Nichole Tucker

The FDA has granted accelerated approval to the subcutaneous formulation of daratumumab (Darzalex Faspro) with hyaluronidase-fihj as treatment of patients with light chain (AL) amyloidosis, announced Genmab A/S in a press release.1

Approval was granted to the combination based on results from the phase 3 ANDROMEDA clinical trial (NCT03201965) for which results were recently presented during the 2020 American Society of Hematology (ASH) Annual Meeting.

“AL amyloidosis is a devastating and potentially fatal blood disorder that, until now, did not have any U.S. FDA-approved therapies. This makes today’s approval of Darzalex FASPRO a critical step forward for patients in the U.S. in dire need of treatment options,” said Jan van de Winkel, PhD, chief executive officer, Genmab A/B, in a statement.

ANDROMEDA randomized patients 1:1 to receive bortezomib (Velcade), cyclophosphamide, and dexamethasone (VCd) on a weekly basis for 6 cycles in combination with subcutaneous daratumumab 1800 mg for 2 weekly cycles, followed by another 3 to 6 cycles given every 2 weeks, which was followed by subcutaneous daratumumab 1800 mg every 4 weeks. Treatment was continued until major organ deterioration–progression-free survival (MOD-PFS) or until patients reached a maximum of 24 cycles, or weekly VCd for 6 cycles.2

Median follow-up time in the study was 15.7 months (range, 0.0-24.1), and the median duration of treatment was 15.8 months (range, 0.1-24.1) in patients who received D-VCd compared with 5.3 months (range, 0.03-7.3) in the VCd arm. Patients were evaluated for the primary end point of complete response (CR) rate as well as secondary end points including PFS, objective response rate, disease control rate, safety, and quality of life.

Daratumumab plus hyaluronidase-fihj achieved hematologic CR rate of 53% in 195 patients compared with 18% in patients who received VCd, odds ratio [OR], 5.1; 95% CI, 3.2-8.2; 

The addition of daratumumab to VCd (D-VCd) also achieved higher rates of best hematologic response at any time in the study. Specifically, the rates observed in the D-VCd arm versus the VCd arm were 56.9% versus 18.7%, (OR, 5.68; 95% CI, 3.58-9.00; 

 <.0001. In the subset of patients with a free light chain (FLC) 20 mg/L or lower, the best hematologic response rate for the D-VCd arm was 71.3% compared with 20.2% in the VCd alone arm (OR, 9.8; 95% CI, 6.1-15.7; 

 <.0001). Notably, the patients who demonstrated a difference between involved and uninvolved FLC of less than 10 mg/L, the best hematologic response rate was 65.6% for the daratumumab combination arm versus 30.6% for the VCd alone arm (OR, 4.3; 95% CI, 2.8-6.6; 

 <.0001). In addition, patients who had International Society of Amyloidosis criteria showed a best hematologic response rate of 49.2% when treated with D-VCd versus 23.3% when treated with VCd alone (OR, 3.25; 95% CI, 2.09-5.06; 

Treatment with the daratumumab combination also induced a significantly prolonged MOD-PFS compared with VCd alone. In particular, MOD-PFS events were seen in 17.4% of patients on D-VCd versus 27.5% of patients who received VCd alone (HR, 0.58; 95% CI, 0.36-0.93; 

At the time of the ASH presentation, safety was reported as being consistent with prior studies. No new safety signals were observed. Investigator noted, however, that the D-VCd arm had a higher rate of cardiac and renal responses at 6 months (42%) when compared with the VCd alone arm (22%) for cardiac, and renal was 54% versus 27%, respectively.

Adverse reaction related to D-VCd reportedly occur in ≥20% of patients. The most commonly observed adverse reaction include upper respiratory tract infection, diarrhea, peripheral edema, constipation, fatigue, peripheral sensory neuropathy, nausea, insomnia, dyspnea, and cough. In addition, serious adverse reactions can occur, which commonly include pneumonia (9%), cardiac failure (8%), and sepsis (5%). Adverse reaction with the combination can be fatal in about 11% of patients. The adverse reaction that may lead to death included cardiac arrest (4%), sudden death (3%), cardiac failure (3%) and sepsis (1%).

ANDROMEDA is an open-label, active-controlled, randomized protocol study. Patients were eligible to enroll is they had AL amyloidosis with at least 1 organ impacted, no prior therapy for AL amyloidosis or multiple myeloma, cardiac stage I to IIIA disease, and an estimated glomerular filtration rate of at least 20 mL/min

Genmab Announces that Janssen has been granted U.S. FDA approval for DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj) for patients with newly diagnosed light-chain (al) amyloidosis. News release. January 15, 2020. Accessed January 15, 2020. 

Comenzo RL, Kastritis E, Minnema MC, et al. Reduction in absolute involved free light chain and difference between involved and uninvolved free light chain is associated with prolonged major organ deterioration progression-free survival in patients with newly diagnosed AL amyloidosis receiving bortezomib, cyclophosphamide, and dexamethasone with or without daratumumab: results from ANDROMEDA. Presented at: 2020 ASH Annual Meeting & Exposition; December 5-8, 2020; virtual. Abstract 552.

Articles

The FDA has granted accelerated approval to the subcutaneous formulation of daratumumab with hyaluronidase-fihj as treatment of patients with light chain amyloidosis.










FDA Approves Daratumumab With Hyaluronidase-fihj in AL Amyloidosis

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Treatment with the multi-target tyrosine kinase inhibitor (TKI) anlotinib (AL3818) led to a significant improvement in progression-free survival (PFS) along with a tolerable and manageable safety profile in Chinese patients with refractory metastatic colorectal cancer (mCRC), according to results from the phase 3 ALTER0703 trial presented during the 2021 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium.

In the mCRC treatment paradigm, anti-angiogenic therapy is considered to be the standard-of-care, however, few options exist for patients in later-line settings. Preliminary data from a cohort of 31 patients suggested that anlotinib monotherapy may be an appropriate option. The agent previously achieved an objective response rate (ORR) of 6.45% (95% CI, 0.8%-21.4%), which include partial responses (PRs) in 6.45% of patients and stable disease (SD) in 83.87% for a disease control rate (DCR) of 90.32% (95% CI, 74.2%-98.0%). The survival data for this early research shows a median PFS of 5.62 months (95% CI, 3.80-7.32), and a median overall survival (OS) of 9.33 months (95% CI, 8.46-10.21).

To further explore the anti-tumor efficacy of anlotinib as well as the safety of the agent, the ALTER0703 study involved administration of the drug in third-line setting of mCRC and beyond in patients who received 2 or more prior lines of chemotherapy. The population was 18 years of age or older and all patients enrolled had an ECOG performance score of 0 or 1, adequate bone marrow, renal, and liver function.

In a 2:1 randomization, 282 patients in the study were given anlotinib 12 mg daily every 3 weeks in combination with best supportive care (BSC). The other 137 patients enrolled were given a matching placebo in combination with BSC. Treatment was continued until disease progression or intolerable toxicity.

The primary end point explored in the study was OS, and the secondary end points included PFS, ORR, DCR, safety, and quality of life (QoL).

In the anlotinib arm, the median age determined at baseline was 57.5 years (range, 49.0-64.0) with 75.5% of patients being below 65 years of age, notably. In comparison, the placebo arm had a median age of 55.0 years (range, 48.0-63.0) with 81.0% being under the age of 65 years. Most patients in the study were male including 62.8% of the experimental arm and 66.4% of the control arm. Fewer patients in the anlotinib arm had an ECOG performance status of 1 (69.9%) compared with the placebo arm (76.6%). The primary site of disease in the anlotinib arm versus the placebo as determined at baseline was the colon for 50.4% versus 40.2%, the rectum for 45.7% versus 56.9%, and both for 3.9% versus 2.9%, respectively. RAS or BRAF status observed at baseline was wildtype for 36.5% of the anlotinib arm versus 33.6% for the placebo arm, mutant for 45.4% versus 41.6%, and unknown for 18.1% compared with 24.8%, respectively.

Liver metastasis was observed at baseline in 76.6% of patients in anlotinib arm compared with 70.1% in the placebo arm. The time from diagnosis to metastases was less than 18 months for 83.7% of the anlotinib arm versus 82.5% of the placebo arm but was 18 months or more for 16.3% versus 17.5%, respectively.

In terms of prior treatment, 30.5% of the anlotinib reported that they had received prior anti-VEGF therapy, compared with 31.4% of the placebo arm. Eighty-nine percent of the anlotinib arm reported undergoing prior surgery versus 88.3% of the placebo arm. Finally, 35.5% of the anlotinib group reported that they had prior radiotherapy compared with 39.4% of the placebo arm.

Assessment of the primary end point showed that the median OS did not meet the requirements for significance. However, treatment with anlotinib yielded a longer median OS of 8.57 months (95% CI, 7.82-9.72) versus 7.16 months (95% CI, 6.24-8.80) in the placebo arm (HR, 1.02; 95% CI, 0.82-1.27; 

 = .87). A subgroup analysis of OS revealed an OS benefit with anlotinib among patients with RAS/BRAF wild-type disease. The median OS observed with anlotinib in this subgroup was 11.0 months (95% CI, 8.6-14.1) compared with only 6.7 months (95% CI, 3.5-11.1) among patients given placebo.

Secondary end point survival assessment showed a median PFS of 4.14 months (95% CI, 3.38-4.50) with anlotinib versus 1.45 months (95% CI, 1.41-1.51) in the placebo arm (HR, 0.34; 95% CI, 0.27-0.43; 

In terms of responses to therapy, anlotinib led to an ORR of 4.26% (95% CI, 2.2-7.3%) with PRs in 4.26%, SD in 71.63%, and progressive disease (PD) in 16.67%. Notably, 7.45% of the anlotinib group was not evaluable for response. Overall, the DCR in the experimental arm was 75.9% (95% CI, 70.5%-80.8%). In comparison, the placebo arm had an ORR of only 0.73% (95% CI, 0-4.0%). The odds ratio (OR) for the difference in ORR between the anlotinib and placebo arms was 0.165 (95% CI, 0.021-1.286; 

 =.069). There was 1 PR in the placebo arm while the remaining patients achieved only SD (29.92%) or had PD (53.28%). Response data was not evaluable for 16.06% of the placebo group. Compared with the anlotinib arm, the DCR control rate among patients who received placebo was 30.7% (95% CI, 23.1%-39.1%) showing a significant difference (OR, 0.140; 95% CI, 0.089-0.221; 

None of the adverse events (AEs) observed in the study were unexpected according to investigators led by Yihebali Chi, MD, PhD, of the Cancer Hospital at the Chinese Academy of Medical Sciences and Peking Union Medical College. AEs occurred in 99.7% of the anlotinib arm and 95.6% of the placebo arm. In addition, grade 3 or higher AEs occurred in 66.7% of patients who received anlotinib versus 35.8% of those given placebo. Treatment-related AEs occurred in 97.5% of the anlotinib population compared with 86.1% of the placebo population, and these treatment-related AEs were grade 3 or higher for 52.5% of patients versus 19.7%, respectively. Also, treatment-related serious AEs occurred in 12.4% of the anlotinib arm versus 7.3% of the placebo arm.

Hypertension was the most common AE observed. Pneumothorax was the most common treatment-related serious AE, which occurred in 4 patients in total.

The results from ALTER0703 suggest that patients with 

 wildtype mCRC may experience longer survival outcomes on treatment with anlotinib, although further research is needed to confirm the potential of anlotinib in this patient population.

Chi Y, Shu V, Ba Y, et al. The efficacy and safety of anlotinib in refractory colorectal cancer: A double-blinded, placebo controlled, randomized phase III ALTER0703 trial. Presented at: 2021 ASCO Gastrointestinal Cancers Symposium; January 15–17, 2021; virtual. Abstract 65.

Treatment with the multi-target tyrosine kinase inhibitor anlotinib led to a significant improvement in progression-free survival along with a tolerable and manageable safety profile in Chinese patients with refractory metastatic colorectal cancer. according to results from the phase 3 ALTER0703 trial.

Anlotinib Improves PFS in RAS/BRAF Wildtype-Positive Metastatic Colorectal Cancer 

The FDA granted approval to the antineoplastic tyrosine kinase inhibitor, crizotinib (Xalkori), as treatment of pediatric patients 1 year of age and older and young adults with 

 alteration-positive relapsed or refractory systemic anaplastic large cell lymphoma (ALCL), Pfizer announced in a press release. Crizotinib is the first biomarker-driven therapy approved for the treatment of this patient population.

Crizotinib is not approved for the treatment of adult patients with

-positive ALCL, as safety efficacy has not been proven in this specific population. 

“We are proud to deliver the first biomarker-driven therapy for children and young adults with ALCL. Xalkori offers a meaningful new treatment option for young patients with relapsed or refractory 

-positive ALCL,” said Chris Boshoff, MD, PhD, chief development officer, Oncology, Pfizer Global Product Development. “Xalkori transformed the treatment of 

-positive non-small cell lung cancer as the first biomarker-driven therapy for that disease, and this approval is a notable milestone in our journey to continue to follow the science to address cancers with significant unmet need.”


Approval was granted based on data from phase 2 clinical trials including the phase 1/2 ADVL0912 study (NCT00939770), and the phase 1B A8081013 study (NCT01121588). In the ADVL0912 trial, crizotinib was administered to patients aged 16 years to 50 years with relapsed/refractory solid tumors or ALCL with 

 mutations or amplifications. The study completed in 2020 after first revealed the antitumor activity of crizotinib in the study population, most specifically for those with 

-translocated ALCL as well as in patients with myofibroblastic tumors.

The study included 79 patients who were assessed for the coprimary end points of crizotinib’s maximum tolerated dose and recommended phase 2 dose, as well as the incidence of toxicities. Secondarily, the end points explored included the number of patients from each subgroup with a response to crizotinib, and the number of patients with minimal residual disease, and steady state peak concentration.

Crizotinib led to an objective response rate (ORR) of 88% in the study. Of the patients who responded to therapy, 39% maintain their response for 6 months, and 22% maintained their response for 12 months. 

Based on the results of the study, 280 mg/m2 twice daily was set at the MTD of crizotinib recommended for use in the second phase of the study. Crizotinib at the 280 mg/m2 was well-tolerated in patients.

Grade 4 adverse events (AEs) during cycle 1 were observed in the study. The events included neutropenia (n = 2), and liver enzyme elevation (n = 1). Two cases of grade 3 AEs were reported including 2 cases of lymphopenia and 8 of neutropenia. It was also noted that crizotinib had a mean steady state peak concentration of 630 ng/mL with a 4-hour (range, 1-6) time to reach the peak.

In terms of the secondary trial end points, objective responses were observed n 79 patients which included complete responses in 9 patients and partial responses in 5 patients. Notably, in the ALK-positive ALCL population, crizotinib achieved antitumor activity in all but one patient. In the neuroblastoma subgroup, the inflammatory myofibroblastic tumor group, and non–small cell lung cancer group, antitumor activity was also achieved.

Crizotinib also demonstrated antitumor activity in the A8081013 study of patients with ALK-rearranged hematologic tumors, including patients with ALCL.

The overall study population included 44 patients and of those patients, 14 had

-positive diffuse large B-cell lymphoma. Crizotinib led to an objective response rate of 60%, which included a CR in 9 patients and a PR in 4 patients. One patient also achieved stable disease which lasted for over 12 months. These results combined led to a clinical benefit rate of 67%.

AEs were observed in the entire study population, but most AEs were grade 1 or 2. Of the AEs observed, the most common were vomiting (47%), visual impairment (40%), asthenia (27%), cough (27%), and neutropenia (27%). Notably, grade 3 vomiting and neutropenia were observed.

Grade 4 events of abdominal pain, increased creatinine phosphokinase, lymphopenia, and multi-organ failure occurred in 4 patients. There was also 1 patient who experienced grade 5 central nervous system hemorrhage.

1. Pfizer’s XALKORI® (crizotinib) Approved by FDA for ALK-positive anaplastic large cell lymphoma in children and young adults. News release. Pfizer. 14. 2021. Accessed January 14, 2021.

2. Mossé YP, Lim MS, Voss SD, et al. Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children's Oncology Group phase 1 consortium study. Lancet Oncol. 2013;14(6):472-480. doi:10.1016/S1470-2045(13)70095-0

3. Gambacorti-Passerini C, Horibe K, Braiteh F, et al. Safety and clinical activity of crizotinib in patients with alk-rearranged hematologic malignancies. Blood. 2013;122(21);4342. doi:10.1182/blood.V122.21.4342.4342

The FDA granted approval to the antineoplastic tyrosine kinase inhibitor, crizotinib, as treatment of pediatric patients 1 year of age and older and young adults with ALK alteration-positive relapsed or refractory systemic anaplastic large cell lymphoma.










FDA Approves Crizotinib in Pediatric ALK+ Relapsed or Refractory Systemic ALCL

The investigational, potent, oral CDK9 inhibitor, zotiraciclib (ZTR/TG02) in combination with temozolomide (Temodar), demonstrated early improvement in progression-free survival (PFS) as treatment of patients with recurrent high-grade gliomas, meeting the primary end point of the phase 1B 17-C-0009 trial clinical trial (NCT02942264).

Topline results announced in a press release by the developer of zotiraciclib, Adastra Pharmaceuticals, Inc, noted a profound extension of median PFS benefit among the patients in the study who had 

-mutated with zotiraciclib plus temozolomide compared with those who received temozolomide alone. In addition, the phase 2 dose of zotiraciclib was determined as the drug was found to be well-tolerated in patients, addressing the co-primary end point of determination of the maximum tolerated dose.

"Because preclinical data demonstrated the ability of ZTR to inhibit CDK9, enhance apoptosis and cause mitochondrial dysfunction and ultimately ATP depletion in glioma cells, we were optimistic about this first-in-human glioma trial," said Jing Wu, MD, PhD, of National Cancer Institue (NCI) and the principal investigator of the 17-C-0009 trial, in a statement. "The data from the phase 1b trial support our initial expectations and reinforce our energies to continue to investigate ZTR as a treatment for patients with gliomas."

Full results from the study are expected to be presented by the NCI, which conducted the trial, at an upcoming medical conference and published.

"We are very grateful to our NCI colleagues, the patients, and their families for their participation in this trial. Recurrent high-grade gliomas are aggressive malignant brain tumors and remain difficult cancers to treat. Currently, available agents used for the treatment of gliomas offer little or no proven benefit; new therapeutic options are needed," said Scott Megaffin, chief executive officer, Adastra Pharmaceuticals, Inc, in a statement. "We are exceptionally encouraged by the potential of zotiraciclib as a new treatment alternative for patients with recurrent high-grade gliomas. On the basis of these findings, Adastra is in active preparation of a registration-enabling clinical study of ZTR in patients with recurrent high-grade gliomas, in addition to work now underway to expand the application of ZTR to additional solid tumors and hematologic malignancies."

In the phase 1B portion of the study, patients with recurrent gliomas received the oral combination of zotiraciclib plus temozolomide in 28-day cycles. Zotiraciclib was administered 3 days before cycle 1, and then for 4 days during every cycle. Temozolomide was administered 7 days on and 7 days off for some patients and daily for other patients. All patients in the study continued treatment until disease progression or unacceptable toxicity.

Patients were eligible to enroll in the study given they have recurrent disease proven by either histology or imaging. Enrollees were required to be 18 years of age or older with no more than 2 prior disease relapses, and they must have undergone prior standard therapy for their primary disease. The required Karnofsky performance score for enrollment was > 60%. Patients must have also had adequate bone marrow function and completed treatment for prior toxicities in order to enroll in the study.

Any patient who received or who were on current treatment with an investigational drug were ineligible for the trial, as were patients who received prior bevacizumab (Avastin). Presence of serious medical condition, laboratory abnormality, or psychiatric illness were also grounds for exclusion from the study.

Adastra Pharmaceuticals announces positive top-line data from phase 1b clinical trial of zotiraciclib in the treatment of recurrent high-grade gliomas. News release. Adastra Pharmaceuticals. January 14, 2021. Accessed January 14, 2021. 

The investigational, potent, oral CDK9 inhibitor, zotiraciclib in combination with temozolomide, demonstrated early improvement in progression-free survival as treatment of patients with recurrent high-grade gliomas, meeting the primary end point of the phase 1B 17-C-0009 trial clinical trial.

Nichole Tucker | Authors

Articles

FDA Approves Daratumumab With Hyaluronidase-fihj in AL Amyloidosis

Anlotinib Improves PFS in RAS/BRAF Wildtype-Positive Metastatic Colorectal Cancer

FDA Approves Crizotinib in Pediatric ALK+ Relapsed or Refractory Systemic ALCL

Zotiraciclib Plus Temozolomide Shows Early PFS Benefit in Recurrent Gliomas