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Oral Targeted Therapy For The Treatment Of Non–small Cell Lung Carcinoma

KEY POINTS

Targeted cancer therapies are a group of oral medications directed at tumours harbouring specific driver mutations that occur in a subset of patients with cancer.

Around one-third to one-half of patients with advanced non–small cell lung carcinoma may harbour an actionable mutation, which can be identified from molecular analysis of a biopsy or surgical specimen.

Patients treated with targeted therapy generally have better symptom control, response rates (i.E., shrinking tumours), and overall survival than those treated with conventional chemotherapy.

Targeted therapy is typically well tolerated and does not carry the same risks of emesis, alopecia, immunosuppression, and febrile neutropenia as chemotherapy.

Lung cancer is the leading cause of cancer-related death in Canada, with non–small cell lung carcinoma (NSCLC) making up 85% of cases.1 Lung cancer has been associated with a poor prognosis, particularly for patients with metastatic disease. Since Health Canada's initial approval of gefitinib in patients with advanced NSCLC in 2003, targeted therapies have emerged as an important treatment option for patients and are now widely used in clinical practice.

What is targeted therapy?

Targeted therapies are a group of personalized anti-cancer medications. While chemotherapy attacks all rapidly dividing cells, targeted therapies select for cancer cells that harbour specific genomic driver alterations. Driver alterations are the principal trigger of growth for cancer cells, and many of these driver alterations now have matched targeted therapies. About 30%–50% of patients with NSCLC harbour a tumour-driver alteration and about 50%–75% of these are targetable.2 The prevalence of specific driver alterations varies by patient age, degree of tobacco exposure, ethnicity, and histology.2

Small-molecule tyrosine kinase inhibitors are the most common type of targeted therapy used in the treatment of NSCLC, and they work by inhibiting tyrosine kinase enzymes. Tyrosine kinase enzymes are membrane-spanning proteins made up of an extracellular (ligand-binding domain) and an intracellular kinase domain. Under normal physiologic conditions, ligand binding of the extracellular domain results in phosphorylation of downstream proteins, leading to their activation in a highly regulated fashion. The presence of an activating oncogenic alteration causes the tyrosine kinase enzyme to become constitutively active (i.E., does not need ligand binding to be in the "on" position), which drives cancer cell growth and proliferation. Targeted therapies treat cancer by inhibiting these overactive tyrosine kinase enzymes. Practically, targeted therapies are oral medications that can be taken at home without the number of hospital attendances associated with intravenous therapies.

Who is eligible for targeted therapy?

To assess whether targeted therapy is a suitable option, patients must undergo molecular profiling of their tumour. Molecular testing can be performed on most biopsy specimens, often on the same sample used to make the initial histopathologic cancer diagnosis. In some instances, especially when the procurement of a biopsy is difficult, analysis of circulating tumour DNA in the patient's blood can also identify tumour-related gene alterations. Modern next-generation sequencing techniques can test for multiple alterations in parallel. Next-generation sequencing capacity has rapidly improved in Canada in recent years, although the turnaround time for molecular testing varies, with the ideal scenario being 1–2 weeks from biopsy to result. Figure 1 depicts the workflow in assessing candidacy for targeted therapy.

Figure 1:

A schematic depicting the workflow of assessing patients for and prescribing targeted therapy. (A) The patient undergoes a biopsy for histopathologic diagnosis of non–small cell lung carcinoma. (B) Tumour tissue is sent for molecular analysis. If a driver mutation is detected, the patient may be a candidate for a targeted agent. (C) The patient reviews the results with their oncologist and consents to targeted therapy. (D) The prescription can be filled at an outpatient pharmacy, and targeted therapy can be taken at home.

Molecular testing is performed reflexively (i.E., ordered by the pathologist) for newly diagnosed non-squamous lung cancers at most institutions, while others require a requisition from the oncologist. Many Canadian cancer centres offer in-house molecular testing, but others will send tissue samples externally for molecular analysis. All standard-of-care molecular testing can be performed in Canada.

What is the evidence of benefit?

Metastatic NSCLC is associated with poor clinical outcomes. Efficacy of cancer treatments is generally measured by response rates (proportion of patients with substantial tumour shrinkage), quality of life, and overall survival. Before the introduction of targeted therapy in the management of metastatic lung cancer, patients treated with chemotherapy had a median survival of less than 9 months, with response rates in the range of 25%–35%; only 10% of patients survived to the 2-year mark.3

Targeted therapy has improved outcomes tremendously, whereby most patients receiving a targeted drug have major tumour shrinkage, symptom improvement, and longer survival. 4 In the context of metastatic cancer, targeted therapies are given with palliative intent, with the goal improving quality of life and overall survival rather than to cure cancer. However, 2 targeted therapies, alectinib and osimertinib, have been shown to significantly decrease rates of recurrence when given as adjuvant treatment after surgery among patients with non-metastatic disease.5,6

Ten different alterations have been identified, treated with 20 effective targeted therapies (Table 1).7 Mutations in the epidermal growth factor receptor (EGFR) gene were initially discovered in 2004, and are the most common mutations identified in NSCLC. Among patients harbouring a classic EGFR mutation, osimertinib, an EGFR kinase inhibitor, approved by Health Canada for the treatment of non-metastatic NSCLC in 2021, has proven to be the optimal agent, with a median overall survival of 38.6 months, compared with 31.8 months for people receiving older generations of EGFR kinase inhibitors.8 Patients with metastatic NSCLC involving anaplastic lymphoma kinase (ALK) translocations have a 5-year survival rate of more than 60% when treated with alectinib, compared with 45.5% among those treated with crizotinib, the first ALK inhibitor approved.9 For patients with RET translocations treated with selpercatinib, 84% of patients had a major tumour shrinkage, with the response being durable for close to 2 years, although no comparator arm was used in this single-arm, phase 2 study.10 Figure 2 shows the radiographic response of a patient harbouring a RET mutation treated with selpercatinib. Targeted agents directed at KRAS, BRAF, MET, NTRK, ROS1, and HER2 have also shown meaningful clinical benefit, although in some cases, the data are too recent to report 5-year survival rates.2,4 Patients can receive targeted therapy at home with remarkable response rates and the ability to maintain quality of life and symptom control, in addition to better odds at long-term survival.11–13

Table 1:

List of Health Canada–approved targeted agents by the genes harbouring the sensitizing alteration7

Figure 2:

Axial computed tomography (CT) chest scans of a female patient in her late 80s, diagnosed with metastatic lung adenocarcinoma harbouring a RET rearrangement (ERC1 exon 17 to RET exon 12) treated with selpercatinib (A) at the time of diagnosis and (B) 9 months after starting therapy, showing radiographic response below the aortic arch.

The efficacy of targeted therapies is heterogeneous and varies depending on the specific drug and target protein. This results in variable magnitudes of benefit with regard to response rate, progression-free survival, and overall survival. Given the rarity of certain actionable mutations, many targeted agents have been studied only in single-arm, phase 2 clinical trials.

What are the harms?

Targeted therapies have more favourable adverse effect profiles than chemotherapy. Adverse effects are specific to the agent used and the protein being inhibited. They are usually mild and can typically be managed supportively. Table 2 provides an overview of adverse effects related to targeted therapy. If symptoms persist or affect a patient's quality of life or functionality, dose reductions are usually considered as the next step in management. Severe or life-threatening adverse effects are uncommon; thus, the risk–benefit balance for targeted therapies almost always favours treatment, unlike traditional cytotoxic chemotherapy. Unlike chemotherapy, targeted therapies do not cause notable immunosuppression and most patients presenting with fever can be managed as per routine clinical practice. Most targeted agents require regular blood work to monitor blood counts and electrolytes, as well as kidney and liver function. Some agents may require cardiac testing (e.G., electrocardiography, echocardiography). This monitoring is typically organized by the patient's oncologist.

Table 2:

Adverse effects related to targeted therapy classes, grouped by their target gene*

What are the resource implications and how is targeted therapy accessed?

Targeted therapies are usually more costly than chemotherapy and sometimes more than immunotherapy. Using estimates from wholesale prices in the United States, the average cost of targeted therapy is US$5000–US$10 000 monthly. Treatments are usually continuous until signs of cancer progression in the metastatic setting. 14,15 However, costs vary considerably between agents, and are much lower in Canada than the list price as the prices paid by provinces are heavily discounted based on negotiation by the pan-Canadian Pharmaceutical Alliance, although these negotiated prices are not publicly available. In general, the costs of targeted therapies are likely to decrease as more agents expire from patent and become available as generic medications.

Interprovincial differences to access these drugs exist, leading to disparities across Canada. For instance, oral cancer drugs are funded the same way as intravenous drugs in some provinces (e.G., British Columbia), but through different pathways in other provinces (e.G., Ontario). Accessing therapies when they are not provincially funded is challenging. Options include public or private insurance, private pay, and compassionate access or co-pay programs through pharmaceutical companies.

What can be expected in the future?

Targeted therapy is the standard of care for patients with metastatic NSCLC driven by alterations in select oncogenes. In the future, these agents are likely to be used in earlier stages of disease with the aim of improving cure rates. Further expansion of targeted therapies will be observed as molecular testing becomes part of routine practice, as more patients with targetable mutations will be identified. More targetable alterations are being discovered. From the first mutation (EGFR) in 2004, to the second (ALK fusion) in 2009, 10 alterations have been identified, with other candidates in discovery. In addition, as mechanisms of resistance to targeted therapies are better understood, new agents are being developed that target resistant cancer cell clones.

Acknowledgement

The authors acknowledge Joshua Belair for assistance in preparing Figure 1.

Footnotes

Competing interests: Natasha Leighl reports research funding or materials from Amgen, AstraZeneca, Eli Lilly, EMD Serono, Guardant Health, Inivata, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda; honoraria from BeiGene, Bristol Myers Squibb, Janssen, Merck, Novartis, and Takeda; travel support from AstraZeneca, Merck Sharp & Dohme, Roche, Janssen, Sanofi, and Guardant Health; and participation on data safety monitoring boards for Mirati and Daichii Sankyo. Normand Blais reports honoraria from Amgen, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Eli Lilly, EMD Serono, Ipsen, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, Servier, and Takeda. Paul Wheatley-Price reports consulting fees or honoraria from Merck, AstraZeneca, Roche, Bristol Myers Squibb, Amgen, Lilly, Novartis, Sanofi, Pfizer, GSK, Janssen, SteriMax, Bayer, and Daiichi Sankyo. He participated on data safety monitoring board for the REaCT-HER TIME and POISE trials, and is a past president and current board member with Lung Cancer Canada. No other competing interests were declared.

This article has been peer reviewed.

For a patient perspective on targeted cancer therapy, see www.Cmaj.Ca/lookup/doi/10.1503/cmaj.240465

The authors have obtained patient consent.

Contributors: All of the authors contributed to the conception and design of the work, drafted the manuscript, revised it critically for important intellectual content, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is noncommercial (i.E., research or educational use), and no modifications or adaptations are made. See: https://creativecommons.Org/licenses/by-nc-nd/4.0/

Reformulating A Novel Therapeutic For Lung Cancer

The outlook is grim for those suffering from the most common form of lung cancer. Most patients survive for only four to five months with palliative care, having been diagnosed too late for chemotherapy or targeted treatment, and those who do receive treatment often suffer from deleterious effects including nausea, wasting and delirium. There is clearly a high unmet need for a therapeutic that can help these people.

Enter ValiSeek's VAL401, a repurposed treatment for lung and other cancers that is poised to meet this challenge. With a unique mechanism of action, decades of data supporting its safe use, and preclinical proof of effectiveness, the drug is set to help patients with non-small-cell lung cancer (NSCLC) and address a multi-billion-dollar market.

VAL401 is a reformulation of Risperdal (risperidone), an antipsychotic used since 1993 as a first-line treatment for chizophrenia and bipolar disorder. Work carried out by scientists at Warwick University ultimately led to the discovery that Risperdal inhibits HSD10 (hydroxysteroid dehydrogenase type 10), an enzyme involved in the processing of steroids and fats. While normally located in the mitochondria, HSD10 is overexpressed (approximately tenfold) in cancer cells, where it is also accessible from the cytoplasm. Inhibition of HSD10 disrupts cancer energy metabolism, thereby breaking the cancer cell cycle.

Although Risperdal has no anticancer effects when administered alone, its anticancer activity is switched on when it is combined in a 1:1 ratio with rumenic acid (a nutritional supplement derived from safflower oil). "Acting as a functional excipient, rumenic acid is essential for delivery of risperidone into tumor cells for activity," said Suzanne Dilly, CEO of ValiSeek, which was established in 2014 to develop the novel cancer therapeutic.

ValiSeek has combined the ingredient risperidone and rumenic acid in a patent-protected gelatin-capsule formulation, VAL401, for oral delivery. The drug reduces cellular activity in many different cancer cell lines, including prostate, pancreatic, lung and breast adenocarcinomas. VAL401 has also demonstrated preclinical efficacy in lung, prostate and pancreatic models, slowing tumor growth by at least 50% and significantly improving survival. "VAL401 has a unique mechanism of action—different to that of current cancer treatments—so cross-resistance is unlikely," added Dilly, who is also the CEO of Tangent Reprofiling, whichformed ValiSeek as a joint venture with ValiRx.

Figure 1: Diagram of the phase 2 clinical trial outcomes scheme

Having progressed VAL401 through preclinical development, ValiSeek is currently testing VAL401 in a small-scale phase 2b trial involving 20 patients with very late-stage NSCLC for whom chemotherapy has failed (Fig 1). The single-arm, open-label study is assessing progression-free survival, quality of life and overall survival of patients, as well as recording the pharmacokinetics, drug metabolism, safety and tolerability of the drug in comparison to historical clinical records for Risperdal.

Given Risperdal's record under its currently approved usage, treatment with VAL401 is expected to provide significant improvements in quality of life for cancer patients. Among these secondary benefits are the potential to counteract wasting, delirium caused by chemotherapy, and opioid-induced nausea. "One of the main measures we are looking at is quality of life; a meaningful improvement would be very attractive for these late-stage cancer patients," said Dilly.

Complete trial results are expected by the end of 2017. Pharmacokinetic data so far suggest no difference relative to conventional usage, and patients are tolerating the treatment well.

As an antipsychotic, Risperdal is typically taken for at least two years, and it has a well-established safety record derived from decades of clinical use. The equivalent dose of Risperdal in VAL401 (up to 10 mg daily) is within the range licensed as safe and tolerable for neural use with minimal side effects; preclinical toxicology has revealed no side effects beyond those expected from Risperdal, with preclinical pharmacokinetic data allowing for bridging from VAL401 to the historical full clinical data package on Risperdal. "VAL401 will provide a potential cancer treatment with a good safety profile, with a clear route to market supported scientifically by the extensive history of the drug's use, yet protected commercially by the detail of the reformulation," said Dilly.

With the active pharmaceutical ingredient readily available, manufacturing of VAL401 is relatively simple and, at $1,000 per patient per year, inexpensive. (Second-line therapeutics currently on the market for NSCLC sell for about $33,000 to $50,000 per annum.)

ValiSeek is keen to discuss acquisition proposals and is also looking for licensing partners with the resources to fully exploit VAL401 and move it through the clinic and quickly to market on a disease-specific and/or geographical basis. Advanced NSCLC—which accounts for over 80% of all lung cancer cases—is the lead indication, and represents a worldwide market projected to increase from $5.1 billion in 2013 to $7.9 billion in 2020. Although the drug was initially a second-line therapy, its label could potentially be expanded to include first-line, maintenance and combination therapies, further increasing the market.

Additional codevelopment opportunities are also available for any adenocarcinoma, particularly pancreatic and prostate cancers—markets worth around about $1.2 billion (2015) and $18.6 billion (2017), respectively, and for which there is also high unmet need. The historical data on Risperdal minimize the need for safety and tolerability clinical trials, and thus provide a swift path to efficacy trials in cancer patients.

"Our reformulation allows risperidone to access previously unexploited anticancer activity, offering patients treatment without devastating side effects," said Dilly. "VAL401 is safe and tolerable, has efficacy against various cancers, and is simple and cheap to manufacture with an abbreviated route to market."

Emerging Biomarkers And Tumor Heterogeneity Lead The Way In Lung Cancer

Trials in small cell lung cancer and non–small cell lung cancer are fueling excitement in the oncology community.

Ongoing clinical trials in small cell lung cancer (SCLC) and non–small cell lung cancer (NSCLC) are fueling excitement in the oncology community with research efforts focusing on understanding the biology and heterogeneity of SCLC, and FDA approvals in 2024 in the NSCLC setting. Anne Chiang, MD, PhD, a faculty member at the 25th Annual International Lung Cancer Congress®, sponsored by Physicians' Education Resource (PER®), LLC, addressed a number of practice-changing trials and regulatory updates in the lung cancer setting, ahead of the conference from July 25 to 27, 2024, in Huntington Beach, California. "We're starting to understand more about the biology, heterogeneity, and molecular subtypes of SCLC disease that we can potentially exploit," Chiang, an associate professor and associate cancer center director, clinical initiatives, at the Yale School of Medicine in New Haven, Connecticut, told Targeted Therapies in Oncology, during an interview ahead of the conference.

SCLC Setting

In the SCLC setting, Chiang highlighted the findings1 from Carl M. Gay, MD, PhD, and colleagues, who looked at patterns of 4 SCLC subtypes that were defined by the transcription factors ASCL1, NEUROD1, and POU2F3 or low expression of all 3 transcription factor signatures accompanied by an inflamed gene signature (SCLC-A, N, P, and I, respectively).1 The researchers noted that SCLC-I demonstrated greater benefit when immunotherapy was added to chemotherapy, whereas the other subtypes had distinct shortcomings.

These investigators validated these subtypes using RNA sequencing from treatment-naive patients enrolled in the phase 3 IMpower133 trial (NCT02763579).2 Results from IMpower133 demonstrated that patients who received atezolizumab (Tecentriq), carboplatin, and etoposide had a median overall survival of 12.3 months compared with 10.3 months in the control group.3 Progression-free survival (PFS) was also statistically improved at 5.2 months in the experimental arm compared with 4.3 months in the control arm.3 In the trial, patients received atezolizumab plus carboplatin and etoposide (n = 201) or placebo plus carboplatin and etoposide (n = 202).

The median follow-up for overall survival (OS) was 22.9 months, with 302 deaths reported. Median OS was 12.3 and 10.3 months with atezolizumab plus carboplatin and etoposide and placebo plus carboplatin/etoposide, respectively (HR, 0.76; 95% CI, 0.60-0.95; P = .0154).4

Another biomarker that appears promising is the Schlafen 11 (SLFN11) gene, said Chiang. Findings from the phase 2 S1929 trial conducted by the SWOG Cancer Research Network and presented at the 2023 American Society of Clinical Oncology Annual Meeting showed more improvement in PFS in patients with SLFN11- expressing SCLC who received atezolizumab plus talazoparib (Talzenna) than in patients who received atezolizumab alone.5

"As we gain more information, we'll hopefully disprove the myth that small cell lung cancer is a disease with 1 treatment approach," Chiang said. "We need to understand better the heterogeneity associated with SCLC in order to use a targeted approach."

To further our understanding, Chiang recommends talking to the pulmonary team to make sure tissue samples of SCLC tumors are adequate, as sometimes only a limited sample of tissue is obtained by f ine needle aspirate, even though SCLC is characterized by bulky disease. She noted that in NSCLC, adequate tissue samples are needed to determine PD-L1 status for treatment decisions. "If there were a tissue requirement [for SCLC], I think we'd be able to push the field forward."

Four Approvals

In the early months of 2024, the FDA approved 4 agents in the NSCLC setting: tepotinib (Tepmetko) in patients with MET exon 14 skipping alterations,6 osimertinib (Tagrisso) plus chemotherapy based on the FLAURA2 (NCT04035486) data,7 amivantamab-vmjw (Rybrevant) plus chemotherapy in patients with exon 20 insertion mutation–positive NSCLC,8 and alectinib (Alecensa) as an adjuvant treatment for ALK-positive NSCLC.9

"What an exciting year," Chiang said. In her practice, Chiang has had positive experiences using tepotinib. "It's a great agent for our patients, but we still need to manage adverse events such as peripheral edema and pleural effusion. But it's exciting to have a new treatment option for these patients with rare MET exon 14 [skipping] mutations."

FDA approval for tepotinib was based on findings from the phase 2 VISION trial (NCT02864992) in which investigators reported that the overall response rate among 164 treatment-naive patients was 57% (95% CI, 49%-65%), and 40% of responders had a duration of response of 12 months or longer.6

Results from the FLAURA2 trial led to the FDA approval of osimertinib and platinum- based chemotherapy in patients with EGFR exon 19 deletions or exon 21 L959R mutations.7 "When discussing whether or not to use this regimen with patients upfront, a key factor will be the difference between coming into the office every 2 to 3 months to monitor scans and side effects of an oral pill vs coming into the office every 3 weeks to receive IV chemotherapy in addition to the osimertinib," Chiang said.

Amivantamab-vmjw in combination with carboplatin and pemetrexed was approved in the first-line setting for patients with locally advanced or metastatic NSCLC whose tumors harbor EGFR exon 20 insertion mutations.8 In the ALINA trial (NCT03456076), 257 patients were randomly assigned to receive alectinib 600 mg orally twice daily or platinum-based chemotherapy following tumor resection.9

For the Community Oncologist

For the community oncologist, understanding the biology of the tumors and their treatment response, whether for SCLC or NSCLC, is becoming more important, Chiang said. "To obtain tissue so that we can understand what subtypes or biomarkers are present and to determine how to target effective therapies to those patients is key in both small cell and NSCLC," Chiang continued. "Moving agents earlier into the neoadjuvant setting, or even into the adjuvant setting, is important to help our patients receive that benefit before the disease has reached the metastatic stage," she said.

Chiang noted that she is looking forward to the presentations, which will highlight the role of antibody-drug conjugates (ADCs) including, "ADCs and Immunotherapy: Can We Achieve Synergy?"; "Are Biomarkers Important for ADCs in Lung Cancer?"; "ADCs in Driver Mutation-Positive NSCLC: Do We Have a Real Signal?"; and "ADCs in Early-Stage NSCLC: Is This a Good Fit?" They are scheduled for July 27, 2024.

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