Gottlieb. “We announced that we’re going to start doing that in 5 cities, but that’s a small number.”

Each day, testing strategies continue to evolve and change, in response to the spread of the disease, with wider adoption of this testing strategy possible in the coming week. Additionally, several companies are now working to find treatments for the virus, including Gilead Sciences and Moderna.

Shifting topics in his keynote address, Gottlieb noted that innovation has been a mainstay in oncology for the past 2 decades, as new treatments have dramatically improved the long-term outcomes across several types of cancer. Innovation at the FDA has largely been driven by strategic changes made to endpoints, to allow for faster approval via surrogates. Looking solely for an improvement in overall survival has become steadily more difficult to achieve, he said, as treatments become more effective.

“The time required, and the large number of patients required, in the trial to demonstrate improvement or superiority over an otherwise effective regimen and in order to power that study it wouldn’t be practical, you couldn’t enroll it,” said Gottlieb. “We would potentially be denying effective drugs to patients who face life-threatening disease.”

Most of these changes were facilitated by a greater understanding of the biology that drives cancer, with a milestone approval seen with imatinib (Gleevec), which was the first targeted therapy approved by the agency. Other recent examples of innovation include immune checkpoint inhibitors and tumor agnostic approvals, he said.

Tissue-agnostic approvals were brought about following changes to the clinical trial designs, which was another key change at the FDA to foster greater innovation. FDA granted its first tissue-agnostic approval in 2017 for the PD-1 inhibitor pembrolizumab (Keytruda) for patients with unresectable or metastatic, microsatellite instability-high or mismatch repair deficient tumor tumors. This was followed by approvals for larotrectinib (Vitrakvi) and entrectinib (Rozlytrek) for patients with solid tumors harboring an NTRK fusion.

“We moved toward tissue-agnostic drug approvals, where you get the approval based on a molecular subtype rather than phenotype,” Gottlieb said. “You might be able to study multiple tumor types within one trial. The opportunity is forcing the agency to continue to evolve. It really was a palpable sense of real opportunity about what was happening.”

Hematology/Oncology (Cancer) Approvals & Safety Notifications. FDA Website. bit.ly/2EP6v4b. Accessed March 7, 2020.

This article was originally published on OncLive as, "

Gottlieb Addresses Coronavirus, Innovation in Keynote Address.

Articles

At this point, the number of new confirmed cases of coronavirus infection seems to change every day, with more than 100,000 infections reported worldwide.

Expert Addresses Coronavirus and Cancer Innovation

Frontline maintenance therapy with the combination of olaparib (Lynparza) and bevacizumab (Avastin) improved median progression-free survival (PFS) by 5.5 months compared with bevacizumab and placebo for patients with newly diagnosed, advanced ovarian cancer following prior treatment with a platinum-based chemotherapy plus bevacizumab, according findings from the phase III PAOLA-1 trial presented at the ESMO Congress 2019.

The median PFS in the olaparib arm was 22.1 months compared with 16.6 months in the placebo arm, representing a 41% reduction in the risk of progression or death with the addition of the PARP inhibitor (HR, 0.59; 95% CI, 0.49-0.72; 

 <.0001). This benefit was observed across all patient subsets but was more pronounced for those with tumors testing positive for 

m) and for those with a homologous recombination deficiency (HRD) score of ≥42 by the myChoice HRD Plus assay (HRD-positive).

“PAOLA-1 met its primary objective, demonstrating a statistically significant improvement in PFS in the intent-to-treat population when olaparib, compared with placebo, was added to first-line standard-of-care bevacizumab maintenance treatment,” said study author Isabelle Ray-Coquard, MD, PhD, from the Centre Leon Bérard, Université Claude Bernard, in Lyon, France. “This was the first randomized trial to explore the efficacy and the safety of the combination of olaparib and bevacizumab in patients with newly diagnosed ovarian cancer.”

The PAOLA-1 trial randomized patients to receive bevacizumab at 15 mg/kg every 3 weeks on day 1 with olaparib tablets at 300 mg twice daily (n = 537) or matched placebo (n = 269). All patients had newly diagnosed FIGO stage III or IV high-grade serous or endometroid ovarian, fallopian tube, or primary peritoneal cancer. Patients were enrolled regardless of the type or extent of surgery (upfront or interval). All patients had received prior platinum-based chemotherapy and bevacizumab for ≥3 cycles and had no evidence of disease, a complete response, or a partial response upon enrollment.

There was a median of 6 weeks from the last cycle of chemotherapy to randomization in the study, Ray-Coquard noted. “It is an important point to consider when comparing the results to other data,” she said. The median time from first cycle of chemotherapy to randomization was 7 months.

“Patient selection was not restricted by surgical outcome or 

 mutation status, so participants represent the general population of women with advanced ovarian cancer,” Ray-Coquard said. “Previous studies of relapse have suggested benefits from combining anti-angiogenic agents and PARP inhibitors and today’s results appear to support this. In addition, olaparib did not increase side effects compared to placebo.”

m subgroup, the median PFS was 37.2 months with olaparib and bevacizumab compared with 21.7 months for placebo and bevacizumab (HR, 0.31; 95% CI, 0.20-0.47). The 24-month PFS rate was 76% in the olaparib group versus 39% for placebo. In the HRD-positive group, which included those with t

m, the median PFS was 37.2 months compared with 17.7 months (HR, 0.33; 95% CI, 0.25-0.45). In HRD-positive patients who did not have a 

 mutation, the median PFS was 28.1 months with olaparib and 16.6 months with placebo (HR, 0.43; 95% CI, 0.28-0.66).

“Prespecified subgroup analyses showed that patients with tumor 

 mutations and patients with a positive HRD status had the greatest PFS benefits,” said Ray-Coquard. “The results reveal a patient population beyond t

m patients, who are HRD-positive, that experiences substantial benefit from maintenance treatment with olaparib and bevacizumab.”

There were more grade ≥3 adverse events (AEs) in the olaparib arm compared with the placebo group; however, there was no clinically meaningful difference in health-related quality of life between the arms. Dose interruptions were required for 54% of those in the olaparib group compared with 24% in the placebo arm. Dose reductions were required for 41% and 7% of patients and dose discontinuations were needed for 20% and 6% of patients, in the olaparib and placebo groups, respectively.

The most common grade ≥3 AEs in the olaparib group and placebo arms, respectively, were hypertension (19% vs 30%) and anemia (17% vs <1%). There were 4 treatment-emergent deaths in the placebo group and 1 in the olaparib arm.

“The main goal in ovarian cancer is to avoid relapse after first-line therapy because otherwise, the probability of cure is quite low,” ESMO discussant Ana Oaknin, MD, PhD, from the Vall d´Hebron Institute of Oncology, said in a statement. Based on this goal, she added that “the combination of bevacizumab and olaparib as maintenance therapy should become a new standard of care for patients with advanced ovarian cancer...this trial is a significant step forward in treatment for these women.”

In December 2018, the FDA approved olaparib monotherapy as a frontline maintenance treatment for patients with deleterious or suspected deleterious germline or somatic 

-mutated advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to frontline platinum-based chemotherapy.

This approval was based on findings from the phase III SOLO-1 trial,

 in which olaparib monotherapy reduced the risk of disease progression or death by 70% compared with placebo in patients with 

-mutant advanced ovarian cancer who were in complete or partial response to platinum-based chemotherapy (HR, 0.30; 95% CI, 0.23-0.41; 

 <.0001). The median PFS had not yet been reached in the olaparib arm and was 13.8 months with placebo.

Comparing the SOLO-1 results to the PAOLA-1 findings, Ray-Coquard noted that “in 

-mutated patients, the HR is 0.31 in favor of the combination of olaparib and bevacizumab [in PAOLA-1]. This is similar to what we observed in the SOLO-1 trial, where olaparib monotherapy was compared with placebo. The PFS in the control arm is longer in PAOLA-1 than the SOLO-1 trial, which is due to the use of bevacizumab.”

A version of this article originally appeared on OncLive

Frontline Olaparib/Bevacizumab Maintenance Combo Extends PFS in Ovarian Cancer

Ray-Coquard IL, Pautier P, Pignata S, et al. Phase III PAOLA-1/ENGOT-ov25 trial: Olaparib plus bevacizumab (bev) as maintenance therapy in patients (pts) with newly diagnosed, advanced ovarian cancer (OC) treated with platinum-based chemotherapy (PCh) plus bev. Presented at: ESMO Congress 2019, Barcelona, Spain, September 27 to October 1, 2019. LBA2_PR.

Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. 

. 2018;379(26):2495-2505. doi: 10.1056/NEJMoa1810858.

At the 2019 European Society for Medical Oncology, new study results showed promise for a frontline combination therapy for patients with newly diagnosed, advanced ovarian cancer. 

Frontline Combo Therapy Shows Improved Results for Ovarian Cancer Treatment

Optimizing the methods for preclinical research with an emphasis on patient-derived models, may help speed up the translation of new treatment advances from the laboratory to the clinic, according to a presentation by Charles M. Rudin, MD, PhD, at the 2019 International Lung Cancer Congress.

"Bench to beside is not a one-way street. It is there and back again. It is how can we do discovery research in the laboratory and turn it rapidly into clinical development and patient care but then really, also, in the reverse direction, it's using patient data to try to inform which research questions are relevant," said Rudin, chief, Thoracic Oncology, Memorial Sloan Kettering Cancer Center (MSK). "Optimizing preclinical models could enhance both discovery science and clinical translation."

There are many available models for preclinical research, all of which have limitations for immediate applicability to the clinical setting. The two most common models are cancer cell lines and human cell line xenografts. Both of these options allow for rapid and affordable research; however, there is poor correlation with clinical outcomes. With the growth of genetic manipulation, genetically engineered mouse models have grown in popularity, although these models are restricted by a lack of heterogeneity and complexity.

Two of the more clinically relevant models are patient-derived xenografts (PDX) and circulating tumor cell-derived xenografts, Rudin said. These models have the heterogeneity and complexity that is reflective of human disease; however, they are often not susceptible to genetic engineering and may represent an immunosuppressed microenvironment. Overcoming some of these liabilities could permit for more rapid development, he noted.

To this end, Rudin said that MSK has devoted extensive resources to developing a PDX library for various types of thoracic malignancies, with more than 250 banked samples. These PDX lines were subjected to extensive sequencing using MSK-IMPACT to characterize genetic alterations. As an early example of the success of this approach, Rudin described a study looking at resistance to cisplatin and etoposide in small cell lung cancer (SCLC).

In this preclinical study, molecular characteristics were examined between the mice models with an initial complete response to cisplatin and etoposide and those with a partial response. These findings were then compared with their human counterparts from which the cells were derived, uncovering a strong correlation between the response in mice and those seen in humans.

The next step for the research was to determine why sensitivity to cisplatin and etoposide was lost after 6 months of treatment. From this, the gene SLFN11 was identified as a potential mechanism for resistance. Those with SLFN11 expression were chemosensitive whereas those with SLFN11-low expression were more chemoresistant. Moreover, expression of this gene typically diminished following initial treatment with cisplatin and etoposide.

"One of the genes we think is very important is SLFN11. SLFN11is thought to be the single strongest determinant of sensitivity to TOP1 inhibitors across all the cell lines, and this is silenced with chemoresistance," said Rudin. "We can show that SLFN11 is epigenetically modulated, and we found that EZH2 inhibitors can turn this gene back on and resensitize tumors."

The ability to induce SLFN11 expression with an EZH2 inhibitor was quickly translated to a clinical study that is currently ongoing at MSK, with the goal of preventing chemoresistance in patients with SCLC. In the phase I/II trial, the oral EZH1/2 inhibitor DS-3201b is being combined with fixed-dose irinotecan for patients with recurrent SCLC (NCT03879798).

"This is just one of many examples that we might bring forward. This was a previously unsuspected pathway in the laboratory that we were able to define on the discovery side and quickly translate because of these representative models," said Rudin.

One of the challenges with PDX is the inability to effectively perform genome editing but Rudin noted that researchers at MSK are looking to overcome this hurdle. For this, a Cas9 marker was introduced into the PDX genes, using an ex vivo spin transduction with a pSpCTRE lentivirus. This allowed for 90% of the PDX tumors to have inducible Cas9 markers, Rudin noted. The approach was verified using EGFR-targeted gene editing, which was capable of producing various sensitivity states for the EGFR gene.

"Now we have models where we have the same EGFR-mutant tumor with sensitivity, with T790M, and C797S, all in the same complex genetic environment," said Rudin. "I think this will be a way that we can accelerate drug development to the clinic."

This article originally appeared on OncLive as, "

Novel Research Methods Could Expedite Drug Development.

Drug Development May Speed Up Thanks to New Research Methods

Axicabtagene ciloleucel (axi-cel) elicited a 2-year overall survival (OS) rate of 51% in patients with refractory large B cell lymphoma, representing a clear plateau in the survival curve, according to long-term findings from the ZUMA-1 trial presented at the 

At a median follow-up of 27.1 months, the 24-month progression-free survival (PFS) rate was 39% with the CD19-targeted CAR T-cell therapy. The median PFS was 5.9 months. Moreover, 39% of patients continued to have an ongoing response, with a median duration of response that was not yet reached for those who achieved a complete remission (CR). Additionally, the median OS was not yet reached.

"This 2-year assessment demonstrates that axi-cel can induce durable remissions in a substantial proportion of patients with an acceptable long-term safety profile," lead investigator Sattva Neelapu, MD, professor of Lymphoma & Myeloma at The University of Texas MD Anderson Cancer Center, said in a statement. "There also is evidence of gradual B-cell recovery in most patients with refractory large B-cell lymphoma who otherwise have limited treatment options."

In October 2017, the FDA approved axi-cel as a treatment for adults with relapsed or refractory NHL, based on findings from the ZUMA-1 trial. The study evaluated 108 patients, consisting of 101 from the phase II portion of the trial and 7 from the phase I group. In phase II, patients were enrolled into 2 cohorts consisting of those with diffuse large B-cell lymphoma (DLBCL; n = 77) and those with primary mediastinal large B-cell lymphoma (PMBCL), high grade B-cell lymphoma, and DLBCL transformed from follicular lymphoma (TFL; n = 24).

Prior to infusion of axi-cel, a conditioning regimen of fludarabine (30 mg/m

) was administered for 3 days. Axi-cel was administered as a single infusion of modified autologous T cells at a target dose of 2 x 106 CAR-positive T cells/kg. The treatment was manufactured successfully for 99% of patients, and 91% of patients received treatment with the CAR T-cell therapy.

The best achieved objective response rate (ORR) with axi-cel was 83% by investigator assessment and 74% by central review, with CR rates of 58% and 54%, respectively. At this analysis, 39% of patients continued to respond to therapy by investigator assessment and 36% were still responding by central review. Overall, 93% of those in response at month 12 continued to respond at 24 months.

In those with double expresser or high-grade B cell lymphoma (n = 37), the ORR was 91% and the CR rate was 70%. Overall, 48% of these patients continued to respond to therapy at the analysis.

CAR-positive T cells persisted over time in patients with ongoing responses. At the 24-month assessment, 66% of patients in response continued to have detectable CAR gene-marked T cells. B cell aplasia resolved by month 9 for most patients, with 61% having detectable B cells in the blood. By month 24, 75% of patients had detectable B cells. Overall, 31% of patients required intravenous immunoglobulins.

The investigators noted that there were no new cases of cytokine release syndrome or neurotoxicity reported following the 1-year follow-up analysis. Other grade 3/4 events did manifest, however, including grade 3 mental status change, grade 4 myelodysplastic syndrome, grade 3 lung infection, and 2 grade 3 bacteremia events. None of these events were determined to be related to axi-cel.

Grade ≥3 treatment-emergent cytopenia occurred in 86% of patients, including neutropenia (80%), thrombocytopenia (40%), and anemia (45%). There were significantly fewer cytopenias present on or after 3 months (grade ≥3 events occurred in 17% of patients).

Neelapu SS, Ghobadi A, Jacobson CA, et al. 2-Year Follow-up and High-Risk Subset Analysis of Zuma-1, the Pivotal Study of Axicabtagene Ciloleucel (Axi-Cel) in Patients with Refractory Large B Cell Lymphoma. Proceedings from the 2018 ASH Annual Meeting and Exposition; December 1 to 4, 2018; San Diego, California. Abstract 2967.

Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1—2 trial [published online ahead of print, December 2, 2018]. 

Axi-Cel Efficacy Persists at 2-Year Assessment for Large B-Cell Lymphoma

Axicabtagene ciloleucel (axi-cel) elicited a 2-year overall survival (OS) rate of 51% in patients with refractory large B cell lymphoma, representing a clear plateau in the survival curve.

The anti-BCMA CAR T-cell therapy bb21217 demonstrated an objective response rate (ORR) of 83.3%, with a very good partial response (VGPR) or better rate of 75% in patients with heavily pretreated relapsed/refractory multiple myeloma, according to initial results from a phase I study presented at the 

In the preliminary results from the phase I study, responses deepened over time, with complete remissions (CR) achieved out to 10 months following infusion. The CR or stringent CR rate was 25%, with a minimal residual disease (MRD)-negativity rate of 100% in this group. The time to first response and best response were both 1 month.

"bb21217 demonstrated promising early clinical activity in heavily pretreated patients with relapsed/refractory multiple myeloma at first dose level tested," said Nina Shah, MD, from the University of California, San Francisco. "Longer follow-up in a larger patient population will clarify the depth and durability of bb21217 tumor responses and dose response."

The bb21217 CAR T cell is an enhancement of the 

, which previously demonstrated promising findings in multiple myeloma. In findings presented at the 

 bb2121 demonstrated a median PFS of 11.8 months and a median duration of response of 10.8 months. The CR or stringent CR rate was 50% and 36.4% of patients had a VGPR.

To create bb21217, the first-generation BCMA-targeted CAR T cell construct was cultured with the PI3 kinase inhibitor bb007, to enrich for T cells with a memory-like phenotype. Cells of this phenotype are thought to persist and function longer than non-enriched CAR T cells, Shah noted.

"CAR T cells manufactured with and without bb007 eliminate tumors in established multiple myeloma xenografts equally well," Shah said. "Opposite flank tumor rechallenge resulted in no tumor growth in mice treated with bb007 cultured CAR T cells, suggesting longer persistence of anti-tumor effect."

The phase I study of bb21217, which was labeled CRB-402, enrolled patients in a 3+3 dose escalation schema with doses beginning at 150 x 10

. At the October 2018 data cutoff, cells were collected for 13 patients for treatment manufacturing, and 12 patients had received treatment at the starting 150 x 10

 dose. Lymphodepleting treatment was given with fludarabine at 30 mg/m

The median age of patients enrolled in the study was 63 years (range, 44-69), and the median time since diagnosis was 5 years. Most patients had an ECOG performance status of 1 (75%) and an ISS stage of III (33%). More than half of patients (58%) had high-risk cytogenetics and the median number of prior regimens received was 7. Eighty-three percent of patients had received 1 to 2 prior autologous stem cell transplants.

At the median follow up of 26 weeks, biomarker and bone marrow analysis indicated a rapid response to bb21217. There was robust CAR-positive T cell expansion following infusion, which was independent of tumor burden, and T cells remained detectable 9 months following infusion.

"Bone marrow plasma cell clearance was observed by day 15, and there was a dramatic decline in FLC and soluble BCMA in all responders by month 1," said Shah. "M protein decline was delayed, resulting in an evolving IMWG response. Sustained soluble BCMA suppression was observed up to month 9, consistent with ongoing plasma cell aplasia resulting from functional CAR T cell persistence."

All-grade cytokine release syndrome (CRS) occurred in 67% of patients, most of which was grade 1 or 2 in severity. One patient had grade 3 CRS and no patients had a grade 4 event. The median time to onset of CRS was 4.5 days. Neurotoxicity occurred in 25% of patients, 1 incidence was in a patient with high tumor burden and rapidly progressing disease at baseline (grade 4 encephalopathy and grade 3 CRS). There was no dose limiting toxicity.

In addition to these AEs, there was 1 case of grade 3 catheter-related infection; however, there were no other severe infections reported in the study. Neutropenia occurred in 83% of patients and resolved by day 32 for 58% of patients. All except 1 patient had recovered by day 65. Thrombocytopenia occurred in 50% of patients, and most recovered by day 32. Overall, 4 patients experienced 1 or more serious AE and there were no deaths in the study.

"The safety profile appears consistent with known toxicities of CAR T cell therapies," Shah said. "Future study is needed to assess durability of response at the current dose, as well as safety and activity at higher doses of bb21217."

Dose escalation within the phase I study remains ongoing. The study is currently assessing a higher 300 x 10

 CAR-positive T cells dose in both high and low disease burden cohorts (NCT03274219).

Shah N, Alsina M, Siegel DS, et al. Initial Results from a Phase 1 Clinical Study of bb21217, a Next-Generation Anti Bcma CAR T Therapy. Presented at: 2018 ASH Annual Meeting; December 1-4, 2018; San Diego. Abstract 488.

Raje NS, Berdeja JG, Lin Y, et al. bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: Updated results from a multicenter phase I study. 

Next-Generation BCMA CAR T-cell Therapy Effective for Heavily Pretreated Myeloma

The anti-BCMA CAR T-cell therapy bb21217 demonstrated an objective response rate of 83.3%, with a very good partial response or better rate of 75% in patients with heavily pretreated relapsed/refractory multiple myeloma, according to initial results from a phase I study presented at the 2018 ASH Annual Meeting.

The FDA has approved the CD22-directed recombinant immunotoxin moxetumomab pasudotox (Lumoxiti) for the treatment of adult patients with relapsed or refractory hairy cell leukemia (HCL) who have received at least 2 prior lines of therapy, including treatment with a purine nucleoside analog. 

The approval was based on findings from single-arm, open-label study that included 80 patients with HCL, wherein moxetumomab pasudotox induced a complete remission (CR) lasting for over 180 days (durable CR) for 30% of patients. The objective response rate (ORR) was 75%. The agent was approved with a Boxed Warning regarding the potential for grade 3/4 capillary leak syndrome (CLS) and hemolytic uremic syndrome (HUS), which occurred in 2.5% and 5% of patients, respectively.

“Lumoxiti fills an unmet need for patients with hairy cell leukemia whose disease has progressed after trying other FDA-approved therapies,” 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 in a statement. “This therapy is the result of important research conducted by the National Cancer Institute that led to the development and clinical trials of this new type of treatment for patients with this rare blood cancer.”

The phase III study enrolled patients across 34 centers in 14 countries. Moxetumomab pasudotox was administered at 40 µg/kg intravenously on days 1, 3, and 5 of each 28-day cycle. Overall, 50 patients completed a full 6 cycles of treatment (62.5%), with patients most commonly discontinuing due to CR with minimal residual disease (MRD) negativity (15%) and adverse events (15%).

The median age of patients enrolled in the study was 60 years, with 6% having a prior splenectomy and 4% having an HCL variant. The median blood counts were 11.10 g/dL, 0.81 x 103per µL, and 68 x 103 per µL for hemoglobin, neutrophils, and platelets, respectively. Eighty-five percent of patients had HCL involvement in the bone. The median number of prior lines of therapy was 3 (range, 2-11), with 75% of patients had received prior rituximab (Rituxan) and 18% had received a BRAF inhibitor.

By independent review, out of the 75% ORR,  41% of patients had a CR as their best response, with 35% of patients having a CR with MRD negativity. The partial response rate was 34% and 15% of patients had stable disease. By investigator assessed criteria, the durable CR rate was 48%, with 51% of patients having a CR as their best response. The MRD-negative CR rate was 33% and the ORR was 79%.

At 16.7 months’ median follow-up, the median duration of CR had not yet been reached, nor had median progression-free survival. In a 12-month landmark analysis, 92% of patients who achieved a CR (n = 33) remained in remission with a CR. All patients who achieved an MRD-negative CR (N = 27) remained in remission at 6 months and 79% continued to test negative for MRD at 12 months (95% CI, 51%-92%).

A treatment-related adverse event (TRAE) of any grade was experienced by 90% of patients treated with moxetumomab pasudotox. The most common TRAEs were nausea (27.5%), peripheral edema (26.3%), headache (21.3%), and pyrexia (20%). Grade 3/4 TRAEs occurred in 30% of patients, with the most common events being lymphocyte count decrease (7.5%), HUS (5%), and CLS (2.5%). CLS and/or HUS developed during any treatment cycle for the 10 patients with these events and all resolved with supportive care and/or treatment discontinuation.

“With very few treatments available, there remains significant unmet medical need for people with relapsed or refractory disease," senior investigator Robert J. Kreitman, MD, head of Clinical Immunotherapy Section, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, said in a statement when the findings were presented. "The response rates observed in this trial, and elimination of the residual leukemia cells that cause relapse in some patients, highlight the potential impact this potential new medicine could have on patients and the management of this disease.”

The approval for moxetumomab pasudotox was granted under the FDA's priority review and fast track designations. Additionally, the medication was granted an orphan drug designation.

Kreitman RJ, Dearden C, Zinzani PL, et al. Moxetumomab pasudotox in heavily pretreated patients with relapsed/refractory hairy cell leukemia: Results of a pivotal international study. 

FDA Approves Moxetumomab Pasudotox for Hairy Cell Leukemia

The FDA has granted a breakthrough therapy designation to LOXO-292 for the treatment of patients with advanced 

 fusion—positive thyroid cancer who require systemic therapy, have progressed on prior treatment, and have no other acceptable alternative treatment options.

LOXO-292 is an oral and selective investigational new agent being evaluated for the treatment of patients with cancers that harbor abnormalities in the RET kinase.

According to a statement from Loxo Oncology, the developer of the selective RET inhibitor, this designation supplements the t

wo other breakthrough therapy designations granted to LOXO-292

 in September 2018 for the treatment of patients with RET fusion—positive non–small cell lung cancer (NSCLC) or RET-mutant medullary thyroid cancer (MTC).

The decision is based on data from the ongoing phase I/II LIBRETTO-001 trial (NCT03157128), which is the basis for the other 2 breakthrough therapy designations.

The first two designations are specifically for the treatment of patients with metastatic 

 fusion—positive NSCLC who require systemic therapy and have progressed following platinum-based chemotherapy and an anti–PD-1 or anti–PD-L1 therapy; and for the treatment of those with 

-mutant MTC who require systemic therapy, have progressed following prior treatment, and have no acceptable alternative treatment options.

Updated interim data of the LIBRETTO-001 study, which included patients with 

 fusion-positive thyroid cancer (n = 38), were presented at the 88th Annual Meeting of the American Thyroid Association.

Approximately 3.5 months of additional follow-up were available, as were first follow-up scans for the 9 most recently enrolled patients. At a median follow-up of 8.4 months, results showed that 94% (n = 16) responding 

-mutant MTC patients remained on therapy. A total 100% (n = 7) of responding patients with RET fusion-positive thyroid cancer remained on therapy, with a median follow-up of 8.5 months.

Inclusion of new restaging data for the most recently enrolled patients demonstrated a 59% overall response rate (ORR; 56% confirmed ORR) in the presented subset of 

-mutant MTC patients, and a 78% confirmed ORR (95% CI, 40-97) in the 

The phase II LOXO-292 dose has been determined as 160 mg twice daily, with dose exploration at 200 mg twice weekly ongoing to further characterize LOXO-292 safety and efficacy.

Of the 82 patients in the safety analysis, most treatment-emergent adverse events (TEAEs) were grade 1 in severity and determined to not be related to LOXO-292. TEAEs observed in ≥10% of patients were diarrhea (15% grade 1, 7% grade 2, 1% grade 3), fatigue (9% grade 1, 13% grade 2, 0% grade ≥3), dry mouth (21% grade 1, 0% grade ≥2), constipation (17% grade 1, 2% grade 2, 0% grade ≥3), hypomagnesemia (12% grade 1, 1% grade 2, 0% grade ≥3), cough (11% grade 1, 1% grade 2, 0% grade ≥3), headache (10% grade 1, 1% grade 2, 1% grade 3) and nausea (9% grade 1, 4% grade 2, 0% grade ≥3). Four patients experienced grade 3 treatment-related adverse events (AEs), which comprised tumor lysis syndrome, increased ALT/AST, diarrhea, and thrombocytopenia. All AEs resolved with dose interruption.

Preliminary findings of LIBRETTO-001 were presented at the 2018 ASCO Annual Meeting. In the ongoing study, the ORR was 77% (95% CI, 58%-90%) for patients with 

 fusion—positive NSCLC. At the April 2018 data cutoff, no patients with NSCLC had developed progressive disease (PD), with 90% remaining on treatment with LOXO-292. Also, all patients (n = 3) with measurable intracranial lesions responded to therapy with the selective inhibitor.

-mutated MTC, the ORR was 45%, with 1 complete response (CR) and 1 additional CR awaiting confirmation. Two patients in this group developed PD and 93% continued to receive treatment with LOXO-292. Additionally, in 2 patients with a resistance mutation in V804M, there was a substantial reduction in tumor size. In 4 enrolled patients with no known activating 

 alteration, there was no response with LOXO-292.

At the April 2018 data cutoff, 82 patients had been treated across 7 cohorts of LOXO-292, with doses ranging from 20 mg daily to 240 mg twice daily. The trial enrolled patients with 

fusion group (N = 49) included 38 patients with NSCLC, 9 with papillary thyroid cancer, and 2 with pancreatic cancer. The 

-mutated arm consisted solely of patients with medullary thyroid cancer (n = 29).

The median age of patients in the trial was 61 years (range, 17-88) and the primary ECOG performance status score was 71%. The median number of prior therapies was 3 (range, 1-9). Nearly one-third of patients received ≥2 prior multikinase inhibitors (29%), with 66% of patients receiving at least one of these agents prior to study entry. Prior immunotherapy was received by 24% of patients and brain metastases were present for 15% of patients.

 fusion-positive NSCLC (n = 38), there were 20 partial responses (PRs) and 3 PRs that were still awaiting confirmation on subsequent scans. Four patients had stable disease and 3 were not yet evaluable. Across all patients with 

 fusion-positive cancer, the ORR was 77% (95% CI, 61%-89%), which consisted entirely of partial responses. Six patients had stable disease.

 fusion partners for patients with NSCLC. In those with the most common partner, KIF5B (n = 16), the ORR was 81%. In those with non-KIF5B partners, the ORR was 82%. Responses were observed regardless of the starting dose and prior treatment.

For those with MTC, responses were also observed regardless of starting dose and mutation type. Moreover, there was a substantial decline in carcinoembryonic antigen (CEA) and calcitonin levels following treatment with LOXO-292.

The agency’s breakthrough therapy designation is intended to expedite the development and review of drugs designed to treat a serious or life-threatening disease or condition when preliminary clinical evidence indicates that the agent may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.

Drilon AE, Subbiah V, Oxnard GR, et al. A phase 1 study of LOXO-292, a potent and highly selective RET inhibitor, in patients with RET-altered cancers. 

FDA Grants LOXO-292 Breakthrough Designation for RET Fusion-Positive Thyroid Cancer

The FDA granted breakthrough therapy designation to the oral agent LOXO-292 for the treatment of RET fusion–positive non–small cell lung cancer (NSCLC) or RET-mutant medullary thyroid cancer (MTC).

FDA Grants Breakthrough Therapy Designation to LOXO-292 for NSCLC, MTC

The use of the anti-BCMA chimeric antigen receptor (CAR) T-cell therapy bb2121 showed promised in the treatment of patients with relapsed/refractory heavily pretreated multiple myeloma, according to results of a study presented at the 2018 ASCO Annual Meeting.

Participants in the multicenter phase I CRB-401 study experienced a median progression-free survival (PFS) of 11.8 months and a median duration of response of 10.8 months.

At the March 29, 2018, data cutoff for the trial, the median follow-up for patients treated with a >150 x 10

 dose was 194 days. At this point, the complete response (CR) or stringent CR rate was 50%, with an additional 36.4% of patients having a very good partial response (VGPR). The objective response rate (ORR) was 95.5%. In contrast, those treated with an inactive dose (50 x 10

) had an ORR of 33.3% and a 1.9-month median duration of response.

Responses to bb2121 were seen regardless of BCMA expression levels for patients treated with a 450 x 10

 dose. In those with low BCMA expression, the ORR was 100% at a median of 168 days of follow-up. The sCR/CR rate in this group was 37.5% and the VGPR was 50%. In those with high BCMA expression, the ORR was 91% after 311 days of follow-up. The sCR/CR rate was 54.5% and the VGPR rate was 27.3%.

"bb2121 at active doses induces deep and durable responses in heavily pretreated multiple myeloma patients," said lead author Noopur Raje, MD, director Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center. "It didn't matter if you had low or high BCMA expression, patients still responded, and the majority of plasma cells do express BCMA."

In the first portion of the study, patients received bb2121 in doses ranging from 50 x 10

 (N = 21). In a subsequent dose expansion stage, an additional 22 patients received bb2121 at 150 to 450 × 10

 CAR+ T cells. Prior to infusion of the CAR T-cell therapy, patients received conditioning with fludarabine (30 mg/m

In the dose escalation stage, all patients tested positive for BCMA expression. In the dose expansion phase, patients with low expression (<50%; n = 10) and high expression (≥50%; n = 12) were included. The median follow-up for the escalation stage was 345 days compared with 87 days in the expansion arm.

The median age of patients in the escalation stage was 58 years (range, 37-74), and 38% had high-risk cytogenetics. In the expansion group, the median age was 65 years and high-risk cytogenetics were present for 41% of patients. Patients had received 7 and 8 prior therapies, in the escalation and expansion groups, respectively. Twenty-nine percent and 32% of those in the escalation and expansion groups, respectively, were penta-refractory.

All 16 evaluable responding patients were negative for minimal residual disease (MRD). In this group, the median PFS was 17.7 months. "MRD-negativity in the bone marrow was seen very early on, as early on as a month," noted Raje. In 2 patients without a response, both tested MRD-positive. In the nonresponding group, the median PFS was 2.7 months.

When looking at persistence of the bb2121 CAR+ T cells, the vector was detectable at 6 months for 44% of patients (n = 7). By month 12, the vector was detectable for 20% of patients (n = 2). Peak expansion numbers were higher in responding patients compared with nonresponders (

"A dose response relationship was observed across all active doses, and we did see higher CAR T cell expansion in patients who were responders versus nonresponders," Raje said.

The most common grade ≥3 treatment-emergent adverse events (TEAE) of interest for bb2121 were neutropenia (79%), thrombocytopenia (51%), anemia (44%), cytokine release syndrome (CRS; 5%), and neurotoxicity (2%). Low-grade CRS occurred in 63% of patients and low-grade neurotoxicity was apparent in 33% of bb2121-treated patients.

Most TEAEs were treatable and resolved rapidly. By day 32, absolute neutrophil counts increased to ≥1000/μL for 78% of patients. Platelet counts recovered to ≥50,000/μL for 55% of patients by day 32. There were no grade 4 CRS events and no fatal CRS or neurotoxicity events. Tocilizumab was required for 21% of patients had corticosteroids were administered for 9% of patients.

"Interestingly enough, we found that this product is extremely well tolerated," said Raje. "We did see CRS in almost 60% of patients, but most of it was managed and it was grade 1 and 2 with very little grade 3 CRS, and we just had 1 patient with grade 4 neurotoxicity who is now completely recovered."

Based on an earlier assessment of the dose escalation trial, bb2121 was granted a breakthrough therapy designation in November 2017. A global phase II trial, known as KarMMa, is currently open for enrollment, and will serve as the basis for a regulatory submission for bb2121. The trial plans to enroll 94 patients with relapsed/refractory multiple myeloma (NCT03361748).

"Additional trials are planned for multiple myeloma [in earlier settings]. We have now shown the proof-of-concept in these very end-stage myeloma patients," said Raje. "We are doing ongoing studies looking at predictors of response, to see if there are biomarkers to predict toxicity and to see who the patients are who progress and what the mechanisms of those progressions are."

Patients with relapsed/refractory heavily pretreated multiple myeloma could live for an extra progression-free year with the use of the anti-BCMA CAR T-cell therapy bb2121.

CAR T Therapy Extends PFS by 1 Year in Heavily Pretreated Myeloma

A promising CD19-directed chimeric antigen (CAR) T-cell therapy, Lisocabtagene maraleucel (JCAR017; liso-cel), may result in durable remissions among patients with high-risk diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin lymphoma.

According to updated findings from the phase I, multicenter TRANSCEND trial presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, liso-cel demonstrated a durable complete remission (CR) rate of 46% at 6 months for patients with high-risk DLBCL.

At the 6-month assessment for the dose being used in an ongoing pivotal cohort, the ongoing objective response rate (ORR) was 49% (95% CI, 32%-66%) with a CR rate of 46% (95% CI, 30%-63%). Durable responses were seen across poor-risk DLBCL subgroups, particularly those with double- or triple-hit lymphoma (n = 16), where the ORR with liso-cel was 62.5%. Moreover, chemorefractory patients who relapsed in less than 12 months on stem cell transplant had an ORR of 53.3% with liso-cel.

Patients achieving a CR with the pivotal dose had a 12-month overall survival (OS) rate of 89% (95% CI, 72%-96%), with a median OS that was not yet reached. In those with a PR, the median OS was 10.3 months (95% CI, 6.8-not evaluable) and the 1-year OS rate was 33% (95% CI, 9%-60%).

"[Liso-cel] induced durable responses in high-risk patients with relapsed/refractory aggressive non-Hodgkin lymphoma," said lead investigator Jeremy S. Abramson, MD, MMSc, from the Massachusetts General Hospital Cancer Center. "The overall survival findings are far superior to what we might anticipate with traditional therapies in this relapsed/refractory DLBCL population."

In a dose findings portion of the TRANSCEND study, 2 dose levels (DL) were utilized: 5 x 10

 cells (DL1) as a single- or double-dose and liso-cel at 1 x 10

 cells (DL2) as a single-dose. After the dose finding portion of the study, DL1 and DL2 as single infusions were further studied in a core assessment, with DL2 moving into the pivotal cohort focused on DLBCL. Additionally, prior to CAR T cell infusion, patients received lymphodepleting fludarabine (30 mg/m

Liso-cel was successfully manufactured for 99% of patients. There were 102 evaluable patients enrolled in the full study, with 73 assessable in the core group. Of the core population, there were 51 patients treated with the dose selected for the pivotal cohort. Eight patients were successfully treated in the outpatient setting.

The median age of patients in the core group was 60 years (range, 20-82), with 33% ≥65 years of age. Seventy-three percent had DLBCL and 27% had DLBCL transformed from follicular lymphoma. Twenty-two percent had double- or triple-hit lymphoma. Two-thirds of patients (67%) were chemorefractory, and patients had received a median of 3 prior therapies (range, 2-8), with 49% having never achieved a CR to prior therapy. Thirty-eight percent of patients had received a prior autologous stem cell transplant. "Ninety percent of treated patients have at least 1 poor-risk disease feature predictive of short median OS," Abramson noted.

In the core population, 88% of those in a CR at 3 months continued to have a CR at 6 months. After a median of 8 months of follow-up, 93% of patients with a CR at 6 months continued to have an ongoing response. The median duration of response in those achieving a CR was not yet reached (95% CI, 10.2-not evaluable [NE]). Those with a PR had a median duration of response of 2.1 months (95% CI, 1.0-5.0).

"The duration of response curves flatten out after the 3-month point, in both the full and the core datasets," said Abramson.

Across the full study population, the most frequently occurring treatment-emergent adverse events were neutropenia (63%), anemia (53%), fatigue (46%), thrombocytopenia (34%), decreased appetite (29%), nausea (28%), hypotension (26%), cough (26%), headache (25%), dizziness (25%), constipation (25%), and diarrhea (25%).

"The most common adverse events, which occurred in the majority of subjects, were cytopenias. This is expected after fludarabine and cyclophosphamide for lymphodepleting therapy. This was followed by fatigue," said Abramson. "All other toxicities occurred only in a minority of subjects and are low grade, including cytokine release syndrome."

In the full trial across all dose levels, 37% of patients had grade 1/2 cytokine release syndrome (CRS). There was 1 grade 3/4 event (1%). Neurotoxicity of any grade occurred in 23% of patients. Serious neurotoxicity was experienced by 13% of patients, the remainder had a grade 1/2 event. Overall, 43% of patients had either neurotoxicity or CRS.

"We saw a low overall use of rescue medications, including 17% use of tocilizumab and 21% use of corticosteroids," said Abramson. "We see no difference in neurotoxicity or CRS between DL1 and DL2, supporting our decision to explore DL2 in the pivotal cohort."

The pivotal cohort of the TRANSCEND trial exploring DL2 of liso-cel has fully enrolled participants, Abramson noted. "We will continue to evaluate this product in the outpatient setting, including in the pivotal cohort," he added. "We look forward to presenting this data at a future meeting."

If positive, Juno Therapeutics, the company developing liso-cel, plans to submit a biologics license application to the FDA. Based on earlier findings for the CAR T-cell therapy, liso-cel received a breakthrough therapy designation from the FDA for non-Hodgkin lymphoma in December 2016.

Session discussant Caron Jacobson, MD, MMSc, noted that findings for liso-cel from the TRANSCEND trial were competitive with data for the already-approved CAR T-cell therapies axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah).

"Liso-cel is competitive with axi-cel and tisagenlecleucel in terms of efficacy, durability of response, and safety," said Jacobson, from the Dana-Farber Cancer Institute. "However, comparing across studies should be done cautiously, as there may be an impact of bridging therapy on disease burden and toxicity risk, and there are patient eligibility differences. Comparative data may come from single institution experiences with all 3 products."

Abramson JS, Gordon LI, Palomba ML, et al. Updated safety and long term clinical outcomes in TRANSCEND NHL 001, pivotal trial of lisocabtagene maraleucel (JCAR017) in R/R aggressive NHL. 

Silas Inman

Articles

Expert Addresses Coronavirus and Cancer Innovation

Frontline Combo Therapy Shows Improved Results for Ovarian Cancer Treatment

Drug Development May Speed Up Thanks to New Research Methods

Axi-Cel Efficacy Persists at 2-Year Assessment for Large B-Cell Lymphoma

Next-Generation BCMA CAR T-cell Therapy Effective for Heavily Pretreated Myeloma

FDA Approves Moxetumomab Pasudotox for Hairy Cell Leukemia

FDA Grants Breakthrough Therapy Designation to LOXO-292 for NSCLC, MTC

CAR T Therapy Extends PFS by 1 Year in Heavily Pretreated Myeloma

Liso-Cel Shows Promise in High-Risk Diffuse Large B-Cell Lymphoma

CAR T Therapy Extends PFS by 1 Year in Heavily Pretreated Myeloma