Cancer is a nasty disease and the leading cause of death worldwide, accounting for nearly 10 million deaths in 2020, or nearly one in six deaths according to World Health Organisation data.

Companies and medical facilities worldwide are working hard to come up with more effective cancer treatments, with immunotherapy one of the promising approaches for personalised treatment.

One such company listed on the ASX is clinical stage biotech Immutep (ASX:IMM), pioneers in the understanding and advancement of therapeutics for cancer and autoimmune diseases related to Lymphocyte Activation Gene-3 (LAG-3).  Its diversified product portfolio harnesses LAG-3’s unique ability to stimulate or suppress the immune response.

IMM recently presented favourable clinical data  at the ESMO Congress 2023 from its TACTI-002/KEYNOTE-798 Phase 2 trial, which assesses their leading drug, eftilagimod alpha (efti).

Efti, a soluble LAG-3 protein, is undergoing testing in combination with Merck & Co’s anti-PD-1 therapy KEYTRUDA as a first-line treatment for previously untreated metastatic non-small cell lung cancer (NSCLC).

The findings revealed promising outcomes in overall survival, overall response rate, progression free survival, and duration of response across all PD-L1 subgroups.

IMM also reported positive Phase 1 results at ESMO for its investigator-initiated INSIGHT-003 trial, evaluating efti with anti-PD-1 therapy (pembrolizumab) and doublet chemotherapy (carboplatin/pemetrexed) as front-line therapy for metastatic or advanced NSCLC.

The trial showed the triple combination therapy continues to be well tolerated with strong signals of efficacy.

Stockhead caught up with IMM CEO Marc Voigt and founder Professor Frédéric Triebel, who discovered the LAG-3 gene, its functions and medical usefulness while working at Institut Gustave Roussy (IGR), a large cancer centre in Paris.

Immutep surged 11% on Monday after announcing excellent new clinical data from the TACTI-002/KEYNOTE-798 Phase 2 trial evaluating efti. Can you explain more about the trial results?

“We are very excited with these results which exceed our expectations,” Voigt says.

“Essentially, we’re seeing that efti can boost the immune system and improve its anti-cancer response for lung cancer patients, giving them an excellent median Overall Survival benefit of 35.5 months.

“These patients had a PD-L1 tumour proportion score, or TPS (this is how PD-L1 levels are measured in patients) equal to or greater than 1% and represent approximately two-thirds of the non-small cell lung cancer patient population.

“PD-L1 levels are important as they indicate if a patient is likely to respond to KEYTRUDA as a therapy on its own.

What’s also remarkable is we saw strong results across all levels of TPS, including patients who had low levels of PD-L1 and even patients with negative PD-L1 expression who wouldn’t normally be expected to respond to KEYTRUDA, but did when it was in combination with efti.

“This may indicate that efti helps to overcome the primary resistance of tumours towards KEYTRUDA.

“A 35.5-month survival benefit is an entire 12 months of additional survival compared to historical data from the current best option, KEYTRUDA and doublet chemotherapy, and its double the survival benefit patients have seen from receiving KEYTRUDA alone.

“These results are truly significant for patients with non-small cell lung cancer, which is impacts an estimated 1.9 million people annually and unfortunately represents the highest cause of death among cancers.

“In addition to the substantial survival benefit, the combination is safe and very well tolerated.

“Efti plus KEYTRUDA is chemotherapy-free, meaning patients can enjoy a better quality of life without the toxic side effects chemo brings, which is incredibly important for cancer patients.”

What are the next steps now following the successful findings in the Phase 2 trial and can you give us a timeline?

“Immutep will further evaluate efti in first line lung cancer via our upcoming registrational Phase III trial, TACTI-004,” Voigt says.

“Work has already begun on trial design and other preparations.

“Our discussions continue with regulators in the US and Europe as well as other stakeholders and we intend to provide an update on our plans in the next few months.

“TACTI-004 is important because it’s a registrational trial, which means that if it delivers strong results, then we can put together a Marketing Authorisation Application for the European regulatory body, the EMA, to approve efti for use in patients.

“Similarly, we would be able to submit a Biologics License Application to the US FDA for the approval of efti.

“It’s also worth noting that the US FDA granted us Fast Track designation in 1st line NSCLC (TPS > 1%) which means we may be entitled to expediated review of our application for efti.”

“The global market for non-small cell lung cancer will nearly double to $48 billion by 2031, making it an attractive cancer market to enter.

“Within that, it is estimated that immune checkpoint inhibitors (ICIs) like KEYTRUDA will capture roughly half that market or close to $24 billion.

“Combining efti with these ICIs can drive significant benefits for patients including the Overall Survival results in combination with KEYTRUDA that we’ve just announced.

“Success in this market alone could see efti become a significant drug alongside other blockbuster drugs such as KEYTRUDA.”

Who are the large players in the immunocology sector? You’ve licensed some of your compounds. What collaborations have you entered and why?

“Immutep has a leadership role in the immuno-oncology space which is driving a paradigm shift in the way we treat cancer,” Voigt says.

“We’re pioneering new therapies that relate to Lymphocyte Activation Gene-3 (LAG-3) which was discovered by our Chief Scientific Officer, Professor Frédéric Triebel.

“We are the only LAG-3 pure play biotech. Our products harness LAG-3’s unique ability to modulate the body’s immune response, dialling it up to fight cancer or dialling it down to regulate auto immune diseases.

“The first approved LAG-3 product was Bristol-Myers Squibb’s Opdualag which is already reporting rapidly accelerating sales of US$154 million in the June 2023 quarter and are a large player in immuno-oncology.

“Other large players with approved ICI therapeutics such include Merck, Regeneron, Astra-Zeneca, Roche, Merck KGaA, and GSK.

“We’ve already licensed out two products which are being developed by big pharma companies, Novartis and GSK.

“We’re also collaborating with US healthcare laboratory company, Labcorp, to develop LAG-3 immuno-oncology products and services, leveraging our deep know-how in this area.”

The race for better treatments for cancer is competitive. Where do you see Immutep fitting in to this space?

“Efti is showing great efficacy as an immune system booster that greatly enhances the effect of existing drugs and importantly has proved to be very safe in doing so,” Voigt says.

“Beyond, KEYTRUDA we’re also testing efti with chemotherapy and with other immuno-oncology drugs like German Merck/EMD Serono’s avelumab.

“Given efti’s favourable safety profile, we have also initiated two different triple combination studies.

“One combines efti with KEYTRUDA and doublet chemo for lung cancer patients, while another combines efti with radiotherapy and KEYTRUDA for patients with soft tissue sarcoma, a very difficult disease and an orphan drug indication in high need of new therapeutic approaches.

“We see potential for efti to improve the performance of many cancer drugs as part of many combination therapies, as such its highly complementary.”

Having discovered the LAG-3 gene and working towards LAG-3 therapies for most of your career, how do you feel about the result of Immutep’s phase 2 trial?

“Median overall survival is the most robust and significant endpoint in oncology,” Triebel says.

“It’s a reflection of both quantitative analysis, such as the percentage of patients responding to treatment, and qualitative analysis that includes the quality of the response and how long the response lasts to treatment.

“A 35.5-month median Overall Survival for the >1% TPS group of patients is therefore remarkable and unprecedented.

“Importantly, efti has shown very strong results for these patients in other key endpoints as well, including high response rates, strong progression free survival and duration of responses.

“To be able to hit on all these measures for lung cancer patients, without the use of chemotherapy, makes efti quite unique.

“We have long known about efti’s ability to drive a broad anti-cancer immune response and feel like we are just scratching the surface of its potential.”

How do you see the broader immunocology and cancer treatment space developing in the next few years?

“I expect immuno-oncology will expand to underserved indications like breast cancer or other ‘cold tumours’ and also expand to the neo-adjuvant/adjuvant setting in patients with a lower tumour burden,” Triebel says.

“Smaller indications like sarcomas or glioblastomas are also in need of more active immuno-oncology products.

“We are excited about the recently launched trial combining efti with radiotherapy and KEYTRUDA in soft tissue sarcoma in a neoadjuvant setting.

“This trial is being run by a very talented team of doctors at the Maria Skłodowska-Curie National Research Institute of Oncology.

“They believe that efti may transform the immunosuppressed tumour microenvironment of soft tissue sarcomas into one that enables immune checkpoint inhibitors like KEYTRUDA to exert their anti-cancer effect.

“They also see synergies between efti and radiotherapy to arm, activate and proliferate cytotoxic T cells with radiotherapy-induced cancer antigens as a way to target this difficult-to-treat tumour.

“From a big picture perspective within the broader immuno-oncology landscape, we expect to see a rise in combination approaches engaging both the adaptive and innate immune system versus leaning solely on one-half of the equation.

“This more closely resembles how the entire immune system naturally operates and maximises its potential to fight a variety of cancers.

“These combinations can hopefully safely deliver on the promise of increased efficacy and durability to cancer patients.”

Beyond cancer treatment where else do you see LAG-3 treatment being useful?

“We believe LAG-3 immuno-therapy holds tremendous potential in cancer, yet also in autoimmune diseases.

“The flipside of immune checkpoint inhibitors is immune checkpoint agonists, and this is an area of increasing attention within the biotech and large pharma industries, for good reason.

“These checkpoint agonists may play a vital role in treating the underlying causes of autoimmune diseases.

“At Immutep, we have developed the world’s first LAG-3 agonist called IMP761.

“By increasing LAG-3’s natural down-regulation of the auto-reactive memory T cells that are at the centre of many autoimmune diseases, we can target the root cause of autoimmune diseases.

“This is a potential game-changer in the treatment landscape.

“We expect to enter clinic by mid-2024 and look forward to moving close to finding therapeutic solutions that many patients with autoimmune diseases need.”

 

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