what’s been going on in the field?

Checkpoint inhibitors are drugs that harness the immune system to destroy cancer cells. Ever since the first of its kind was approved in the U.S. in 2011, it has been regarded as a breakthrough in immunotherapy research and cancer care. 

But how far has the field come? While some checkpoint inhibitors continue to expand their use, others have faced setbacks due to safety concerns and limited efficacy. With new drug combinations and novel targets emerging, the landscape of checkpoint inhibitors is evolving rapidly.

In this article, we’ll explore the latest approvals, clinical developments, and the next wave of checkpoint inhibitors—examining both their successes and challenges in the fight against cancer.

What are checkpoint inhibitors?

The reason why these drugs are called checkpoint inhibitors is because they block checkpoint proteins. These proteins act as off switches in the body to prevent the immune system from attacking healthy cells. While they are crucial for regulating immune responses and preventing the immune system from overreacting – which leads to autoimmune conditions – they are also, unfortunately, in the case of cancer, exploited by tumor cells to escape destruction.

So, by hindering these proteins, checkpoint inhibitors allow the immune system to attack the cancer cells. The most common checkpoint proteins that these drugs target are PD-1, PD-L1, CTLA-4, and LAG-3. 

Checkpoint inhibitors: which ones have been FDA approved so far?

The first checkpoint inhibitor that was cleared by the U.S. Food and Drug Administration (FDA) is ipilimumab, known by its brand name Yervoy – developed and marketed by pharma giant Bristol-Myers Squibb (BMS) – and it targets CTLA-4. It was initially used to treat advanced melanoma, a type of skin cancer. It has since been authorized to treat kidney cancer, colorectal cancer, and non-small cell lung cancer (NSCLC).

Often, Yervoy is paired with fellow checkpoint inhibitor Opdivo (nivolumab) as part of a treatment regimen to give the immune system the best fighting chance against cancer cells. Unlike Yervoy, the BMS-owned Opdivo blocks the PD-1 checkpoint protein. 

Several other PD-1 inhibitors have been greenlit by the FDA. Merck’s Keytruda (pembrolizumab) and American biotech Regeneron Pharmaceuticals’ Libtayo (cemiplimab), have been on the market since 2014 and 2018, respectively. These are not to be confused with PD-L1 inhibitors.

PD-1 or programmed cell death-1 proteins, are found on the surface of immune cells like T cells, whereas PD-L1, or programmed death-ligand 1, is the ligand that binds to PD-1. By blocking the interaction between PD-1 and PD-L1, these inhibitors prevent cancer cells from switching off T cells and therefore enhance immune responses against tumors. 

Popular PD-L1 inhibitors that have been backed by the FDA are AstraZeneca’s Imfinzi (durvalumab), which bagged approval in 2017, and Roche’s Tecentriq (atezolizumab) – approved in 2016. Most recently, Unloxcyt, developed by Massachusetts-based Checkpoint Therapeutics – now acquired by Indian company Sun Pharma – received the FDA nod to treat advanced cutaneous squamous cell carcinoma, a type of skin cancer, in December. It is the first and only FDA-approved anti-PD-L1 therapy for the disease.

Another checkpoint protein that inhibitor drugs can target is LAG-3, which is also expressed in T cells. So far, the FDA has only given the go-ahead to one LAG-3 inhibitor, relatlimab, and in combination with nivolumab, dubbed Opdualag. The drug combination is currently used to treat metastatic melanoma – cancer that has spread from the original tumor – and more studies are being conducted to evaluate it in other forms of melanoma. However, it failed a phase 3 study in patients with stage 3 and stage 4 melanoma as it did not meet the efficacy endpoint last month.

Why are checkpoint combinations so popular?

Checkpoint drug combinations like Opdualag and Yervoy-Opdivo are a means to amplify efficacy by targeting different immune pathways. Combining CTLA-4 inhibitors and anti-PD-1 inhibitors can widen the scope of T cells and improve the success of the attack by T cells. But a broader scope also means more side effects. 

While the Yervoy-Opdivo combination is regarded as a standard treatment for melanoma, the Opdualag regimen seems to be linked to fewer side effects. Less than 20% of patients who received Opdualag reported serious side effects compared with nearly 60% of the patients who received Yervoy-Opdivo, according to a report by the National Cancer Institute.

PD-1 checkpoint inhibitors clinical trials for cancer: PM8002, ivonescimab, and EMB-09 steer ahead

As approved drugs continue to be studied in the clinic to expand their approval for other cancers, there are various candidates in the clinic as well.

A notable contender is PM8002, a candidate now owned by BioNTech following its $800 million acquisition of China-based Biotheus. In a study of patients with triple-negative breast cancer, those who received the bispecific antibody targeting PD-L1 and VEGF-A had a 69.7% overall survival rate at 18 months. While the drug outperformed Keytruda in clinical trials, questions remain about whether it will produce similar outcomes in larger trials, particularly based on PD-L1 protein levels.

Also last year, California-based Summit Therapeutics surprised the industry with positive phase 3 trial results for its checkpoint inhibitor, ivonescimab – developed by and licensed from China-based Akeso. Patients with lung cancer who received ivonescimab had an average of 11.1 months before their cancer worsened, compared to just 5.8 months for those treated with Keytruda. The risk of progression was reduced by 49% for those on ivonescimab compared to Keytruda. According to Caicun Zhou, the principal investigator of the study, the results from the HARMONi-2 study support ivonescimab as a promising first-line treatment for patients with PD-L1-positive advanced NSCLC. The study results were published in The Lancet last week.

Another PD-1 blocker is EMB-09, developed by Chinese biotech EpimAb Biotherapeutics. Currently in phase 1 trials, it is a bispecific antibody that halts PD-1/PD-L1 inhibitory signaling and activates T effector cells. It has demonstrated immune cell activation preclinically, and its OX40 binding epitope aims to improve the therapeutic window.

New technologies related to checkpoint inhibitors for cancer:

Agenus drug combo moves up amidst rocky road ahead for the biotech

Meanwhile, Massachusetts-based Agenus has a roster of different types of checkpoint inhibitors in its pipeline. It is evaluating various combinations of its three main active molecules – balstilimab, botensilimab, and zalifrelimab – to address solid tumors. Balstilimab is a PD-1 inhibitor, and emerging data suggest that it may have a unique mechanism compared to other PD-1 therapies. The drug candidate has demonstrated stronger efficacy preclinically against PD-L1 negative tumors than pembrolizumab, indicating a broader mechanism that aligns with its clinical effectiveness in both PD-L1 positive and negative cervical cancer.

Botensilimab and zalifrelimab are CTLA-4 antibodies. The former is the first CTLA-4 inhibitor to demonstrate clinical responses across nine cold and treatment-resistant cancers. The most advanced of all of Agenus’ drug combinations is botensilimab-balstilimab for colorectal cancer. Around 78% of patients with colorectal cancer achieved pathologic responses of at least 50% tumor regression, with 56% reaching complete responses, according to study results published in June.

However, this didn’t convince the FDA to grant accelerated approval to the combination. The FDA claimed that the objective response rates may not translate to survival benefits, leaving the company to look for partners to further develop the therapy. Furthermore, Agenus has been the subject of severed ties in the past year. BMS ditched the American biotech’s preclinical asset AGEN1777 in August, three years after paying $200 million to buy the program. 

Delaware-based Incyte – maker of FDA-approved checkpoint drug Zynyz (retifanlimab) – also ended a near-decade-long immunotherapy deal with Agenus, which included a LAG-3 inhibitor, last year. Incyte’s checkpoint pipeline was cut short last year when it let go of two of its PD-L1 candidates. This was part of a larger pipeline slashing plan announced in July. 

LAG-3 inhibitors to take on FDA-approved Opdualag but issues loom

In the space of LAG-3 checkpoint inhibitors for cancer, Regeneron is developing fianlimab to tackle melanoma. A possible rival to relatlimab, the candidate is being studied along with Libtayo. 

The treatment showcased a 57% overall response rate (ORR) among 98 patients at the end of 23 months. It also reported a complete response rate (CR) of 25% and a median progression-free survival (PFS) of 24 months. Notably, 70% of patients experienced some level of tumor reduction. This compares to a 43% ORR among 355 patients who received BMS’ Opdualag at 19.3 months of follow-up. However, the Regeneron trial was riddled with discontinuations, with 78% of patients stopping treatment, citing disease progression and adverse effects.

While fianlimab continues to be developed, Merck’s LAG-3 inhibitor favezelimab has been binned following disappointing trial results. The pharma giant stopped the enrollment of a phase 3 trial – but gave patients on the treatment the option to continue the treatment until the end of the study – after it previously missed overall survival endpoints.

Checkpoint inhibitor safety issues impede treatment in stomach and esophageal cancers 

As checkpoint inhibitors are designed to boost immune responses, on the flipside, this could cause the immune system to go on overdrive and attack various organs. Treatment-emergent adverse events (TEAEs) were partly why some patients stopped taking fianlimab, as mentioned earlier.

On top of that, the FDA has been fairly cautious about which checkpoint inhibitors it approves. It expressed that it was wary of the broad use of these drugs to treat stomach and esophageal cancers. This was also backed by external investigators back in September, who declared that the benefits of the class of drugs were not convincing enough, citing hazard ratios close to 1, which means that risk is almost the same in the treatment and control groups in trials.

“I’m just not sure we want to let their doctors make this decision when these hazard ratios are almost 1, and there are financial and toxicity impacts for these patients,” said Daniel Spratt, from Case Western Reserve University, in a Fierce Biotech report, after voting against checkpoint inhibitors for stomach cancer. 

Beyond traditional checkpoint inhibitors: feats and fails

The promise of PTPN2 inhibitors in cancer therapy

While traditional checkpoint inhibitors typically target PD-1, PD-L1, and CTLA-4, a new era for this class of drugs may have begun. The immune checkpoint PTPN2 – previously dismissed as an undruggable target – acts as a negative regulator of various signaling pathways. Unlike traditional checkpoint inhibitors that directly block cell-surface receptors, PTPN2 inhibitors intercept signaling pathways to improve anti-tumor activity. 

American pharma giant AbbVie and California-based Calico Life Sciences’ ABBV-CLS-484 is a novel PTPN2 inhibitor currently being investigated in phase 1 studies in patients with solid tumors. A study reported that the drug slowed disease progression in mice and also appeared to reduce T cell exhaustion, signaling that the treatment may be able to overcome resistance – a major concern for cancer therapeutics.

The promise of PTPN2 inhibitors captured the attention of German multinational pharmaceutical Boehringer Ingelheim. For up to $1.3 billion, it bought California-based Nerio Therapeutics, snapping up the latter’s PTPN1 and PTPN2 preclinical programs in July.

Setbacks in TIGIT checkpoint inhibitors for cancer

Although PTPN1 and PTPN2 blockers seem to be moving up the ranks, another emerging type of checkpoint drug inhibiting TIGIT has faltered in recent times. In December, Merck dropped its TIGIT candidate vibostolimab, which was being tested in phase 3 trials alongside Keytruda in NSCLC. Vibostolimab was abandoned after a recommendation by an independent data monitoring committee, according to Merck.

Besides, Roche’s TIGIT tiragolumab failed a phase 3 trial in NSCLC, while a trial of another TIGIT drug, domvanalimab, conducted by Arcus Biosciences and Gilead, was halted last year. 

Despite several failures in clinical trials, there is ample research to prove that this class of drugs is capable of killing cancer cells. As new kinds of checkpoint inhibitors crop up, the field is set to grow with new drug combinations and unconventional checkpoint therapies up for review.