As Bayer, Novartis stack up their radiopharmaceutical data at...

As Bayer, Novartis stack up their radiopharmaceutical data at #ESMO21, a key debate takes shape

Amber Tong

Senior Editor

Ten years ago, a small Norwegian biotech by the name of Algeta showed up at ESMO — then the European Multidisciplinary Cancer Conference 2011 — and declared that its Bayer-partnered targeted radionuclide therapy, radium-223 chloride, boosted the overall survival of castration-resistant prostate cancer patients with symptomatic bone metastases.

In a Phase III study dubbed ALSYMPCA, patients who were treated with radium-223 chloride lived a median of 14 months compared to 11.2 months. The FDA would stamp an approval on it based on those data two years later, after Bayer snapped up Algeta and christened the drug Xofigo.

“I’d say in the old days, the notion always was that the radioisotopes could at best be given for palliative purposes,” Volker Wagner, Bayer’s head of clinical development in radiopharmaceuticals, told Endpoints News. “With the advent of Xofigo, things became radically different.”

What Xofigo offered, Wagner said, was proof of concept that with the right isotopes and the right payloads, targeted radiotherapies can not only make a difference on symptoms, but actually extend survival.

Bayer was back at ESMO over the weekend with a pair of postmarketing studies that it says offer real-world evidence suggesting Xofigo still works in this setting even with the emergence of a new generation of prostate cancer treatments. But it also quietly reported a disappointing Phase I effort that it stopped early, underscoring the current limits of these drugs and the uncertainty that remains.

It all arrives at a crucial time as, thanks in part to the interest of both Bayer and its Big Pharma brother Novartis, VCs appear more willing than ever to bet on new startups that are developing conjugates of radioisotopes and targeting molecules to treat a variety of cancers. From earlier players like Fusion and Germany’s ITM to Versant-backed RayzeBio and MPM-founded Aktis Oncology, money is in no shortage for anyone who touts a winning formula for putting together a warhead that can kill cancer cells by radiation and an efficient, accurate guide that can bring it there.

Amid the rising heat in the space, a key technical debate is also starting to take shape: Which type of radioisotope is better for use in targeted radiotherapies? Alpha or Beta?

Bayer champions alpha-emitting radioisotopes for its drugs. Meanwhile, Novartis — which bills itself as the first big company to make “bold bets and large investments” in radioligand therapies in the form of multibillion buyouts of Advanced Accelerator Applications and Endocyte — is presenting a slate of positive data around a late-stage program that utilizes a beta-emitting radioisotope. The new results follows its first approved radiotherapy, Lutathera.

Regardless of that choice, the two companies do agree on one thing. Targeted radiotherapies are here to stay.

“We believe in the potential of radioligand therapy to be a key pillar of cancer care and continue to invest in expanding our platform capabilities,” said Jeff Legos, Novartis’ EVP, global head of oncology and hematology development.

The data

With REASSURE and PARABO, Bayer set out to see whether the positive results Xofigo notched in ALSYMPCA can be replicated in the real world setting across the world.

In short, it did.

Median OS in the larger REASSURE trial, which enrolled patients from multiple countries who were treated by the clinical standards according to their own national guidelines, was 14.7 months. And investigators saw encouraging improvements in pain severity, with 18% of patients reporting complete pain relief overall. PARABO, which was conducted only in Germany, showed similar numbers.

“This data is consistent with the improvements seen in ALSYMPCA,” Wagner said. “So this is very encouraging because as I said, now after many years, with more than — almost 80,000 patients treated with Xofigo […] we can see that the data still holds true in nowadays clinical practice.”

Novartis’ update came from the Phase III VISION study testing the addition of 177Lu-PSMA-617 to standard of care for patients who have exhausted all treatment options. Having already spelled out a median OS benefit of four months and a median radiographic progression-free survival benefit of five months over standard of care in metastatic castration-resistant prostate cancer, it wanted to complete the picture by presenting data on health-related quality of life.

An analysis showed that the 177Lu-PSMA-617 plus standard of care arm delayed patients’ decline in quality of life by an estimated 54%, as measured by the FACT-P scale. The treatment also resulted in an estimated 55% risk reduction of worsening of pain intensity, based on the BPI-SF metric.

“Many patients with metastatic castration-resistant prostate cancer mCRPC live with reduced physical functioning as well as significant pain,” Legos noted, adding that no new safety concerns were reported.

The flop

Even though Xofigo has a highly specific mechanism of action — aiming straight for the bone, it’s particularly effective at stemming cancer that kills via bone metastases — Bayer has been wondering whether its secondary impact could render it a useful companion to immuno-oncology drugs.

Since alpha-based radiotherapies kill cancer cells by double stranded DNA breaks, the theory goes, it basically leads to immunogenic cell death, which could activate I/O drugs like checkpoint inhibitors.

Bayer had already run into one setback last year, when it reported that pairing Xofigo with Roche’s PD-L1 blocker Tecentriq didn’t yield better results than either therapy alone. But prostate cancer is also known as a cold tumor that’s unresponsive to immunotherapies, leaving researchers the possibility of trying this strategy out in a hot tumor.

They turned their eyes to non-small cell lung cancer, tapping Merck’s dominating Keytruda for a combo in a Phase I trial.

But one and a half years after recruitment started, Bayer is throwing in the towel — with data from just eight patients. All of them had tumors that were refractory to checkpoint drugs. One discontinued before starting therapy and another pulled out after cycle 1; among the six who completed the treatment, the best response was recorded as stable disease in one patient. Five others had progressed.

Does this mean Xofigo has a limited role to play beyond? Wagner said the data aren’t really informative on that score.

The original goal, he explained, was to enroll both patients that were I/O refractory and I/O naive or sensitive. As it turned out, given the proliferation of clinical trials in lung cancer, Bayer had a hard time enrolling patients from the latter group.

“So in order then for that study with those patients to become positive, Xofigo would have to overcome basically I/O resistance, which was unlikely,” he said.

Even though Bayer likely won’t launch another trial of its radiotherapy candidates in combination with I/O for lung cancer any time soon, he sees potential in exploring the strategy in kidney cancer, melanoma and thyroid cancer.

The debate

Having defended and stood by Xofigo through safety scares and a restriction in use, Bayer is all in on alpha-emitters. Instead of radium, the company has been trying out targeted thorium conjugates hitting PSMA (for prostate cancer) as well as HER2 (for HER2-low breast cancer), as well as looking into actinium. Whereas beta-emitters, which have been more commonly used for therapeutic purposes, are more penetrant and can travel farther, alpha-emitters are heavy and have powerful energy transfer.

“So with less energy you can kill cancer cells, but because the range of alpha emitters is relatively short, you spare the surrounding tissue,” Wagner said, “which is different from beta emitters that travels much further and not as high energetic, they only cause single strand breaks, so you need more energy to kill cancer cells, and with the broader range, you may run the risk that the tox profile is worse.”

By contrast, Novartis’ in-house programs all revolve around lutetium-177, the beta-emitting isotope used by both Advanced Accelerator Applications and Endocyte, the subjects of $3.9 billion and $2.1 billion buyouts, respectively.

Mentioning lutetium-177 by name multiple times, Wagner noted “a relevant difference for example in fatigue, nausea, vomiting, bone marrow suppression, but also dry mouth” in the VISION study.

According to Legos, though, the shortcomings of beta-emitters could actually make for better drug candidates.

“Alpha-emitters throw off larger particles in a higher energy transfer that travel a shorter range (<100 micrometers). They are more destructive. The short path length suggests that alpha therapy may be very precise, potentially sparing nearby healthy cells, but this also suggests that targeting ligands must reach throughout a tumor to achieve deep responses,” he wrote. “Beta-emitters throw off electrons that travel farther through tissue (a few millimeters), which may help reach and kill tumor cells that don’t express the target receptor.”

For now, Novartis has no plans to switch allegiance from lutetium-177. But Legos added his crew is “actively exploring alpha-based radioligand therapy” — while keeping an eye on emerging research about where it’s most suited.

The bigger challenge

Both Bayer and Novartis are testing their targeted radiotherapies in earlier lines of mCRPC, sometimes in combination with other agents such as anti-hormonal or chemotherapy.

It’s still “relatively early days” for the field, Legos said, as scientists explore and characterize new radioisotopes as well as the various types of targeting constructs — be it small molecules, peptides or antibodies.

No matter which components competitors choose to form their radioligand therapies, though, they will likely face the same challenges in sourcing raw materials, scaling out the supply chain and ensuring timely delivery for both clinical studies and eventual commercialization. Working with radioligand therapies, after all, could mean tackling short time windows measured by days.

“For chemo or even oral treatments, you can basically store them in a pharmacy, you put them on the shelf and then you have them readily available,” Wagner said. “With targeted radionuclide therapies, obviously those are limited by their half lives. So if you let them sit around, they decay and then they are gone, right. So you can’t really store them in advance.”

The italics section is the part which I believe shows the reason why IONIC, if successful, will help put Noxopharm on big pharma’s radar.