Renewed hope with an alternative to chemotherapy
Innovative cancer therapy, LORVIQUA, targets mutations in the brain which first and second-line TKIs have failed to treat.
SINGAPORE | 25 November 2019
The discovery of Anaplastic lymphoma kinase (ALK) gene rearrangements in 2007 had prompted a decade of breakneck development of precision oncology-based oral inhibitors, classified as ALK tyrosine kinase inhibitors (TKIs). Anaplastic lymphoma kinase (ALK) gene rearrangements, ALK overexpression and ALK gene amplification are all forms of ALK mutations which cause cells to grow and divide in an uncontrolled manner. ALK-TKIs works by targeting and blocking excessive growth signals released by ALK receptors on the cell surface, effectively curbing uncontrolled cell multiplication.
In August 2011, the US Food and Drug Administration (FDA) approved the very first ALK-TKI therapy, crizotinib. With a response rate of 74 percent and duration of progression-free survival averaging 10.9 months, it was quickly confirmed to be suitable for commercial use as an evidence-based first-line TKI therapy. Subsequently, more potent second-line ALK-TKIs were gradually introduced into the market – namely ceritinib, alectinib and brigatinib.
While these treatments are indeed superior to traditional pemetrexed platinum doublet chemotherapy, there also presented a few drawbacks. ALK-TKIs block abnormal ALK receptors where they appear in largest numbers—in cancer cells—but they may also affect normal cells which have many ALK receptors, leading to a variety of complications. Compounding the problem, despite the body’s initial dramatic responses to ALK inhibitors, the majority of patients relapse within 1 year, owing to the development of acquired drug resistance.
“Common challenges associated with treating ALK-positive lung cancer, including resistance and the spread of cancer to the brain, have created a need for newer treatment options.” Said Dr Ross Soo, Senior Consultant, Department of Hematology-Oncology, National University Cancer Institute, Singapore.
In response to this unmet need in ALK-Positive lung cancer patients, Pfizer, an American multinational pharmaceutical corporation, has developed a new third-line therapy, specifically developed to target mutations that have recurred after first- and second- line ALK-TKI treatments. This breakthrough therapy, LORVIQUA, is taken orally once daily, and is a safe and effective alternative to chemotherapy.
Monitoring the long-lasting effects and trends of ALK-TKIs on ALK-positive lung cancer patients was crucial to ensuring the effectiveness of LORVIQUA. As a third-line treatment, it has the highest toxicity of all three lines of treatment, and it was vital to ensure that the potency of the treatment was being directed towards the correct source. Multiple studies have shown that disease progression of ALK-positive lung cancer was inevitable and likely to spread to the brain. As such, LORVIQUA has been engineered to be capable of penetrating dense brain tissues to target cancerous growths in the brain, providing patients with a highly targeted treatment option.
Using up-to-date computer software, Pfizer’s scientists were able to synthetise the intricate molecular structure of LORVIQUA through a drug designing process. This unique external configuration of LORVIQUA would enable it to target the widest spectrum of secondary ALK resistant mutations that have arised from previous treatments. “Controlling brain metastasis is especially challenging in ALK-positive lung cancer. This new therapy has shown excellent intracranial responses and it addresses an unmet need in this patient population.” Said Dr Tanujaa Rajasekaran, Consultant, Division of Medical Oncology, National Cancer Centre Singapore.
LORVIQUA’s effectiveness as a third-line ALK-TKI therapy was put to the test in a multinational Phase 2 study. The results of the study showed that nearly 50 percent of the patients treated with LORVIQUA experienced at least a partial or a complete shrinkage of their tumours. Additionally, the patients showed significant improvements in physical and psychological wellbeing, including reduced lung cancer symptoms.
Recognising the immense potential of LORVIQUA in revolutionising ALK-Positive lung cancer treatment, the United States Food and Drug Administration (FDA) granted LORVIQUA under the FDA Accelerated Approval Programme in 2018. A year later, on 25 November 2019, Pfizer announced that the Health Sciences Authority (HSA) had also granted LORVIQUA with the coveted stamp of approval.
Currently, Pfizer’s ongoing study aims to explore the possibilities of LORVIQUA as an option for first-line treatment, through comparing the effects of LORVUIQUA and crizotinib in ALK-positive lung cancer patients who have yet to receive any form of ALK-TKI treatment.
Moving forward, LORVIQUA will undergo a Phase 3 CROWN study which will involve randomized and blind testing in several hundred to several thousand patients. This would allow Pfizer researchers to gain a more thorough understanding of the effectiveness of LORVIQUA, as well as the benefits and the range of possible adverse reactions to the drug.
“Through our growing research pipeline and collaboration efforts, we are committed to pioneer new therapies to address unmet needs. LORVIQUA’s approval in Singapore offers new hope to patients who may not have other treatment options after second-generation ALK-TKIs. We hope that more patients can benefit from this innovative therapy,” said Enver Erkan, Country Manager, Pfizer Singapore.
This article was contributed by Michelle Tan Min Shuen, an editorial intern at World Scientific Publishing Co. and a contributing writer for Asia-Pacific Biotech News. She is from Nanyang Girls' High School, has a keen interest in chemistry and the life sciences, and pursues taekwondo in her free time.