Conor Killmurray

The FDA has extended the review period of the new drug application (NDA) for pacritinib as treatment of patients with myelofibrosis and severe thrombocytopenia, defined as a platelet count less than 50x10

/L. The new target action date is a February 28, 2022, according to a press release issued by CTI BioPharma Corp.

"CTI is continuing to engage collaboratively and constructively with the FDA during review of our NDA," said Adam R. Craig, MD, PhD, president and chief executive officer of CTI Biopharma, in a press release. "We are committed to providing patients suffering from cytopenic myelofibrosis with a new treatment option as soon as possible and are confident in pacritinib's potential to establish a new standard of care."

Pacritinib is an oral macrocyclic Janus kinase inhibitor specifically used to inhibit JAK2, IRAK1, and CSFIR. The JAK family of enzymes promotes normal blood cell growth in patients because JAK is central component in signal transaction pathways. A direct relationship between mutations in these pathways and the development of hematological cancers like myeloproliferative neoplasms, leukemia, and lymphoma has been found by clinicians. Moreover, due to pacritinib’s inhibition of c-fms, IRAK1, JAK2, and FLT3, the agent may be useful for the treatment of acute myeloid leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, and chronic lymphocytic leukemia.

The NDA was based upon results from the phase 3 PERSIST-1 (NCT01773187), the phase 3 PERSIST-2 (NCT02055781), and phase 3 PAC203 trials (NCT03165734).

PERSIST-1 looked at 327 patients with myelofibrosis who either received pacritinib or the best available therapy.

 By week 24 of the study, researchers found that 19% of patients in the pacritinib arm achieved the primary endpoint of spleen reduction size by 35% or more, compared to 5% in the control group. Moreover, 90 patients in the control group were switched to pacritinib at a median of 6.3 months on the trial.

PERSIST-1 led to PERSIST-2 which enrolled 311 participants with myelofibrosis who also had thrombocytopenia, and the primary endpoint of the study was to compare efficacy of pacritinib to the best available therapy.

 Patients were divided into 3 arms; in arm 1, patients received pacritinib once daily; in arm 2, patients received pacritinib twice daily; and in arm 3, patients received the best available therapy.

Twice a day pacritinib was associated with better outcomes compared to patients on the best available therapy. Eighteen percent of patients in the twice-daily pacritinib arm had a spleen reduction of 35% or greater compared to 3% of patients on the best available therapy.

In the PAC203 trial an estimated 348 patients have been enrolled and were randomized to receive 200 mg of the approved agent compared to the physician’s choice of therapy.

 Fifty-four patients received 200 mg of pacritinib twice daily and 5 saw a reduction of spleen size. Fifty-five patients who received 100 mg twice per day and 1 patient saw a reduction in spleen size compared to those who received the same amount once daily none saw a reduction in spleen size. 

1. CTI BioPharma announces extension of fda review period for pacritinib in myelofibrosis with severe thrombocytopenia. News release. CTI BioPharma. November 30, 2021. Accessed November 30, 2021. 

2. Mesa R, Vannuchhi A, Mead A, et al. Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial. The Lan. Hem. Published: March 20, 2017. doi : https://doi.org/10.1016/S2352-3026(17)30027-3

3. Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs Best Available Therapy, Including Ruxolitinib, in Patients With Myelofibrosis: A Randomized Clinical Trial. 

. 2018;4(5):652–659. doi:10.1001/jamaoncol.2017.5818

4. Gerds A, Savona M, Scott B et al. Determining the recommended dose of pacritinib: results from the PAC203 dose-finding trial in advanced myelofibrosis. 

 2020; 4 (22): 5825–5835. doi: https://doi.org/10.1182/bloodadvances.2020003314

Articles

The FDA has extended the review period of the new drug application for pacritinib as treatment of patients with myelofibrosis and severe thrombocytopenia.


FDA Extends Decision on Pacritinib for Patients With MF and Severe Thrombocytopenia

When comparing nivolumab (Opdivo) plus cabozantinib (Cometriq) vs sunitinib (Sutent) in the first-line setting for patients with advanced renal cell carcinoma (RCC) the safety profile of the combination therapy was manageable and a majority of grade 3 or more adverse events (AEs) were resolved along with stronger efficacy outcomes, according to research presented at the 2021 International Kidney Cancer Symposium (IKCS).

In a post-hoc exploratory analysis of the phase 3 open-label CheckMate 9ER (NCT03141177) trial where 651 patients with advanced RCC were randomized to either the combination of nivolumab plus cabozantinib or sunitinib alone, researchers found that 310 patients in the combination arm had any grade treatment-related AE’s compared to 298 patients in the monotherapy arm.

Moreover, 199 patients in the combination arm had grade 3 or higher AEs compared to 199 in the sunitinib arm, but no patients in the combination arm had grade 5 treatment related AEs. However, there was 1 fatal grade 4 treatment related AE in the combination arm due to small-intestine perforation compared to 2 fatal treatment-related AEs for patients on sunitinib due to grade 5 respiratory distress and grade 4 pneumonia.

To manage these AEs, researchers used dose delays and reductions of treatment and the use of corticosteroids and most patients with at least 1 dose delay or reduction continued therapy in both arms. In comparison of the 2 arms, patients on the combination arm had a longer time to dose reduction or delay in comparison to patients on sunitinib.

Overall, patients on the combination of nivolumab and cabozantinib had a median of 4.1 weeks before a delay and 4.9 weeks before the first dose reduction. In comparison, patients on the sunitinib arm had a median of 1.1 weeks to the first dose delay and a median of 4 weeks till the first dose reduction. When looking at the data overall, there was a median time of 3.6 weeks to either dose delay or reduction for patients in the combination vs 1.7 weeks for patients on the monotherapy.

“Frequencies of dose reductions and dose delays were largely balanced between treatment arms among patients with grade ≥ 3 treatment-related AEs, and almost all patients with at least 1 dose delay or reduction were able to subsequently continue therapy in both treatment arms,” the researchers wrote.

Twenty-six percent of patients in the combination arm with grade 3 or greater treatment related AEs received corticosteroids at about 40 mg or more daily. Ten percent of patients who received the corticosteroids continuously for at least 2 weeks and 4.5% of them received corticosteroids for at least 30 days.

The analysis did not look for significance in the differences between onset of AE to its resolution between both treatment populations. In the nivolumab and cabozantinib arm the shortest median time to onset of the AE was the decreased neutrophil count at 2.3 weeks with a median time to resolution of 6.1 weeks, whereas the shortest time to resolution was 3 weeks for patients who experienced diarrhea. In the monotherapy arm these were similar results.

For the patients who with grade 3 or more treatment-related AEs their time to response on the treatment was also shorter and the overall response rate (ORR) was 55.3% in the combination arm compared to 31.5% in the sunitinib arm. The median time to response in the combination arm was 2.8 months compared to 4.3 months in the monotherapy arm.

“Data reported in this post hoc analysis help better inform the timely detection and proactive management of AEs that may occur with first-line nivolumab plus cabozantinib versus sunitinib in patients with advanced RCC,” the researchers concluded.

Kessler E., Burotto M, Shah A, et al. Outcomes with first-line nivolumab plus cabozantinib versus sunitinibin patients with advanced renal cell carcinoma and treatment-related adverse event timing/management in CheckMate 9ER. Presented at: International Kidney Cancer Symposium, November 5-6, 2021.

In a post-hoc analysis of the CheckMate 9ER trial, researchers found that, along with additional efficacy benefits, the combination of nivolumab plus cabozantinib had manageable adverse events.   

Post-Hoc Analysis Shows Adverse Events With First-line Nivolumab Plus Cabozantinib Are Manageable

In a trial comparing 2 years of treatment on celecoxib (Celebrex), an anti-inflammatory agent, to placebo as adjuvant therapy for patients with 

-negative breast cancer no evidence of a disease-free survival (DFS) benefit was seen, according to research in 

The REACT trial (NCT02429427) was a phase 3 2:1 randomized, double-blinded study that was conducted across 160 centers in the United Kingdom and Germany looking at the efficacy of adjuvant celecoxib vs placebo among a total of 2,639 patients. These patients had completely resected breast cancer with prior local and systemic therapy with a median age of 55 years old.

Most patients' tumors (73%) had estrogen receptor positive disease or progesterone receptor positive and ERBB2 negative disease and 1,265 patients had node positive disease, while 1,111 patients had grade 3 tumors. When splitting up the total patient population 1,763 patients received celecoxib compared to 876 on placebo.

“Patients with breast cancer remain at risk of relapse after adjuvant therapy,” the researchers noted. Celecoxib has been believed to impact certain pathways, such as cyclooxygenase-2, as an anti-inflammatory agent since inflammatory cells are found in the microenvironment of the tumor.2 “Celecoxib has shown antitumor effects in preclinical models of human breast cancer, but clinical evidence is lacking,” the researchers wrote. This phase 3 trial would see if the addition of the anti-inflammatory agent to standard of care therapy would impact the patient’s DFS.

The primary end point of this study was DFS and at a median follow up of 74.3 months, DFS events had been reported in just 487 patients, or 19% of the intention-to-treat population. In the treatment arm 18% (n = 323) had a DFS event with a DFS rate of 84% among those that responded, whereas in the placebo arm 19% (164) of patients had a DFS event with a 83% DFS rate in this group (HR 0.97: 95% CI, 0.80-1.17, 

“Results of abundant clinical studies, although unconvincing, suggest that celecoxib administration is related not only to diminished incidence of cancer but also to the better prognosis in cancer patients,” previous research had cited.3 “In view of the potential variations in response to celecoxib in cancer patients, it seems critical to ascertain target populations for its use.”

For the researchers in the REACT trial, this was not enough support to show a DFS benefit in the 2 year period that patients were observed. According to the researchers, it may still be possible for longer term treatments with celecoxib to yield DFS benefit, but there would need to be further, and potentially wider, studies to test the possibility of this drug in the adjuvant setting.

1. Coombes RC, Tovey H, Kilburn L, et al. Effect of Celecoxib vs Placebo as Adjuvant Therapy on Disease-Free Survival Among Patients With Breast Cancer: The REACT Randomized Clinical Trial. 

. 2021 Sep 1;7(9):1291-1301. doi: 10.1001/jamaoncol.2021.2193

2. Tołoczko-Iwaniuk N, Dziemiańczyk-Pakieła D, Nowaszewska BK, Celińska-Janowicz K, Miltyk W. Celecoxib in Cancer Therapy and Prevention - Review. Curr Drug Targets. 2019;20(3):302-315. doi: 10.2174/1389450119666180803121737

3. Li J, Hao Q, Cao W, Vadgama JV, Wu Y. Celecoxib in breast cancer prevention and therapy. 

. 2018 Oct 26;10:4653-4667. doi: 10.2147/CMAR.S178567

Looking at 2 years' worth of data for patients with ERBB2-negative breast cancer, a study showed that the anti-inflammatory agent celecoxib had no disease free survival benefit. 

Celecoxib Shows No Evidence for DFS Benefit Over 10 Years in ERBB2-Negative Breast Cancer

The role of the targeted inhibitors ramucirumab [Cyramza] or merestinib (LY2801653) first-line cisplatin–gemcitabine in patients with locally advanced or metastatic biliary tract cancer remains investigational, according to new data from 

In a randomized, double-blind, phase-2 study researchers looked at 309 patients assigned to either 8 mg/kg of intravenous ramucirumab (n=106), 80 mg of oral merestinib (n=102), or pooled placebo (n=101), along with cisplatin at 25 mg/m2 and gemcitabine at 1000 mg/m2 on days 1 and 8 in 21-day cycles, for a maximum of 8 cycles.

At the data cut off 10.9 months the median progression free survival (PFS) of patients on ramucirumab was 6.5 months (80% CI 5.7–7.1), 7 months (80% CI, 6.22–7.1) in the merestinib group, and 6.6 months (80% CI, 5.6–6.8) in the pooled placebo group. When comparing patients in the ramucirumab group versus those in the placebo group the hazard ratio was 1.12 (80% CI, .90–1.4; 

 = .48) and was .92 in the merestinib versus placebo arm (80% CI, .73–1.15; 

 = .64). According to the researchers these data showed that each inhibitor was tolerated well in the patient groups but did not improve PFS in them.

Enrolled patients had histologically or cytologically confirmed, non-resectable, recurrent, or metastatic biliary tract adenocarcinoma. They were untreated and 18 years old or older, with an ECOG performance status of 0 or 1, and had an estimated life expectancy of 3 months or more.

Biliary tract cancers are rare and aggressive gastrointestinal malignancies where approximately half of patients survive for less than 1 year after a diagnosis with advanced disease. Thus, researchers were hoping that results from this phase 2 study would allow them to treatment patients longer, but the results show that the chemotherapy and targeted therapy combination remain in the investigational phase.

However, these treatments were both well tolerated by patients when looking at adverse event [AE] data from both arms. The most common grade 3 or worse adverse events were neutropenia with 51 (49%) patients in the ramucirumab group experiencing it compared to 48 (47%) patients in the merestinib group, and 33 patients in the pooled placebo group. This was followed by thrombocytopenia, 36 [35%] patients, 19 patients, and 17 patients, respectively, and anemia.

Serious AEs occurred in 53 (51%) patients in the ramucirumab group, 56 patients (55%) in the merestinib group, and 48 (48%) in the pooled placebo group. Treatment related deaths occurred in 1 patient from the ramucirumab group who had a heart attack, and 2 patients in the merestinib group with 1 patient dying due to pulmonary embolism and 1 due to sepsis.

“The role of these targeted inhibitors remains investigational, highlighting the need for further understanding of biliary tract malignancies and the contribution of molecular selection,” the researchers concluded.

Valle JW, Vogel A, Denlinger CS, He AR, et al. Addition of ramucirumab or merestinib to standard first-line chemotherapy for locally advanced or metastatic biliary tract cancer: a randomised, double-blind, multicentre, phase 2 study. 

. 2021 Oct;22(10):1468-1482. doi: 10.1016/S1470-2045(21)00409-5

Progression-free survival remained unaffected in patients with advanced biliary tract cancer after clinicians added either ramucirumab or merestinib to first-line chemotherapy.

PFS Remains Unaffected in Patients With Advanced Biliary Tract Cancer After Adding Ramucirumab or Merestinib to Chemo

Combining dendritic cell-based immunotherapy (DCVAC/OvCa) with second-line chemotherapy in patients with platinum-sensitive ovarian cancer did not improve progression-free survival (PFS) but did prolong overall survival (OS), according to data from 

In an open-label phase 2 trial (NCT02107950) 71 patients with platinum-sensitive ovarian cancer who relapsed after first-line chemotherapy were randomized to either 10 doses of DCVAC/OvCa every 3-6 weeks plus chemotherapy or chemotherapy alone. PFS was not found to be improved (HR 0.73; 95% CI 0.42–1.28, 

 = 0.27), but median OS was significantly prolonged by 13.4 months in the DCVAC/OvCa and chemotherapy group (HR 0.38, 95% CI 0.20–0.74, 

PFS was the primary efficacy end point of the study along with secondary end points of OS, biological progression-free interval (PFIBIO), objective response rate (ORR), and immune responses.

Median PFS in the treatment arm was 11.3 months compared to 9.5 months in the chemotherapy alone arm, moreover, PFIBIO was not significantly greater in the DCVAC/OvCa at 10.3 months compared to 10.1 months (HR 0.82; 95% CI 0.47–1.43, 

 = 0.478) in the control group. The OS was initially not significant at the time of analysis with a median OS of 23.8 months in the DCVAC/OvCa group vs 21.5 months in the control group (HR 0.63, 95% CI: 0.26–1.54, 

 = 0.30), but these data were immature at the time according to the researchers.

An exploratory analysis, conducted through May 2018, showed an OS increase by 13.4 months in the DCVAC/OvCa group from 29.5 months to 35.5 months of OS. Furthermore, for the 14 of 20 patients withdrawn from the trial the median OS was 7.3 months longer in the DCVAC/OvCa group at 29.5 versus 22.2 months in the chemotherapy arm.

ORR was also greater in the DCVAC/OvCa group at 87.5% (95% CI, 71%–96.5%) compared with the control group at 62.5% (95% CI, 43.7%–78.9%). Risk reduction for death was also 62% in the treatment group compared to chemotherapy alone.

“The reason why DCVAC/OvCa prolonged OS, but not PFS, is not fully clear,” the researchers wrote in their analysis of the study results. “We hypothesize that DCVAC/OvCa induces a delayed, yet durable anticancer immune response that leads to long-term disease stabilization and slower progression, resulting in prolonged survival.”

In both groups, similar proportions of patients experienced treatment-emergent adverse events (TEAEs) from the chemotherapy, however, grade 3 or greater TEAEs were experienced in patients in the control group than the treatment group at 78.4% versus 83.9%, respectively. The most common grade 3 or greater TEAEs were thrombocytopenia (64.9% vs 80.6%), anemia (64.9% vs 67.7%), neutropenia (59.5% vs 67.75), and leukopenia (45.9% vs 32.3%).

All these TEAES occurred in 10 or more patients among each group, and most of these events were related to chemotherapy, according to the researchers. TEAEs reported to be only related to treatment with DCVAC/OvCa were abdominal rigidity, injection site erythema, and lymphadenopathy. Two patients in the treatment arm had TEAEs which led to death compared to none in the chemotherapy group, while only 1 patient had TEAEs that led to trial withdrawal due to chemotherapy.

“DCVAC/OvCa did not improve PFS, but exploratory analyses showed it may have prolonged OS and enhanced surrogate antigen-specific T-cell activity,” the researchers concluded. “These findings warrant confirmation in appropriately powered randomized studies.”

Cibula D, Rob L, Mallmann P, et al. Dendritic cell-based immunotherapy (DCVAC/OvCa) combined with second-line chemotherapy in platinum-sensitive ovarian cancer (SOV02): A randomized, open-label, phase 2 trial. 

. 2021 Sep;162(3):652-660. doi: 10.1016/j.ygyno.2021.07.003

The combination of dendritic cell-based immunotherapy in the second-line of treatment for patients with ovarian cancer proves beneficial. 

Dendritic Cell-Based Immunotherapy Plus Second-Line Chemotherapy Shows Significant OS Increase for Patients with Ovarian Cancer

While looking at data from an equal-access healthcare system, researchers saw continuing racial disparities for overall survival (OS) outcomes between Black women with endometrial cancer (EC) and White women with EC suggesting that factors other than access to care are driving this disparity, according to research from 

Previous studies have shown that the mortality rate for Black women with EC is double that of White women with WC, even though the overall incidence rate is lower among Black women. These studies have also shown that unequal access to care is a factor in these disparities, however, researchers wanted to see what the survival outcomes looked like in an equal-access health care system. Therefore, they used data from the Military Health System (MHS), which provides equal care to its beneficiaries regardless of their racial or ethnic background.

Researchers found, however, that despite compiling data from an equal-access system and adjusting for age, diagnosis period, tumor stage, tumor histology/grade, and whether the patient had adjuvant treatment, the OS disparity between Black and White women with EC persisted (HR, 1.64; 95% CI, 1.19-2.27). Moreover, a multivariable analysis stratified by tumor features and treatment showed that the racial disparity was only among those Black and White patients with low-risk features, defined as stage I/II disease or low-grade EC, or those with no adjuvant treatment.

“While it is not clear why the racial differences in survival were not shown in high-risk tumors assuming more aggressive tumors feature sin Black patients, it might result from complex effects of multiple factors, such as tumor-risk related molecular features, utilization of medical care, and family support,” the researchers wrote when explaining the differences between patients with high-risk and low-risk EC. “One of the factors might be no or minimal financial barriers to and thus wide utilization of adjuvant treatment, which is more widely used for high-grade and late-stage tumors, in the MHS that provides universal care. As a result, racial differences in survival might be mitigated among patients with high-grade or late-stage disease or who received adjuvant treatment.”

Using data from the US Department of Defense’s Automated Central Tumor Registry, the researchers categorized women with EC as either non-Hispanic White (NHW) or non-Hispanic Black (NHB). The study included 144 NHB patients and 1,439 NHW with EC diagnosed between the years 1988 and 2013 with most of the disease diagnosed at stage I, 95 vs 1101 patients, respectively. Moreover, low grade endometrioid cancers made up the majority in both groups with 76.7% (n = 1104) in the NHW group and 54.2% (n = 78) in the NHB group.

In the stage I/II group the difference in OS was significant between the two groups with a HR of 1.81 (95% CI, 1.2-2.8, 

 = .0076). In patients with low grade endometrioid cancer the HR was 2.47 (95% CI, 1.6-3.9, 

 = .00002), whereas the ungraded endometroid group had a 1.03 HR (95% CI, .12-8.6, 

 = .9788). Those patients with no adjuvant treatment had a HR of 2.15 (95% CI, 1.31-3.53, 

 = .0026) compared to an HR of 1.14 (95% CI, 0.12-10.1, 

 = .9098) in patients that could not be confirmed if they had adjuvant treatment. These disparities also persisted throughout each diagnosis period that the researchers split data in with 1988-1994 at a HR of 1.04 (95% CI, .41-2.62, 

 = .9331), 1995-2004 with a HR of 1.68 (95% CI, 1.07-2.65, 

 = .0241), and 2005-2013 at 1.41 (95% CI, .75-2.68, 

“Several factors might explain a poorer survival among Black women than White women when access to care is equal. First, histologic subtype may vary among racial/ethnic groups,” explained the researchers. “Previous studies have reported that Black women were more likely to present with non-endometroid histologic subtypes including serous and clear cell carcinoma, which are more aggressive and have higher risks of recurrence, progression, and mortality. This was also observed in our study, although the numbers of women with these types were too small (data not shown).”

1. Park AB, Darcy KM, Tian C, et al. Racial disparities in survival among women with endometrial cancer in an equal access system. 

. 2021;163(1):125-129. doi: 10.1016/j.ygyno.2021.07.022

2. Smotkin D, Nevadunsky NS, Harris K, Einstein MH, Yu Y, Goldberg GL. Histopathologic differences account for racial disparity in uterine cancer survival. 

. 2012;127(3):616-9. doi: 10.1016/j.ygyno.2012.08.025

Despite researchers compiling data from an equal-access system and adjusting for age, diagnosis period, tumor stage, tumor histology/grade, and whether the patient had adjuvant treatment, the overall survival disparity between Black and White women with endometrial cancer persisted.