imatinib

Ponatinib vs Imatinib in Frontline Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia:A Randomized Clinical Trial

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Ponatinib vs Imatinib in Frontline Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia

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Key Points

Question  Is frontline ponatinib superior to imatinib when combined with reduced-intensity chemotherapy in adults with newly diagnosed Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL)?

Findings  In this randomized clinical trial, ponatinib demonstrated a significantly higher minimal residual disease–negative complete remission rate at the end of induction (34.4% vs 16.7% with imatinib) and a comparable safety profile vs imatinib when combined with reduced-intensity chemotherapy in adults with newly diagnosed Ph+ ALL.

Meaning  These efficacy and safety results support consideration of ponatinib as a frontline tyrosine kinase inhibitor in combination with chemotherapy for adults with newly diagnosed Ph+ ALL.

Abstract

Importance  In newly diagnosed Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL), disease progression due to acquired resistance to first- or second-generation BCR::ABL1 tyrosine kinase inhibitors is common. Ponatinib inhibits BCR::ABL1 and all single-mutation variants, including T315I.

Objective  To compare frontline ponatinib vs imatinib in adults with newly diagnosed Ph+ ALL.

Design, Setting, and Participants  Global registrational, phase 3, open-label trial in adults aged 18 years or older with newly diagnosed Ph+ ALL. From January 2019 to May 2022, eligible patients at 77 sites were randomized 2:1 to ponatinib (30 mg/d) or imatinib (600 mg/d) with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after the cycle 20 phase of the trial. The last date of follow-up for this analysis was August 12, 2022.

Intervention  Patients received ponatinib, 30 mg/d, or imatinib, 600 mg/d, with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after cycle 20. The ponatinib dose was reduced to 15 mg on achievement of minimal residual disease–(MRD) negative complete remission.

Main Outcomes and Measures  The primary end point of this interim analysis was MRD-negative complete remission (≤0.01% BCR::ABL1 [MR4] centrally assessed by reverse transcriptase–quantitative polymerase chain reaction), with complete remission maintained for at least 4 weeks at the end of cycle 3. The key secondary end point was event-free survival.

Results  Of 245 patients randomized (median age, 54 years; 133 [54.3%] female), 232 (ponatinib, n = 154; imatinib, n = 78) who had p190 or p210 dominant isoforms verified by the central laboratory were analyzed for the primary end point. The MRD-negative complete remission rate (primary end point) was significantly higher with ponatinib (34.4% [53/154]) vs imatinib (16.7% [13/78]) (risk difference, 0.18 [95% CI, 0.06-0.29]; P = .002). At the data cutoff, event-free survival had not met the prespecified number of events. Median event-free survival was not reached in the ponatinib group and was 29 months in the imatinib group. The most common adverse events were similar between treatment groups. Arterial occlusive events were infrequent and comparable between groups (ponatinib, 2.5%; imatinib, 1.2%).

Conclusions and Relevance  Ponatinib demonstrated a superior rate of MRD-negative complete remission at the end of induction vs imatinib when combined with reduced-intensity chemotherapy in adults with newly diagnosed Ph+ ALL. The safety profile of ponatinib was comparable with imatinib.

Phase II study of dovitinib in patients with metastatic and/or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib.

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This prospective, phase II trial evaluated the efficacy and safety of dovitinib in patients with metastatic and/or unresectable gastrointestinal stromal tumours (GISTs) after failure of at least imatinib and sunitinib.

methods:

Patients received oral dovitinib, 500 mg once daily, for 5 consecutive days, followed by a 2-day rest, every 28 days. The primary endpoint was disease control rate (DCR; objective response+stable disease (SD)) at 24 weeks, assessed by computed tomography (CT) scan according to RECIST v1.0. Metabolic response was evaluated by positron emission tomography (PET)–CT scans performed at baseline and after 4 weeks of treatment.

results:

Between September 2011 and April 2012, 30 patients were enroled. DCR at 24 weeks by RECIST v1.0 was 13% and one patient (3%) had a partial response. Based on the European Organization for Research and Treatment of Cancer PET response criteria, four patients (13%) had a metabolic partial response after 4 weeks of treatment. At a median follow-up of 8.3 months (range, 6.3–12.2 months), median progression-free survival (PFS) was 3.6 months (95% confidence interval (CI), 3.5–3.7 months) and median overall survival was 9.7 months (95% CI, 6.0–13.4 months). Metabolic progressive disease at Week 4 was significantly associated with shorter PFS (P=0.03). Grade 3/4 adverse events included asthenia (20%), neutropenia (13%), thrombocytopenia (10%), and hypertriglyceridaemia (10%). Most toxicities were manageable by dose modification.

conclusion:

Dovitinib showed modest antitumour activity with manageable toxicities in heavily pretreated patients with advanced GISTs.

Source: BJC

 

 

Do we need tougher drug patent laws?

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History has witnessed numerous drug patent wars, but in April 2013, the Indian Supreme Court did something which captured the attention of the international media. It denied a patent to the beta crystalline form of Imatinib mesylate, a life saving anticancer drug, to the Swiss pharmaceutical company Novartis. The verdict was noteworthy because this drug is patented in more than 38 countries including the US, Russia, and China. Today this drug is being manufactured by generic drug companies in India. Is this a victory against the monopoly of pharmaceutical giants, or has India set a dangerous precedent which will discourage the innovation of future drugs?

As a researcher myself, I understand the importance of patent protection for any intellectual property. Patents give exclusive rights to the innovators for a limited period of time which acts as an incentive for future research and development (R&D). According to estimates, a company spends between US$ 500 million to US$ 2 billion for the discovery, research, testing, and marketing of a new drug. [1] In addition, patents encourage innovators to make their discoveries available for public use.

So why did the court rule against these relevant arguments?

Patentability of a product relies heavily on its novelty. The court argued that the product was not unique, but merely a tweaked version of an already known compound, noting that Imatinib was patented in many countries in 1996. Many researchers are making similar observations about other pharmacological agents and accusing the companies of “evergreening,” a practice which enables them to claim a new patent by slightly modifying the chemical composition of a known drug. Recently an article in the BMJ pointed out that about 85-90% of all new drugs since the mid 90s provide few or no clinical advantages for patients. [2] Even Brian Druker, who developed the beta version of Imatinib, believes in the need for novel, and not just modified drugs.

After the court’s decision, Novartis said it would pull out all R&D investments from India. It should be noted that India has never been a home to new drug discoveries as its priority is to provide cheap medicines to as many people possible. In other words, India has a different role to play in the pharmaceutical industry. India is a major market for manufacturing drugs in their generic form and providing them cheaply to patients in India as well as in other developing and poor countries. For instance, a 400mg pill of the drug in question is being manufactured by Novartis at US$99 each and the same by a generic drug manufacturer at a cost of around US$9. [3] No wonder Médecins Sans Frontières and other charitable health organisations hailed the court’s decision. This brings us to the question of affordability. 81% of the Indians live on less than US$2.5 a day. Predatory pricing and a market monopoly will make healthcare costlier for those living in the developing world as well as for those struggling in the developed. We do not want life saving drugs to be luxury goods.

It has been argued that stricter patent laws will encourage innovation. This is true to some extent as innovators will then be forced to push their limits to develop novel and better products. But we cannot afford to overstretch the strings. If the innovators are denied of their deserved rights and royalties, the intent to discover and invent will die. Some suggested that pharmaceutical companies should act morally and take into account the economic condition of the country they are selling in before pricing their products.

Coming back to our initial question: do we need tougher drug patent laws? There is no simple answer to this. Patients’ interests come first and they must be provided with the best medicines at an affordable price but we also need to incentivise the innovative thinking. A consensus on this patent vs patient issue can only be achieved by debate and discussion.

Source: BMJ

FDA Approves New Drug to Treat Chronic Myelogenous Leukemia.

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The Food and Drug Administration has approved bosutinib (Bosulif) to treat chronic myelogenous leukemia (CML), a blood and bone marrow disease that usually affects older adults. Bosutinib is intended for patients with chronic, accelerated, or blast phase Philadelphia chromosome-positive CML who are resistant to or who cannot tolerate other therapies, including imatinib (Gleevec).

Most people with CML have a chromosomal aberration called the Philadelphia chromosome, which causes the bone marrow to make an abnormal tyrosine kinase enzyme called Bcr-Abl. This enzyme promotes the proliferation of abnormal and unhealthy infection-fighting white blood cells called granulocytes. Bosutinib is a tyrosine kinase inhibitor (TKI) that works by blocking Bcr-Abl signaling.

Bosutinib’s safety and effectiveness were evaluated in a clinical trial involving 546 adults with chronic, accelerated, or blast phase CML. All of the patients had been previously treated with at least one TKI, either imatinib or imatinib followed by dasatinib (Sprycel) and/or nilotinib (Tasigna).

Among patients with chronic phase CML, 34 percent of patients who had been treated previously with imatinib and 27 percent of those who received more than one prior TKI achieved a major cytogenetic response within 24 weeks.

Among patients with accelerated phase CML who had received at least one prior TKI, 30 percent had their blood counts return to the normal range (a complete hematologic response) by week 48, and 55 percent achieved a complete hematologic response, no evidence of leukemia, or return to chronic phase (an overall hematologic response) by week 48. Among patients with blast phase CML who had received at least one prior TKI, 15 percent had a complete hematologic response and 28 percent an overall hematologic response by week 48.

The most common side effects observed in those receiving bosutinib were diarrhea, nausea, a low level of platelets in the blood, vomiting, abdominal pain, rash, anemia, fever, and fatigue.

Source: NCI

 

Assessment of antiangiogenic effect of imatinib mesylate on vestibular schwannoma tumors using in vivo corneal angiogenesis assay.

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Angiogenesis and the platelet-derived growth factor (PDGF) pathway are active in the pathogenesis of vestibular schwannomas (VSs). The purpose of this study was to test whether imatinib mesylate (Gleevec), a PDGF receptor (PDGFR) blocker, reduces angiogenic capacity in sporadic VS and in VS associated with neurofibromatosis Type 2 (NF2) using a corneal angiogenesis assay.

Methods

From 121 VS tissue samples stored in the tumor bank at the Marmara University Institute of Neurological Sciences, 10 samples (6 from sporadic cases, 4 from NF2-associated cases) were selected at random for use in this study. Expression of PDGF-A and PDGF-B and their receptors was evaluated in sporadic and NF2-associated VS as well as in glioblastoma (GBM) and normal brain tissue by means of immunohistochemistry and Western blot analysis. Corneal angiogenesis assay was then used to evaluate the angiogenic capacity of tissue specimens from sporadic and NF2-associated VS with and without imatinib treatment as well as positive and negative controls (GBM and normal brain tissue).

Results

The angiogenic potential of the sporadic and NF2-associated VS tumor tissue differed significantly from that of the positive and negative control tissues (p <0.05). Furthermore, NF2-associated VS showed significantly lower angiogenic potential than sporadic VS (p <0.05). Imatinib treatment significantly reduced the angiogenic potential in both the sporadic VS and the NF2-associated VS groups. The level of PDGF-A and PDGFR-α as well as PDGF-B and PDGFR-β expression in sporadic VS and NF2-associated VS also differed significantly (p <0.05) from the levels in controls. Additionally the level of PDGFR-β was significantly higher in sporadic VS than in NF2-associated VS (p <0.05).

Conclusions

The findings of this study indicate that NF2-associated VS has significantly more angiogenic potential than sporadic VS and normal brain tissue. Additionally, imatinib reduces the angiogenic activity of both sporadic and NF2-associated VS. The authors conclude that imatinib may be a potential treatment for VS, especially for NF2-associated lesions that cannot be cured with resection or radiosurgery.

Source: Journal of Neurosurgery.

GIST patients taking Novartis drug Glivec .

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Study in JAMA reports significant survival benefit in certain GIST patients taking Novartis drug Glivec® for three years after surgery

 

  • First large Phase III study to demonstrate significant survival benefits of extending treatment with Glivec for three years compared to one year following surgery
  • Important finding for treatment of KIT+ GIST patients who are at risk of recurrence following complete resection of primary tumor
  • Publication follows European Commission approval of new label based on these data

 

The Journal of the American Medical Association (JAMA) today published a Phase III study that showed significant survival benefits for patients meeting the study inclusion criteria who received three years of treatment with Glivec® (imatinib)[1] after surgery to remove KIT (CD117)-positive gastrointestinal stromal tumors (KIT+ GIST) compared to one year of treatment[1]. The study results were first presented at the 47th Annual Meeting of the American Society of Clinical Oncology (ASCO) plenary session in June 2011[2].

 

Gastrointestinal stromal tumors are a rare, life-threatening cancer of the gastrointestinal tract. The major cause of GIST is an abnormal form of the protein KIT which causes cells to grow uncontrollably and become cancerous[3]. Patients with GIST are at risk of recurrence following complete resection of primary GIST[4].

 

According to data published in JAMA from this international, multicenter, open-label Phase III clinical trial, at five years, 66% of patients taking Glivec for three years after surgery for KIT+ GIST remained free of recurrence (RFS) compared to 48% who had received Glivec for only one year after surgery (p<0.001; HR 0.46, 95% CI 0.32-0.65). In addition, at five years, 92% of patients taking Glivec for three years after surgery were alive (OS) compared to 82% who had received Glivec for only one year after surgery (p=0.02; HR 0.45, 95% CI 0.22-0.89). Four hundred patients entered the study. Median patient follow-up was 54 months[1].

 

Based on this data, in February 2012, the European Commission approved an update to the Glivec label to include three years of treatment after surgery for adults with KIT+ GIST.

 

“This study shows a significant recurrence-free survival benefit in adults with KIT+ GIST from adjuvant treatment with Glivec and provides important evidence to inform the clinical care of these patients after surgery,” said Heikki Joensuu, M.D., Ph.D., Professor, Oncology, University of Helsinki. “These data are likely to result in a new standard of care for these patients.”

 

About the SSG Phase III trial

This multicenter, prospective, randomized study for the evaluation of adjuvant treatment with Glivec of histologically confirmed KIT+ GIST was conducted by the Scandinavian Sarcoma Group (SSG) and the Sarcoma Group of the Arbeitsgemeinschaft Internistische Onkologie (AIO)[5]. The primary endpoint was to compare, within the first five years, recurrence-free survival in patients with a greater than 50% estimated risk of GIST disease recurrence, following diagnosis and treatment with adjuvant Glivec for either 12 or 36 months. The secondary endpoints included overall survival and treatment safety[2].

 

Inclusion criteria for risk of recurrence was defined as tumor diameter >5.0 cm and mitotic count >5/50 high power fields (HPFs); or tumor diameter >10.0 cm; or tumor of any size with a mitotic count >10/50 HPFs; or tumors ruptured into the peritoneal cavity.

 

Almost all patients experienced side effects while taking Glivec. Glivec was generally well tolerated. The proportion of patients who discontinued Glivec during the assigned treatment period for reasons other than GIST recurrence was 25.8% in the 36-month group and 13% in the 12-month group[2].

 

Novartis provided the study drug and supported the study financially. Additional funding was received from the Academy of Finland, Cancer Society of Finland, Sigrid Juselius Foundation and Helsinki University Research Funds.

 

About Glivec (imatinib)

Glivec® (imatinib) is approved in more than 110 countries for the treatment of all phases of Ph+ CML, for the treatment of adult patients with KIT (CD117)-positive gastrointestinal stromal tumors (GIST), which cannot be surgically removed and/or have metastasized and for the treatment of adult patients following complete surgical removal of KIT+ GIST.

Source: Novartis Release.