Drug Combination Successfully Targets Cancer’s “Death Star” Protein

A drug combination targeting multiple mutant versions of cancer’s ‘death star’ protein has shown promise in a small, early-phase clinical trial for some patients with advanced lung, ovarian and thyroid cancer.

The two-drug combination was effective against advanced cancers with a range of mutations to the KRAS gene – dubbed the ‘death star’ because its protein drives one in four cancers and has a largely impenetrable, drug-resistant surface.

The phase I trial tested the drugs VS-6766 and everolimus in 30 patients with a range of mutations to KRAS – including 11 with highly advanced, non-small cell lung cancer.

Half of the group of patients with lung cancer have not yet seen their cancer progress at six months – about twice as long as the expected benefit of chemotherapy at such an advanced stage of disease.

The research was led by a team from The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust and is being presented today (Monday) at the American Society of Clinical Oncology (ASCO) 2022 annual meeting.

Innovative dosing schedule

Previous trials which aimed to drug multiple KRAS variants in a similar way did not succeed because of severe side effects in patients. The current trial uses an innovative dosing schedule to limit toxicity. Patients received the two drugs twice weekly for three weeks, followed by a week off.

Patients on the trial had already received several prior cancer treatments including chemotherapy and state-of-the-art immunotherapy. But their cancers stopped responding  because they had adapted to treatment and evolved drug resistance.

Yet the new drug combination shrank tumours by more than 30 per cent in two of the 11 patients with lung cancer, and controlled tumour growth in nine. It also produced responses in patients with advanced ovarian and thyroid cancers – and the researchers plan to further expand this cohort.

Some 40 per cent of lung cancers, 45 per cent of bowel cancers and 90 per cent of pancreatic cancers are driven by mutant versions of KRAS.

Until recently KRAS mutations were extremely difficult to target. The first effective drug was approved in the US in 2021, but it can only target one variant of KRAS called G12C. Of patients with KRAS driven lung cancer, only 40 per cent have a G12C mutation, meaning the majority cannot benefit from currently available KRAS targeted drugs.

Opening up treatment options

Rather than drugging KRAS itself, VS-6766 and everolimus render KRAS less effective by simultaneously blocking the two pathways that KRAS relies upon to drive growth. This means the drug combination may also target cancers that are driven by many other KRAS mutations, opening up treatment options for other patients for whom current treatments have stopped working.

Targeting KRAS-fuelled cancer in two separate ways aimed to delay the evolution of drug resistance and prevent cancer from progressing. Identifying unique treatment combinations that can counter cancer’s ability to develop treatment resistance is a major focus of scientists at The Institute of Cancer Research (ICR).

The ongoing trial is being funded by Verastem Oncology.

The researchers hope to confirm the findings in a larger group of patients. If that is successful, they will take the combination through to later-stage trials.

A new treatment paradigm for targeting KRAS

Professor Udai Banerji, Deputy Director of Drug Development at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, said:

"Our early-stage study shows that an innovative drug combination can effectively target multiple mutant versions of KRAS – which is one of the most dangerous mutations in cancer, and one of the hardest to create treatments against. This could represent a new treatment paradigm for targeting KRAS mutations across multiple tumour types including lung and low-grade serous ovarian cancer.

"Many groups have walked away from trying to simultaneously drug the two pathways we know KRAS relies upon to drive growth because side effects were too severe for patients. We are heartened that by using an innovative dosing schedule, we’ve managed to slow cancer’s progression in several patients who had run out of treatment options. If we see similar findings in a larger number of patients, we could see this combination taken through larger clinical trials."

'Really promising'

Dr Anna Minchom, Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust and Leader of the Thoracic Oncology Drug Development Team at The Institute of Cancer Research, London, who is presenting the data at ASCO 2022, said:

‘It’s great to see that this innovative drug combination is showing potential for treating patients with a range of cancers, who have run out of other treatment options. Patients with KRAS- mutated non-small cell lung cancer, apart from those with a subtype known as KRAS G12C, do not currently have targeted treatment options. This was a small early-phase trial, but to see that patients are responding to this treatment, and are not experiencing severe side effects, is really promising.’

Sally Wells (pictured), 53, from Dartford, was diagnosed with stage 4 ovarian cancer in 2016 and joined the trial in 2019 at The Royal Marsden. Three years later the treatment is still working, and she has been able to spend time with her husband, children and grandchildren.

“Prior to being diagnosed I had virtually no symptoms. I was just decorating one day and knocked my stomach on a ladder which caused a pain that didn’t go away. I was advised to go to A&E, and following scans, blood tests and a biopsy I was diagnosed the stage 4 ovarian cancer, which had spread to my liver and bowel. It was a complete shock.

“I had six courses of chemotherapy, I lost my hair and with that I felt like I lost me as well. Just before Christmas 2018, after running out of treatment options, I was told that there was nothing else that could be done for me and I returned home knowing that I was coming to the end of my life. I was then given the amazing news that I was able to join this trial at The Royal Marsden. It was my only hope, and I would have done anything to extend my life. It’s been three years now and I’m doing well. This treatment has been life changing and has enabled me to continue living a busy life with my children and grandchildren.”

Reference: Minchom AR, Sanchez Perez V, Morton C, et al. Phase I trial of the RAF/MEK clamp VS-6766 in combination with everolimus using an intermittent schedule with expansion in NSCLC across multiple KRAS variants. JCO. 2022;40(16_suppl):9018-9018. doi: 10.1200/JCO.2022.40.16_suppl.9018

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