NSCLC new treatments: A look at what is coming

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For decades, non-small cell lung cancer (NSCLC) stood as one of the formidable challenges in oncology, often diagnosed late and treated with limited options. But now, it looks like the therapeutic field is changing. From immunotherapies to small molecules, the landscape of NSCLC treatments is expanding.

In this article, we delve into the different kinds of therapies in the running to potentially address NSCLC, particularly late-stage cancer that is often difficult to treat.

NSCLC treatments: current state of the field

The most common form of lung cancer, NSCLC comprises 87% of people with lung cancer, according to Cleveland Clinic. Compared to small cell lung cancer (SCLC), NSCLC is less aggressive and does not form in the bronchi – the two large tubes that carry air from your windpipe – of the lungs. It actually develops in cells called epithelial cells that line the airway.

Also unlike SCLC, it grows more slowly, however, it can spread to other parts of the body before people experience noticeable symptoms. That’s why early detection of NSCLC is key.

Current treatments for NSCLC vary based on the stage of NSCLC. For patients with stage 1 NSCLC, surgery is typically most sought after. But for those patients with stage NSCLC who are at a higher risk of the cancer coming back, an adjuvant treatment – an additional cancer therapy to lower the risk of cancer recurrence – such as chemotherapy and immunotherapy, is given.

In the case of stage 2 NSCLC, neoadjuvant treatment – given before primary care, which is often surgery – is offered to patients. Cancerous lymph nodes are also removed. However, stage 3 and 4 NSCLC are where current treatment options are scarce and more likely to cause the return of cancer.

That’s why there are different kinds of drug candidates in the clinic trying to combat this inadequacy. And some of the candidates could be on their way beyond the clinic, as they are being evaluated in late-stage trials. These include three drugs in particular, being developed by big pharma.

Can these clinical stage big pharma drugs address NSCLC?

The first is the bispecific antibody volrustomig, owned and developed by British pharma giant AstraZeneca. Volrustomig is designed to enhance the body’s immune response against cancer. This happens by blocking two checkpoint proteins called PD-1 and CTLA-4. As a result, T cells remain active and can attack cancer cells better.

The therapy has been undergoing a phase 3 evaluation since the end of 2023 and around 900 patients worldwide are part of the randomised trial. Volrustomig is intravenously given in combination with chemotherapy, and its safety and efficacy are being compared with the approved checkpoint inhibitor pembrolizumab and chemotherapy.

The drug offers a more targeted approach as it is designed to preserve overall immune function, according to a report by Synapse. Similarly, AstraZeneca has another NSCLC checkpoint inhibitor up its sleeve. Rilvegostomig targets the checkpoints TIGIT and PD-1. A phase 3 study trialing the drug among 880 patients with NSCLC began in November and is expected to end in 2029.

AstraZeneca is also developing datopotamab deruxtecan, which is an antibody-drug conjugate (ADC) for locally advanced NSCLC. ADCs are composed of a monoclonal antibody that fits into tumor antigens when binding to them, a chemotherapy drug, and a linker protein that keeps the monoclonal antibody and the chemotherapy connected. In the case of datopotamab deruxtecan, the therapy has been engineered to target the TROP2 protein expressed on tumor cells.

AstraZeneca, which is advancing datopotamab deruxtecan along with Japanese pharma giant Daiichi Sankyo, received the nod from the U.S. Food and Drug Administration (FDA) for datopotamab deruxtecan to treat HER2-negative breast cancer in January.

This was following positive results from a pooled phase 2 and 3 analyses NSCLC trial back in December. It was found that in 42.7% of 117 patients with NSCLS who have a mutation in the epidermal growth factor receptor (EGFR) gene, the ADC demonstrated a confirmed objective response rate (ORR).

Myung-Ju Ahn, professor of Hematology-Oncology at the Department of Medicine at the Sungkyunkwan University School of Medicine in Seoul, explained that although approved NSCLC drugs, especially tyrosine kinase inhibitors, have significantly improved outcomes for patients with advanced EGFR-mutated NSCLC, most patients eventually experience disease progression.

“These results suggest datopotamab deruxtecan could offer patients with EGFR-mutated non-small cell lung cancer a much-needed option in the pre-treated metastatic setting,” said Ahn in a press release.

In fact, the drug achieved overall survival without chemotherapy being used in combination with it. The safety profile of the medicine was consistent with previous reports of NSCLC trials, and no new safety concerns were identified. The most common side effects were stomatitis – mouth inflammation – alopecia – hair loss – nausea, fatigue, decreased appetite, and constipation. But in 23% of patients, grade 3 and higher adverse effects took place.

However, it seems like datopotamab deruxtecan has only redeemed itself after a phase 3 failure revealed in September. The study saw that the therapy “did not reach statistical significance” in a trial in patients with nonsquamous NSCLC.

NSCLC treatments: tyrosine kinase inhibitors popular with the FDA

When Ahn pointed out that tyrosine kinase inhibitors (TKIs) have been game-changing for NSCLC, she was probably referring to the flurry of approvals that the class of drugs obtained in the past few years.

This is a class of drugs that block the enzyme tyrosine kinase, which is responsible for regulating cell growth and division.

In January, the TKI lazertinib was greenlit by the European Commission in combination with the monoclonal antibody amivantamab to treat locally advanced NSCLC. This was following the FDA’s go ahead for the same indication in September. Lazertinib, sold under the brand names Lazcluze and Leclaza, has been licensed by American pharma giant Johnson & Johnson from the South Korean pharmaceutical Yuhan, which retains the rights of the drug in South Korea.

In cancer cells, lazertinib inhibits the EGFR gene, where it forms a bond with a specific site on the gene. It blocks the EGFR downstream signalling cascades and promotes the damage of EGFR-mutant lung cancer cells.

Similarly, Bristol Myers Squibb’s repotrectinib, known as Augtyro, and Merck’s tepotinib, also called Tepmetko, have been authorized to target NSCLC. Augtyro received clearance for locally advanced or metastatic ROS1-positive in November and Tepmetko bagged accelerated approval in 2021, followed by traditional approval in 2024 for patients with NSCLC who have MET exon 14 skipping alterations – a type of mutation where the exon 14 region of the MET gene is skipped.

Currently, zipalertinib is a TKI that is nearing the finish line. The Massachusetts-based Cullinan Therapeutics’ drug hit the primary endpoint in a phase 2b trial of ORR, the company announced in January. This comes three years after the candidate snagged Breakthrough Therapy Designation from the FDA. More is yet to be disclosed about the study.

KRAS inhibitor glecirasib edges closer to approval in China

Another inhibitor drug that could broaden the scope for NSCLC treatments is glecirasib. The Jacobio Pharma-owned drug is a KRAS inhibitor, meaning that it blocks the production of the KRAS enzyme by binding to a site on it in order to inactivate it. This promotes anti-tumor effects by preventing cancer cells from proliferating.

According to a phase 2 study published in Nature Medicine in January, glecirasib had a 47.9% ORR in patients at a median progression-free survival of 8.2 months, and a median overall survival of 13.6 months. Glecirasib’s new drug application is currently being reviewed by Chinese regulators.

Yinxiang Wang, chief executive officer (CEO) of Jacobio, expressed that the KRAS inhibitor will be explored in combination with the company’s SHP2 inhibitor JAB-3312 to eventually be regarded as the standard of care for NSCLC. In a bid to bring these two drugs to Chinese markets, Jacobio sold the licensing rights in China to Shanghai-based Allist Pharmaceuticals for 150 million Chinese yuan ($21 million) in August. This is promising news after pharma giant AbbVie blew off a deal with Jacobio for JAB-3312 two years ago.

Immunotherapies in the clinic

Innovent’s IBI363 nabs fast track designation

While inhibitor drugs work by suppressing proteins and enzymes to target cancer, immunotherapies kind of do the opposite. They typically enhance the body’s own immune system to fight cancer cells. One such immunotherapy for NSCLC is IBI363. The Chinese company Innovent Biologics’ bispecific antibody not just blocks the PD-1 and PD-L1 pathway, it also activates the IL-2 pathway, which prompts T cells to attack tumor cells.

In February, the company garnered attention when IBI363 was granted Fast Track Designation by the FDA for the indication. This was backed by promising efficacy data presented at the World Conference on Lung Cancer (WCLC) in September. The drug had a 50% ORR and a disease control rate (DCR) of 88.9%.

Moreover, the drug achieved a 36.4% and 31.8% ORR in patient groups consisting of people with a PD-L1 tumor proportion score (TPS) less than 10 and greater than 10, respectively. A PD-L1 TPS refers to the percentage of tumor cells that express the PD-L1 protein and is a measure to predict how well a patient responds to immunotherapy. These results imply that IBI363 has an advantage in PD-L1 low-expression populations.

“IBI363 has demonstrated potent anti-tumor activity regardless of PD-L1 expression levels. This suggests that IBI363 may not only advance treatment for immunotherapy-resistant populations but also for cold tumors with low or no PD-L1 expression,” said Hui Zhou, senior vice president of Innovent, in a press release. “Moving forward, we will continue to explore IBI363 in early-line treatment and in combination therapies.”

Innovent has seen success in the NSCLC therapeutic space this year as its TKI limertinib was approved by the National Medical Products Administration (NMPA) in China in January.

Candel Therapeutics’ CAN-2409 extends overall survival

Meanwhile, Massachusetts-based Candel Therapeutics’ CAN-2409 has been gaining ground in the NSCLC treatment field, particularly because it was recently revealed that the medicine could improve the chances of survival for patients. CAN-2409 is an off-the-shelf therapy that delivers the herpes simplex virus thymidine kinase (HSV-tk) gene to tumors. The HSV-tk enzyme converts valacyclovir – an antiviral given in combination with CAN-2409 – into a toxic substance that kills cancer cells.

Given together, the drugs boost a T cell-mediated response against tumors. In a phase 2a trial, the NSCLC immunotherapy – also being tested in prostate cancer and pancreatic cancer studies – achieved a prolonged median overall survival (mOS) of 24.5 months in patients with advanced NSCLC who had not responded well to previous treatments, including chemotherapy and checkpoint inhibitors.

“The survival benefit seen in this study is striking, especially when compared to both the current standard of care treatment of docetaxel chemotherapy and other therapies under investigation for this patient group,” said Charu Aggarwal, principal investigator of the study, in a press release in March.

Cancer vaccine tedopi tested in international study

Another immunotherapy nearing the finish line is tedopi. But different from CAN-2409 and IBI363, French company OSE Immunotherapeutics’ tedopi is a cancer vaccine. These vaccines, unlike vaccines against infections, are designed to train immune cells to attack cancer cells. The immune system is exposed to antigens linked to cancer cells, which it recognises and kills. Similarly, tedopi, which contains epitopes that have been optimized from five cancer antigens, triggers T cells to get rid of cancer cells.

The candidate is in a phase 3 trial in patients with NSCLC who possess the HLA-A2 antigen and have developed resistance to checkpoint inhibitor drugs. The ongoing study is being conducted in sites across Europe, Canada, and the U.S. The vaccine is expected to follow prostate cancer vaccine Provenge’s footsteps – the first cancer vaccine to receive FDA nod – as it won positive recommendations from the FDA and the European Medicines Agency (EMA) two years ago.

MAIA Biotechnology’s THIO ‘uncaps chromosomes’ to attack cancer cells

Meanwhile, Chicago-based MAIA Biotechnology has come up with a different kind of medicine to combat NSCLC. It has a number of clinical studies trialing its prized possession THIO. It is derived from the small molecule ateganosine, which targets telomeres – the caps at the ends of chromosomes.

Telomerase is the enzyme that maintains the length of telomeres, but in cancer, this enzyme allows for uncontrolled cell division. So, to stop telomerase, which is present in more than 85% of all cancers, MAIA’s ateganosine integrates into the telomeres to compromise their function and uncap the chromosome ends to aid cell death.

Specifically for third line NSCLC, when all else has failed to treat the cancer, THIO triumphed in a phase 2 trial, where in combination with approved monoclonal antibody Libtayo, it had a 38% ORR. This ORR significantly exceeded standard of care ORR in patients with difficult-to-treat NSCLC, according to the company. A phase 3 study is in the works.

Treating NSCLC: combination therapies the way to go

Combination therapy for lung cancer treatment is among the latest, most exciting advances in lung cancer research, according to a report by the Lung Cancer Foundation of America. More than five decades ago, scientists found out that using a combination of medicines improves the chances of all cancer cells being eliminated.

Often, immunotherapies are paired with chemotherapies, radiotherapies, and targeted therapies, as a sole therapy may not suffice to shrink a tumor. As mentioned earlier, stage 2 NSCLC is treated with neoadjuvant treatment followed by primary treatment to boost the efficacy of the primary therapy as well as decrease the spread of cancer. As for adjuvant therapy, it is given after primary treatment to reduce cancer recurrence.

At present, most drug candidates are tested in combination with approved therapies in clinical trials – like volrustomig, which is combined with chemotherapy, lazertinib in combination with a monoclonal antibody, CAN-2409 with an antiviral, and THIO along with Libtayo, to name a few.

As the goal is to minimize the likelihood of cancer returning, the promise of these combination therapies in the clinic is encouraging. And with many of these therapeutic candidates in late-stage studies, it will be interesting to see which ones make it past approval and into the market.