Debu Tripathy, M.D.

In this issue of CURE, we examine the science behind bispecific antibodies such as Tecvayli (teclistamab-cqyv) — how they work and the impact they have had on patients with multiple myeloma.

Those patients include Cindy Brown, who in 2020 joined a clinical trial at the City of Hope Comprehensive Cancer Center in Los Angeles for Tecvayli, an immunotherapy drug that targets a protein called B-cell maturation antigen, or BCMA, found specifically on multiple myeloma cells. Tecvayli activates a patient’s immune system by binding to the CD3 receptor on T cells and the BCMA protein on myeloma cells. Bispecific antibodies act as a bridge and can bring cells or proteins on the cell membrane together to facilitate certain processes like triggering the immune system.

Therapies such as Tecvayli offer providers a targeted approach, honing in on cancer cells while sparing healthy tissues with the goals of fewer side effects and better outcomes for patients. With the FDA approval of Tecvayli and other BCMA-targeted therapies like Elrexfio (elranatamab-bcmm), a new era in multiple myeloma treatment has arrived.

However, questions persist regarding the optimal timing and sequencing of these therapies, as well as potential mechanisms of resistance and long-term management strategies. Ongoing research continues to examine these complexities, pointing the way toward potential future breakthroughs and treatment options.

More CURE® coverage on multiple myeloma:

Early Intro to Carvykti Is 'Promising' for Patients With Myeloma

Linvoseltamab to Be Reviewed for Relapsed, Refractory Myeloma

FDA Approves Dosing Reduction of Tecvayli in Relapsed, Refractory Myeloma

Blenrep Combo for Relapsed, Refractory Myeloma Improves Outcomes

Newer technologies can speed up innovations needed to refine this approach, and the next generation of drugs are likely to be even more powerful and applicable to a growing list of cancer types.

Cindy’s story is illustrative of the impact that immunotherapy has had in transforming the lives of patients with cancer.

“It’s been remarkable for me in terms of success. It’s super well-tolerated,” Brown says. “If you met me and didn’t know who I was, you would have no idea I was sick.”

Professor of Medicine Chair, Department of Breast Medical Oncology

The University of Texas MD Anderson Cancer Center

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Articles

Here is a run-down of some topics we covered in the Spring 2024 issue of CURE.

The Impact of Immunotherapy on Multiple Myeloma

In this special issue of CURE, we examine some of the latest developments in the treatment of ALK-positive non-small cell lung cancer (NSCLC). This subtype of lung cancer, representing about 5% of NSCLC diagnoses, is characterized by a fusion of the anaplastic lymphoma kinase, or ALK gene, and has seen impressive advancements in recent years. Since the protein encoded by the ALK fusion gene is unique to the cancer cells, it can be targeted specifically with drugs that inhibit its enzymatic activity.

There are approximately 10,000 new cases of ALK-positive NSCLC each year, with an average survival of seven years and approximately 70,0000 patients with the disease currently living in the United States. And, there are between 90 and 100 clinical trials in the United States and the European Union allowing patients with ALK-positive NSCLC, Dr. Ken Culver, director of research and clinical affairs for ALK Positive, tells CURE.

Alecensa (alectinib) was initially approved by the Food and Drug Administration in 2015 for the treatment of ALK-positive NSCLC that had metastasized, or spread to other areas of the body, and progressed on targeted therapy Xalkori (crizotinib). Findings from the phase 3 ALINA trial have shown that treatment with Alecensa reduced the risk of death or disease recurrence by 76% when compared with platinum-based chemotherapy in patients with stage 1B to 3A ALK-positive NSCLC.

More CURE® coverage of ALK-positive NSCLC:

Phase 2 Trial Assessing Novel TKI Begins in ALK-Positive NSCLC, Solid Tumors

FDA Grants Priority Review for Alecensa in Some ALK-Positive NSCLC

Iruplinkalkib Reduced Risk of Progression, Death in ALK-Positive NSCLC

Alecensa Reduces Recurrence, Mortality Risk in Lung Cancer Subset

Other research has demonstrated a postsurgical benefit from Xalkori-based therapy among patients with operable disease, with authors of one retrospective study writing that their findings “confirmed the effective and feasible therapeutic approach of postoperative targeted therapy” for patients with ALK-positive NSCLC. Researchers are also calling for therapies to become even more specific in order to target subtypes of ALK-positive NSCLC.

“Finding those differences and leveraging the advantage is really key to the future,” says Dr. Stephen Liu of Georgetown University's Lombardi Comprehensive Cancer Center.

With advancements in ALK-targeting treatments making waves in the oncology world, patients are experiencing extended survival and improved outcomes. Research continues to propel progress forward, with ongoing clinical trials and novel treatments on the horizon.

As we navigate the complexities of cancer treatment and care, it is essential to recognize the integral role of research and innovation in driving progress. The field of oncology continually witnesses rapid evolution, offering new avenues of hope for patients and their loved ones. While challenges persist, so do creativity and the next generations of clinical trials and ultimately more successful options for patients.

Professor of Medicine Chair, Department of Breast Medical Oncology
The University of Texas MD Anderson Cancer Center

This special issue of CURE Lung Cancer takes a deeper dive into ALK-positive non-small cell lung cancer. 

Targeting ALK-Positive NSCLC

We are all used to shortages of a wide variety of commodities. They may seem more acute in recent times because of the sheer volume of materials being produced, shipped and consumed by the growing number of individuals joining the global economy. Coupled with more recent disruptions in supply chains due to worker shortages related to COVID-19, people leaving the workforce and myriad other factors, shortages can erupt and also resolve quickly. 

Cancer drugs are no exception to this phenomenon, despite their critical importance.

More CURE® coverage of the chemotherapy shortage:

Patients Respond to the Ongoing Chemo Drug Shortage

Here’s How One Cancer Center Is Handling the Chemo Shortage

Chemo Drug Shortage Requires a ‘Holistic Solution’

Expert Discusses Chemo Shortage: ‘Likely to Last’ 3 to 4 Months

Expert Identifies Chemo Shortage as a 'Simple Tragedy of US Health System’

Currently, the Food and Drug Administration (FDA) lists 119 drugs as being in short supply, including 25 cancer drugs, noting that definitions of shortages vary and that the degree of shortage can shift quickly. 

Among the notable drugs in short supply are the platinum-containing agents carboplatin and cisplatin — compounds that are able to bind to and crosslink DNA to inhibit its division and impede cell growth. The drugs are used for several cancer types and may not always be easily substituted. How do oncologists deal with chemotherapy drug shortages? General guidelines are being developed and modified, but they are based on several principles that include first looking for a substitute that is proven to yield somewhat equal therapeutic results. 

Also, doctors should prioritize a drug’s use in situations where the impact is greatest, such as offering a chance to cure a patient or increase their survival. There may be situations where dose or length of treatment modifications can be done safely — again, based on actual clinical data and not just conjecture. Many cancer centers and practices are adopting their own processes and guidelines for cancer drug shortages; patients may want to inquire about these with their care team if they are on treatment.

Additionally, the FDA has provisions that can be exercised in some situations, such as extending drug expiration dates — some of which are arbitrary — or when stability of the drug is known due to its chemical structure. Accelerat- ing approvals of new production lines or relaxing import rules for medicines that may be available elsewhere also may help. 

In addition, there is a focus on preventing or anticipating shortages. Companies are required to inform the FDA of impending production interruptions, issues that may affect availability or product integrity, and any disruption in shipping and distribution. Pharmacies and hospitals are also expected to maintain healthy inventories, while being aware of expiration dates.

Altogether, it is a shared responsibility by the pharmaceutical and health care industries to prevent, be prepared for and manage cancer drug shortages if and when they occur. The expansion of the cancer pharmaceutical/biotechnology sectors is reassuring not only in the sense that more effective and safer drugs are being developed, but that there may be more options if supplies become hampered.

Currently, the Food and Drug Administration lists 119 drugs as being in short supply, including 25 cancer drugs.

The Shared Responsibility to Prevent, Prepare For and Manage Drug Shortages

DNA mutations in tumors are sometimes known as driver mutations and when they alter proteins the encode can impart a cancer-like characteristic such as an accelerated growth rate, ability to invade and spread or resistance to cancer drug therapies. 

Many of these mutations, known to be present in certain tumors at the time of diagnosis, are termed truncal mutations, whereas others can be acquired over time — especially those that result in resistance to the drug the patient is taking. Drugs targeting the estrogen receptor (ER) have been a staple of the treatment of ER-positive breast cancer, which make up about 75% of all cases. 

Because estrogen can induce production of growth factors that spur tumor cell proliferation, ER overexpression is one of the shortest pathways to developing breast cancer.

Once these cancers are established, they are dependent on ER, so treatments that lower estrogen levels, such as aromatase inhibitors, are often effective initially. But cancer cells have a high mutation rate, so mutations that happen to be in the ESR1 gene and that allow ER to be activated in the absence of estrogen, so those cells continue to divide, taking over the tumor cell populations. 

ESR1 mutations are rarely present in untreated breast cancers (less than 1%), but after exposure to aromatase inhibitors, resistant tumors that progress and exhibit an ESR1 mutation becomes present in 40% of cases. The discovery of ESR1 mutations allowed scientists to develop a new class of drugs called oral selective estrogen receptor degraders (SERDs), some of which have been shown to be very effective against cancers harboring these alterations.

The first randomized trial completed compared a SERD known as Orserdu (elacestrant) to Faslodex (fulvestrant), an older SERD given by injection, and Orserdu was found to significantly improve progressionfree survival, particularly in cases with ESR1 mutations. As a result of these data, 

he drug was approved by the Food and Drug Administration

 on Jan. 27, 2023, specifically in the presence of this mutation after progression on endocrine therapy. 

This augurs in a new era for treating refractory hormonally driven breast cancer. Even newer ER-degrading drugs such as PROTACS (proteolysis targeting chimeras) are in early phases of testing and will offer an array of options that have fewer side effects than chemotherapy, which has been the long-standing option after resistance to hormonal therapies. There are many other examples of acquired mutations to cancer therapies involving other cancer-driving genes through a variety of mechanisms and this is facilitating the development of many new strategies that will continue to change the landscape of targeted therapeutics.

Professor of Medicine Chair, Department of Breast Medical Oncology 

The knowledge of DNA mutations continues to shape the way that breast cancer is treated. 

Debu Tripathy, M.D.

The Impact of Immunotherapy on Multiple Myeloma

Targeting ALK-Positive NSCLC

The Shared Responsibility to Prevent, Prepare For and Manage Drug Shortages

Changing the Landscape of Breast Cancer Care

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