Silas Inman

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.

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The novel coronavirus spreading across the world represents a distinct challenge for all physicians, especially oncologists who commonly treat patients who have compromised immune systems.

Gottlieb Addresses Coronavirus, Innovation in Keynote Address

Gene profiling assays can accurately and reproducibly assist decision making for patients with hormone receptor (HR)-positive breast cancer, with the ultimate goal of improving outcomes or avoiding toxicity, according to a presentation at the 

“This is an area that touches all of the specialties of breast cancer treatment,” said Tripathy, professor and chair, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center. “In the last 10 to 20 years, we’ve gotten more sophisticated tools, such as gene profiling, to further build out the subsets. We’re focusing on the benefits of chemotherapy, and there are many established prognostic factors that we all commonly use."

Table. Short- and Long-Term Effects of Treatment (Click to Enlarge)

National Comprehensive Cancer Network (NCCN) treatment recommendations provide guidance on the optimal test to utilized, based on the level of clinical evidence demonstrated in prospective validation, registry, population-based, and clinical trials. Based on findings from TAILORx and MINDACT trials, respectively, category 1 recommendations are given for Oncotype Dx for node-negative, HR-positive/HER2-negative disease and MammaPrint for node-negative to 1 to 3 node-positive breast cancer. Of these 2 tests, Oncotype DX is listed as preferred by the guideline and is the only to provide predictive value.

“There are many other assays that may be performed just as well but they aren’t tied to a randomized clinical trial,” Tripathy said.

 included more than 10,000 patients with HR-positive, HER2-negative, axillary node-negative breast cancer. Patients were stratified by risk using the Oncotype DX assay, with 9719 having follow-up information available for analysis. Overall, 69% (n = 6711) had an intermediate recurrence score of 11 to 25; 17% (n = 1619) had a score of 10 or lower; and, 14% (n = 1389) had a score of 26 or higher.

Those in the low-risk group received endocrine therapy alone while patients in the high-risk group were treated with the combination of chemotherapy and endocrine therapy. Patients in the intermediate group were randomized to receive either endocrine therapy alone (n = 3399) or chemotherapy plus endocrine therapy (n = 3312). Endocrine therapy most commonly consisted of an aromatase inhibitor for postmenopausal women and tamoxifen alone or with an aromatase inhibitor for premenopausal women.

After a median of 7.5 years of follow-up, endocrine therapy alone was noninferior to chemotherapy plus endocrine therapy for invasive disease-free survival (DFS) in the intermediate group (hazard ratio, 1.08; 95% CI, 0.94-1.24; 

 = .26). Moreover, freedom from recurrence at a distant site was similar between the two groups (hazard ratio, 1.10; 95% CI, 0.85-1.41; 

For those >50 years, there was no additional benefit observed with the addition of chemotherapy for patients with risk scores from 0 to 25. In those 50 years of age or younger, however, there was a benefit for adding chemotherapy in the intermediate risk group, although the rationale behind this is still unclear, Tripathy noted.

In this age group in those with a recurrence score of 16 to 20, there was a 1.6% different between for 9-year distant recurrence. In the 21 to 25 recurrence score group, 6.5% more patients recurred at 9 years in the endocrine alone arm compared with the chemotherapy plus endocrine arm (86.9% vs 93.4% freedom from recurrence rates).

“This might be explained by the fact that women in the younger age group can undergo menopause with chemotherapy, and it might be that benefit and not chemotherapy that is helping them,” said Tripathy. “This is still controversial to see whether we should be using chemotherapy or ovarian suppression instead. This is still a dilemma.”

 helped establish the 70-gene MammaPrint test as a tool for determining whether chemotherapy could be withheld. For this study, patients were stratified based on their clinical and genetic risk. Those with low risk by both measures (n = 2745) did not receive chemotherapy while those with high-risk for both were treated with chemotherapy (n = 1806). A second group with clinical-low but genetic-high (n = 592) risk or clinical-high but genetic-low (n = 1550) risk were randomized to receive chemotherapy or no chemotherapy.

In those with clinical-low/genetic-high risk, the 5-year distant metastasis-free survival (MFS) was similar regardless of treatment type, illustrating an ability to avoid chemotherapy. In the chemotherapy arm, the 5-year distant MFS rate was 95.8% compared with 95.0% in the chemotherapy-free arm (hazard ratio, 1.17; 95% CI, 0.59-2.28; 

 = .657). For those with clinical-high/genetic-low risk, the 5-year distant MFS was 95.9% in the chemotherapy group versus 94.4% in the chemotherapy-free arm (hazard ratio, 0.78; 95% CI, 0.50-1.21; 

“With this assay, you can really take the higher-risk group, primarily the node positive ones, and, if they have a low recurrence score, you might surmise that based on these data they may not benefit from chemotherapy,” said Tripathy. “This is what is reflected in the ASCO guidelines.”

The ASCO guidelines4 note that clinical utility for MammaPrint is only indicated in patients with high clinical risk, for both those with node-negative and node-positive cancers. ASCO also updated its guidelines, following the presentation of the TAILORx results. In these guidelines, chemotherapy is listed as having little to no benefit for those age >50 years with an Oncotype DX score of <26 or those with ≤50 years with a score of <16.

For the NCCN guidelines there are 5 gene tests listed for invasive breast cancer, specifically Oncotype DX, MammaPrint, Breast Cancer Index (BCI), Prosigna (PAM 50), and Endopredict.

 Each of these assays examines different molecular characteristics and varying quantities of genes. The Oncotype DX test uses the expression of 21 genes, MammaPrint examines 70 genes, Prosigna is a 50 gene profile, BCI examines 7 key genes and ratios, and EndoPredict is a 12-gene panel. Additional assays continue to be assessed and will be added to the guidelines once they’re clinically validated, Tripathy noted.

Breast Cancer, version 2.2020. NCCN website. www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed March 6, 202.

Sparano JA, Gray RJ, Makower DF, et al. Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer. 

Cardoso F, van't Veer LJ, Bogaerts J, et al. 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. 

Andre F, Ismaila N, Henry NL, et al. Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: ASCO clinical practice guideline update—integration of results from TAILORx. 

Tailoring therapy can help avoid many of the short- and long-term side effects associated with various treatments (

). The main prognostic criteria are tumor size, nodal status, tumor grade, and molecule profile, Tripathy noted. Several predictive factors also exist, which should be considered for each patient. In addition to HR status and HER2 expression levels, tumor grade and gene expression profiles can be used to determine the appropriateness of chemotherapy.

Gene profiling assays can accurately and reproducibly assist decision making for patients with hormone receptor-positive breast cancer, with the ultimate goal of improving outcomes or avoiding toxicity.

Gene Profiling Essential Tool for Treatment Tailoring

The anti-BCMA CAR T cell therapy bb21217 demonstrated high very good partial response (VGPR) or better rates in patients with heavily pretreated relapsed/refractory multiple myeloma, with minimal residual disease (MRD) negativity seen in most patients with confirmed responses, according to updated results from the phase I CRB-402 study presented at the 2019 ASH Annual Meeting.

The longest follow-up from the study (median 17.6 months) was available for patients receiving a 150 x 10

 dose of bb21217, which was the lowest dose explored in the study. In this cohort, the complete remission (CR) or stringent CR (sCR) rate was 33% and the VGPR rate was 50%, for an objective response rate (ORR) of 83%. All patients in this group were MRD-negative and the median duration of response was 11.1 months.

 dose cohort, the median duration of response is promising at 11.1 months. In the higher dose cohorts, follow up is short but there are no confirmed responders who have progressed," Jesus G. Berdeja, MD, from the Sarah cannon Research Institute, said during a presentation of the results. "The safety profile of bb21217 in this phase I study of relapsed/refractory multiple myeloma remains consistent with known toxicities of CAR T-cell therapies."

As part of the bb21217 manufacturing process, the CAR T-cell therapy bb2121 is cultured with the PI3 kinase inhibitor bb007 to enrich for T cells with a memory-like phenotype. In preclinical experiments, bb2121 and bb21217 both eliminated an initial tumor in mice; however, when rechallenged with a second tumor in the same mouse, only bb21217 prevented the tumor from growing without retreatment. Additionally, bb21217 also showed higher levels of CCR7 and CD27 compared with bb2121, suggesting higher levels of memory-like T cells, and bb21217 had lower levels of CD57, a marker of T cell exhaustion.

In the phase I study of bb21217, patients were treated with 150 x 10

(n = 6) CAR+ T cells in an initial dose escalation stage. An expansion cohort was opened to further explore the 300 x 10

 doses (n = 6), with the latter selected for further investigation. Lymphodepleting chemotherapy was given with fludarabine at 30 mg/m

 on days -5, -4, and -3 prior to infusion.

Across the study, 41 patients underwent leukapheresis, with 1 withdrawing and 2 receiving the infusion after the data cutoff. There was a 100% manufacturing success rate, although 3 patients were required to undergo remanufacturing prior to treatment. Patients were allowed to receive bridging therapy during the manufacturing process.

"[Time from leukapheresis to infusion] was about 4 to 5 weeks, which is standard for most of these targeted CAR T cells," said Berdeja. "Bridging therapy was left up to the individual investigator but I suspect that about half if not two-thirds of patients had bridging therapy."

The median age of patients enrolled in the study was 62 years (range, 33-74), and the median time since diagnosis was 5.5 years. Most patients had an ECOG performance status of 1 (63%) and an ISS stage of I (29%). A third of patients (34%) had high-risk cytogenetics and the median number of prior regimens received was 6 (range, 3-17). Ninety-five percent of patients had received prior proteasome inhibitors, IMiDs, and an anti-CD38 antibody. Eighty-two percent of patients had received 1 or more prior autologous stem cell transplants.

The median follow-up for patients in the 300 x 10

 doses was 4.0 and 3.3 months, respectively. At these early assessments, the ORR in the 300 x 10

 dose arm was 43%, which included a VGPR rate of 29% and a partial response (PR) rate of 14%. However, Berdeja warned that with the short follow up, these numbers were misleading, as some patients were not included in the analysis.

"Many of these patients had not reached 2 assessments to have a confirmed response and were left off the overall response for these percentages, especially for the 450 group," he said. "As is expected with CAR T cells, the responses will deepen over time."

 dose, the ORR was 57% and was composed of a PR rate of 14%, a VGPR rate of 29%, and an sCR/CR rate of 14%. None of the responding patients had progressed at the time of the data cutoff in September 2019.

The MRD-negative rate was 94% across the full study, with just 1 patient not achieving negative status at the assessment in the 300 x 10

 dose arm. At 6 months, CAR T cells continued to be detectable for 8 of 10 patients (80%). Although the numbers were small, at month 12 bb21217 was detectable in 2 of 4 patients (50%). Of the 2 patients with 18 months of follow up, both still had detectable levels of bb21217 (100%).

"bb21217 drug product is enriched for memory-like T cells, which are associated with robust CAR T cell expansion and less disease progression at month 6," said Berdeja. “Long-term CAR T-cell persistence was observed in 8 of 10 evaluable patients at month 6 and 2 of 2 at month 18.”

All-grade cytokine release syndrome (CRS) occurred in 66% of patients, most of which was grade 1 or 2 in severity; however, 1 patient had a grade 5 CRS event at the 450 x 10

 dose. The median time to onset of CRS was 3 days and the median duration of CRS was 4 days. Neurotoxicity occurred in 24% of patients. There were 2 grade 3 events and 1 grade 4 event, with the remainder being grade 1 or 2. The median time to neurotoxicity onset was 7 days.

Grade 3/4 treatment-emergent adverse events (AEs) included neutropenia (82%), leukopenia (55%), thrombocytopenia (55%), anemia (50%), lymphopenia (34%), hypophosphatemia (21%), infection (18%), hyponatremia (13%), and febrile neutropenia (11%). Half of patients had a serious AE (50%), and 95% had at least 1 grade 3/4 AE.

The expansion arm of the CRB-402 study continues to enroll participants for the 450 x 10

 dose of bb21217. The planned enrollment for the study is 74 patients (NCT03274219).

Berdeja JG, Alsina M, Shah N, et al. Updated results from an ongoing phase 1 clinical study of bb21217 anti-BCMA CAR T cell therapy. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 927. bit.ly/35bET49.

The CAR T cell therapy bb21217 demonstrated high very good partial response or better rates in patients with heavily pretreated relapsed/refractory multiple myeloma.

Updated bb21217 Data Continue to Impress in Multiple Myeloma

The addition of navitoclax to ruxolitinib (Jakafi) showed clinically meaningful spleen responses and improvements in symptoms for patients with primary or secondary myelofibrosis, following the development of resistance to frontline ruxolitinib, according to findings from a phase II study presented at the 2019 ASH Annual Meeting.

In the single-arm study, spleen volume response of ≥35% (SVR35) was achieved by 30% of patients at week 24. Additionally, 53% of patients had resolution of palpable splenomegaly. Sixty-five percent of patients experienced a reduction in symptoms, and 35% of patients experienced a ≥50% reduction in total symptom score (TSS).

"With the addition of navitoclax to ruxolitinib, we were able to observe that there are meaningful spleen responses and improvements in symptom scores," Jacqueline S. Garcia, MD, Department of Medical Oncology, Dana-Farber Cancer Institute, said during a presentation of the findings. "The addition of navitoclax overcomes resistance in patients with uncontrolled myelofibrosis, despite prior prolonged ruxolitinib exposure."

Navitoclax is a small molecule inhibitor of BCLXL, BCL2, and BCLW, which has shown signs of activity in myeloproliferative neoplasm cell lines, including in myelofibrosis. In preclinical models, the combination of JAK2, BCLXL, and BCL2 inhibition was able to synergistically overcome JAK2 mutations and resistance to JAK2 inhibitors.  

The phase II study enrolled 34 patients with primary myelofibrosis (n = 16), post-essential thrombocythemia myelofibrosis (n = 5), and post-polycythemia vera myelofibrosis (n = 13). All patients had received ruxolitinib for ≥12 weeks prior to first dose of navitoclax, with no wash out period prior to the start of the trial. The dose of navitoclax was escalated from 50 mg daily to 300 mg daily over the course of the study. 

Of those available for baseline testing, more than half had high molecular risk (52%). The most common mutations identified were JAK2 (79%) and CALR (21%). Overall, 47% of patients at high-risk had 2 or more mutations. The duration of prior ruxolitinib therapy was 21 months (range, 4-71) and the baseline spleen volume was 1665 cm

The best achieved SVR35 was 43% for the combination. Additionally, 25% of patients saw a reduction in bone marrow fibrosis compared with baseline. There was a 1 grade reduction for 13% of patients and a 2 grade improvement for 13% of patients.

The mean white blood cell count at week 24 was 25.8 x 10

/L. Two patients entered the study with transplant dependence, with 1 becoming transplant independent following the addition of navitoclax. Seven patients entered the study receiving ≥1 unit of packed red blood cells within the past 12 weeks. Of these patients, 57% were transplant-free for ≥12 weeks following treatment with the combination. Platelet counts stabilized during the study, going from 232 x 10

"Although very early transient thrombocytopenia was observed immediately after dosing, as expected, it was manageable with a slow weekly dosing ramp up," said Garcia. "The time frame of the 8-week nadir is similar to what we initially observed with ruxolitinib alone."

The median duration of navitoclax treatment was 330 days, and 68% were able to achieve the maximum tolerated dose of 300 mg. Most patients entered the trial on ruxolitinib doses >10 mg twice daily (BID) but most were able to reduce their dose to 10 mg BID during the study (88%).

A quarter of patients discontinued navitoclax during the study (27%), due to adverse events (AEs; 9%), progressive disease (6%), and other causes (12%). Grade ≥3 AEs of any cause were experienced by 79% of patients receiving the combination. The most common grade ≥3 AEs were thrombocytopenia (44%), anemia (27%), diarrhea (6%), and vomiting (3%). Eight patients experienced a serious AE (24%). There was 1 grade 5 case of pneumonia that was deemed unrelated to navitoclax.

The phase II study is still ongoing to further assess navitoclax alone or in combination with ruxolitinib for patients with myelofibrosis (NCT03222609). Additionally, outside of the United States, an expanded access program is available to gain access to navitoclax (NCT03592576).

Harrison CN, Garcia JS, Mesa JA, et al. Results from a phase 2 study of navitoclax in combination with ruxolitinib in patients with primary or secondary myelofibrosis. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 671. bit.ly/343YuBX.

Navitoclax plus ruxolitinib (Jakafi) showed clinically meaningful spleen responses and improvements in symptoms for patients with primary or secondary myelofibrosis, following the development of resistance to frontline ruxolitinib.

Author | Silas Inman

Articles

Gottlieb Addresses Coronavirus, Innovation in Keynote Address

Gene Profiling Essential Tool for Treatment Tailoring

Updated bb21217 Data Continue to Impress in Multiple Myeloma

Navitoclax Overcomes Ruxolitinib Resistance for Myelofibrosis