ESMO 2019 roundup

The European Society for Medical Oncology (ESMO) is growing in stature, with an increasing number of oncology-focused pharma companies choosing it as a forum to reveal their latest studies. Richard Staines rounds-up the latest data from the conference held this year in Barcelona.

PARP inhibitors took top billing at ESMO, with several pharma companies producing data from a range of cancer types, from ovarian cancer where they first gained a foothold to other diseases such as prostate and breast cancer.

AstraZeneca and Merck & Co produced data that could support a third indication in second line prostate cancer for their Lynparza (olaparib), the first PARP (poly (ADP ribose) polymerase) class drug to gain approval five years ago.

AZ and US Merck had results from the PROFOUND trial, which showed their PARP inhibitor significantly extended progression-free survival in prostate cancer patients with certain gene mutations.

PROFOUND focused on patients with metastatic castration-resistant prostate cancer, who had relapsed after treatment with established first line therapies, Pfizer’s Xtandi and Johnson & Johnson’s Zytiga.

The trial met its goal by reducing risk of progression by 66% in patients with either BRCA1 or 2 OR ATM mutations, compared with a control group treated with either Xtandi or Zytiga.

“GSK needs Zejula to be successful as it was the only reason it bought up the US biotech Tesaro for $5.1 billion – and evidence so far has vindicated this bold move by CEO Emma Walmsley.”

It’s down to AZ and Merck to work out how to present this data to regulators, and whether or not to ask for approval in a slightly broader range of patients.

There was other PARP data on display at ESMO too: the smaller US biotech Clovis had data from its TRITON2 trial, which will lead to a filing in third-line prostate cancer for its Rubraca (rucaparib).

While the data were encouraging, with a 44% response rate in patients with a BRCA1/2 alteration and previously treated with an androgen receptor and chemotherapy, the potential approval of Lynparza in second line could make these findings somewhat academic.

Clovis does not have the evidence to support treatment after a PARP inhibitor – so if Lynparza becomes a standard therapy in second line it seems unlikely that oncologists will be willing to prescribe Rubraca after a failed attempt with AZ’s drug.

GSK on target with Zejula

GlaxoSmithKline fared better with its PARP inhibitor Zejula (niraparib), producing data that back its use in a wider group of ovarian cancer patients in the PRIMA study.

PRIMA tested Zejula in patients who responded to front-line platinum chemotherapy, aiming to compete with Lynparza, which has been approved in this indication on the basis of the SOLO-1 clinical trial results announced at last year’s ESMO.

GSK needs Zejula to be successful as it was the only reason it bought up the US biotech Tesaro for $5.1 billion – and evidence so far has vindicated this bold move by CEO Emma Walmsley.

Zejula reduced risk of disease progression by 38% versus, with the biggest effect seen in patients with BRCA1/2 mutations, but there was also enough of a response across an “all-comers” population to suggest GSK could try for use in a larger population.

AbbVie finally gets joy from veliparib

AbbVie is also trying to get in on the PARP act with its veliparib, but until ESMO had not been having much joy, missing goals in a breast cancer trial in 2016 and flopping in non-small cell lung cancer and triple negative breast cancer phase 3 trials in 2017.

The US pharma finally got a phase 3 win from veliparib at this year’s ESMO, with data from the VELIA trial showing the drug improved survival in patients with newly-diagnosed late-stage ovarian, fallopian tube or primary peritoneal cancers.

This was followed by data from the BROCADE3 phase 3 trial where veliparib improved PFS by about two months compared with placebo in BRCA mutated, triple negative or hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer.

Whether such a narrow survival advantage could translate into a commercial opportunity for AbbVie remains to be seen, however.

KRAS disappointment for Amgen

Earlier in the year Amgen stole the show at ASCO with its AMG 510, which broke new ground by producing a response in cancers expressing a mutation known as KRAS.

The hope was that this could be another “tumour agnostic” drug that works in cancers with certain mutations. However updated results from the same trial have suggested that this may not be the case.

Amgen tested AMG 510 on 960 patients with various solid tumours with the KRAS G12C biomarker. Although the phase 1 trial was supposed to test safety, inevitably the company has scoured through various patient groups to guide future R&D activity.

In results from 12 colorectal cancer patients revealed at ESMO, there was only one partial response, although Amgen noted that 10 of the patients had stable disease, translating into a 92% disease control rate.

New data in non-small cell lung cancer were more promising, with seven partial responses out of 13 patients and stable disease in the remaining six.

Role for Keytruda in TNBC

While Roche’s checkpoint inhibitor immunotherapy Tecentriq (atezolizumab) is already approved in triple negative breast cancer (TNBC), Merck & Co is looking to make inroads in this disease too with its Keytruda (pembrolizunmab).

Data published at ESMO suggest that Merck’s drug could become standard therapy in early TNBC before or immediately after surgery, potentially taking market share from Tecentriq as it would be used earlier in the disease.

Checkpoint inhibitors, and their ability to call in an attack from the body’s T-cells, represent a new way to attack this tough-to-treat disease where chemotherapy had been the only previously available option.

The positive data follow disappointment in the KEYNOTE-119 study earlier this year where Keytruda failed to improve survival in second or third line metastatic TNBC.

Merck’s KEYNOTE-522 trial investigated a regimen of neoadjuvant Keytruda (pembrolizumab), Merck’s anti-PD-1 therapy, plus chemotherapy, followed by adjuvant Keytruda as monotherapy compared with a regimen of neoadjuvant chemotherapy followed by adjuvant placebo.

In the neoadjuvant phase, in the 401 patients receiving Keytruda plus chemotherapy there was a statistically significant increase in pathological complete response versus chemotherapy.

There was a complete response in 51.2% of patients treated with neoadjuvant chemotherapy, compared with 64.8% for neoadjuvant Keytruda plus chemotherapy, in patients with early-stage TNBC.

Pathological complete response, one of the dual primary endpoints was defined as non-invasive residual cancer in breast and lymph nodes.

The improvement seen when adding Keytruda to neoadjuvant chemotherapy was observed regardless of PD-L1 expression.

In the other dual primary endpoint of event-free-survival (EFS), with a median follow-up of 15.5 months, the Keytruda regimen reduced the risk of progression in the neoadjuvant phase and recurrence in the adjuvant phase by 37% – a favourable trend for EFS – compared with the chemotherapy-placebo regimen.

The safety profiles of Keytruda and chemotherapy in KEYNOTE-522 were consistent with previous studies.

There was some exciting new science on display at ESMO, which after ASCO is becoming one of the most influential scientific conferences for oncology.