Author:

Rachel Brazil

Introduction

The importance of platinum-based chemotherapies cannot be underestimated – they are given to about 40% of patients who receive chemotherapy. Much of the research and development leading to the first platinum drug, cisplatin, was carried out in the US, but its discovery launched major research efforts in both the UK and France, producing new generations of platinum drugs with superior properties

Oxaliplatin ‒ the third generation

Oxaliplatin is used to treat colorectal cancer, most often in combination with other chemotherapy agents. The drug was designed to counter the cross-resistance exhibited by cisplatin and carboplatin but was found to be additionally active in colorectal cancer, where few other drugs were effective. It gained European approval in 1996 (initially in France) and is most often used with fluorouracil and folinic acid (leucovorin), in a combination known as FOLFOX, to treat advanced colorectal cancer, and is also used in other digestive cancers

In Paris, at Gustave Roussy cancer centre and Paul Brousse Hospital, a third generation platinum drug did make it to the market. Given his experiences trying to develop a third generation drug at Johnson Matthey, Cleare says: “It was a bit of a miracle that oxaliplatin got accepted.” The American oncologist Joseph Burchenal (1912–2006) noticed that chronic use of cisplatin or carboplatin led to resistance to both treatments ‒ known as cross-resistance. He found that platinum complexes with certain cyclic bidentate ligands did not exhibit cross-resistance, and contacted the world-famous French oncologist and immunologist Georges Mathé (1922–2010), who in 1958 had performed the first successful allogeneic bone marrow transplant.

They started studying a complex based on malonate ligands, named malanto platinum, which forms a six-membered ring, but they came up against the same solubility problem experienced by the UK team. It could only be used when heated to solubilise and then administered quickly before coming out of solution. But Mathé then came across a platinum drug synthesised in the lab of Yoshinari Kidani at Nagoya University in Japan in 1976. Known as oxaliplatin, the platinum was coordinated to a diaminocyclohexane bidentate ligand as well as an ‘oxalate leaving’ group.

Oxaliplatin

The drug had been rejected by labs in the US but, says oncologist Francis Lévi, who has held posts in France and the UK, “Mathé had always been looking for a diamino cyclohexane platinum complex formulation, because its liposolubility could ensure enhanced drug uptake and convey the possibility that it would have a different profile.” The diaminocyclohexane ligand seemed to have some subtle effects on the type of activity that could be achieved, and was less toxic to the kidneys.

Not all oncologists agreed, however. Oncologist Jean-Pierre Armand, now a senior scientific consultant at Gustave Roussy, had worked on another platinum drug in the mid-1980s at the CNRS Laboratory of Pharmacology and Toxicology in Toulouse, which failed. He admits he was sceptical about oxaliplatin’s chances: “I thought this is just a copy of a drug we have; we don’t need to develop it.” The compound had been licensed by French pharmaceutical company Rhone Poulenc (now part of Aventis), and it had also decided not to pursue its development; however, a small Swiss biotech firm, Debiopharm in Lausanne, took it over.

Lévi, worked with Mathé at Paul Brousse Hospital. “There were in vitro studies that had already shown non-cross-resistance of experimental tumours between cisplatin and oxaliplatin,” he says. “It was clear that in cisplatin-resistant tumours, oxaliplatin could be effective.” Mathé set up a phase I trial in 1986, run by oncologist Jean-Louis Misset, which showed that while renal toxicity was low, nausea and vomiting were significant. “The reality at this time was that it was considered to be too toxic to pursue further development.”

Mathé was still convinced oxaliplatin had value, and he started to look for synergies with other drugs. Working with David Machover, a haematologist/oncologist at Paul Brousse Hospital, they found it could be combined with the well-established chemotherapy drug fluorouracil (known as 5FU) and folinic acid (also called leucovorin), which seemed to neutralise the toxic effects. “Because in colorectal cancer we had no effective medicines to offer it was logical to try to test oxaliplatin,” says Lévi. The combination demonstrated superiority over other first-line treatments in colorectal cancers. “This was really the first time that 5FU and oxaliplatin were combined,” says Lévi, “The efficacy was four-fold higher than what we knew with 5FU.”

Lévialso explains that the treatment shrunk metastases so that liver and lung surgery could be performed to remove tumours, even if they had initially been inoperable. “This was a completely disruptive for liver surgeons ‒ they could now consider that a patient with liver metastases from colorectal cancer once considered non-resectable could become resectable,” says Lévi. Armand says finding the right combination was serendipity. “Alone, it’s not a fantastic drug, but when you combine with 5FU then it becomes a fantastic platinum drug.”

Lévi says though that there was a rationale to the development, with improvements seen when specific regimes of 5FU infusions were used. An element of these trials is chronotherapy – aligning medical treatment to circadian rhythms. “Mathé was convinced that this drug had a very strong potential, and so he asked us to investigate whether the timing of giving oxaliplatin could influence the toxicity of the drug.” In 1990, Lévi, Misset, Mathé and others reported improved safety and a higher maximum tolerated dose for chronomodulated versus constant-rate infusion of oxaliplatin in a randomised phase I trial.

Subsequent phase II trials demonstrated efficacy in colorectal cancer patients and, in 1997, Lévi and colleagues conducted a larger multicentre randomised trial of the three drugs to compare chronomodulated to constant-rate infusions. In findings reported in the Lancet, patients experienced up to five-fold less toxicity and greater efficacy by delivering most of the 5FU and folinic acid at night, and most of the oxaliplatin during the day, to line up with when DNA synthetic activity was least and highest in healthy cells.

Armand says that it was only after the initial results of oxaliplatin in combination with 5FU and folinic acid that he became a convert, and at this point his friend, the CEO of Debiopharm, Rolland-Yves Mauvernay (1922–2017), approached him. “He called me and said: ‘Do you want to help me to develop this drug?’” At this point, he says, he became ‘a believer’. Debiopharm ran clinical trials in Paris. The combination became known as FOLFOX, and oxaliplatin was acquired by Sanofi.

The company carried out phase III trials and took the drug to market for use in metastatic colorectal cancer in 1996 in France, in 1999 in the rest of Europe and in 2002 in the US. The drug exhibited a level of activity against colorectal cancer not seen with cisplatin or carboplatin, and is still the treatment of choice for colorectal and also for other digestive cancers.

See also the article, Oxaliplatin (L-OHP): a new reality in colorectal cancer, for descriptions of the key trials.

Latest European research – novel delivery

Platinum drugs remain important although there is no significant work on new complexes. Innovations are mainly in how they can be better delivered.

In 2001, researchers at Henry Dunant Hospital in Athens developed a lipid nanoparticle containing cisplatin, known as lipoplatin (liposomal cisplatin). By encapsulating the drug in spherical vessels made from a lipid bilayer it becomes more concentrated at the tumour site. The new drug-candidate successfully finished phase III human clinical trials, and has shown superiority to cisplatin in combination with paclitaxel to treat non-small-cell lung cancer. Regulon, based in Athens and California, is now commercialising the drug.

See also this article in Nature Reviews Cancer on present day relevance and development of platinum drugs.