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ASCO 2015 roundup: immuno-oncology hits its stride

pharmafile | June 8, 2015 | Feature | Manufacturing and Production, Medical Communications, Research and Development, Sales and Marketing | ASCO, BMS, CLL, pdl1

One year can make all the difference. The 2014 American Society of Clinical Oncology (ASCO) meeting took place just weeks before the world’s first approved PD-L1 inhibitor immunotherapy, Bristol-Myers Squibb’s Opdivo (nivolumab), was shown its first green light in Japan.

Just 12 months later PD-L1 treatments were everywhere at ASCO 2015, as announced trial results solidified immuno-oncology’s status as the most exciting development in cancer treatment for some time.

It was Opdivo itself that stole the show, with data presented by BMS showing when it was used in combination with another of its immunotherapies, CTLA-4 inhibitor Yervoy (ipilimumab), it could shrink 58% of tumours in patients with advanced melanoma.

“[This is] the first time immunotherapies have topped the 50% mark,” says Ana Nicholls, healthcare analyst at the Economist Intelligence Unit.

“ASCO is always used to announce exciting trial results, but this year’s results have been particularly impressive. Recent years have seen the emergence of a new breed of immuno-oncology drugs. The most recent trials, however, suggest that many of these are even more effective when two or more are used together, increasing the number of trial patients who respond to treatment and increasing the duration of the benefit.”

As Nicholls suggests, BMS’ drugs were far from the only immunotherapies being shown off at this year’s conference.

AstraZeneca had its own PD-L1 and CTLA-4 inhibitor cocktail on display with the combination of MEDI4736 and tremelimumab, which showed an overall response rate of 27% in the treatment of non-small cell lung cancer (NSCLC) – one of the most prominent disease areas at the conference.

Meanwhile, Roche announced that its investigational PD-L1 inhibitor MPDL3280A could double the likelihood of overall survival compared to docetaxel chemotherapy in NSCLC.

Merck and Pfizer’s PD-L1 offering avelumab also had preliminary data presented at the conference. Avelumab is co-developed by the two companies as part of a $3 billion deal.

‘Unsustainable’ costs

But this excitement was dampened by the inevitable questions on just how much these treatments are going to cost – particularly Yervoy and Opdivo, where the prospect of combining two already expensive treatments raised some concerns.

Speaking at the conference, Dr Leonard Saltz who is the chief of gastrointestinal oncology at Memorial Sloan Kettering Cancer Center, said: “The unsustainably high prices of cancer drugs is a big problem, and it’s our problem.”

He added that the median monthly price for new cancer drugs in the US had more than doubled, rising from $4,716 in 2000-2004 to around $9,900 in 2010-2014, and cited studies showing that this hasn’t corresponded to increases in the effectiveness of such drugs.

“These drugs cost too much. Cancer drug prices are not related to the value of the drug. Prices are based on what has come before and what the seller believes the market will bear.”

He acknowledged that Yervoy and Opdivo’s benefit is “truly, truly remarkable for a disease that five years ago we thought was virtually untreatable”, but estimated that the treatment would cost $295,000 million per patient for a year of treatment, based on the drugs’ individual prices. In the US, Yervoy costs around $131,000 for a full course of treatment, and Opdivo costs around $150,000 per patient per year.

Although BMS is unable to comment on a price until the treatment has been authorised, in her analysis Ana Nicholls says: “The researchers stressed that given the timing of the trial, they do not yet know how durable the responses are, but the trials suggests they are far longer than with Yervoy alone. There may also be knock-on effects in terms of the cost-effectiveness of these extremely expensive drugs if more patients can benefit, and for longer.”

Precision medicine

Immuno-oncology is not the only treatment area to be garnering great excitement, though. Precision and targeted medicine, where drugs are designed to target specific pathways in cancer or patients with particular biomarkers, also had a strong presence at ASCO.

Pfizer’s ‘first in class’ Ibrance (palbociclib) in combination with AstraZeneca’s Faslodex (fulvestrant) was shown to more than double progression-free survival time, holding off advancement by around five months in women with estrogen-receptor-positive but HER2-negative breast cancer. Ibrance simultaneously blocks two proteins called CDK4 and CDK6 – which are involved in cell division – in cancer cells.

Another targeted breast cancer drug, Roche’s Perjeta (pertuzumab) in combination with Herceptin (trastuzumab) and docetaxel chemotherapy, was shown to reduce the risk of HER2-positive early breast cancer getting worse, recurring or causing death by 31% compared to Herceptin and chemotherapy alone.

The Swiss firm also presented data on venetoclax (co-developed with AbbVie), which inhibits the BCL-2 protein. When used in combination with bortezomib and dexamethasone, the drug demonstrated 83% overall response rate in multiple myeloma patients who are bortezomib-naive.

NSCLC was a key area for precision treatments too. Novartis’ combination of Tafinlar (dabrafenib) and Mekinist (trametinib), which were both acquired from GSK in the companies’ asset-swap deal in March, demonstrated a 63% overall response rate in metastatic BRAF V600E+ NSCLC in a Phase II trial. Meanwhile, Phase II data from the company’s Zykadia (ceritinib) showed that the drug shrank tumours in patients with ALK+ NSCLC.

A Phase I AURA study for AstraZeneca’s investigational drug AZD9291 in EGFRm positive advanced NSCLC found that 81% of patients were progression-free at nine months, and the overall response rate was 73 per cent. This builds on trial results published in April which suggested that the drug could increase progression-free survival to an ‘unprecedented’ 13.5 months in patients with the T790M resistance mutation.

Combinations

Many think the true future of cancer treatment is in combining immunotherapy and precision medicine, as AstraZeneca’s head of global oncology affairs, Steve Olsen, explained in a pre-ASCO media briefing.

“We know that this works with chemotherapy, that poly-chemotherapy for a lot of diseases is better than single agent chemotherapy. With targeted therapies, we believe it’s the same – and especially by combining things such as drugs that rev-up the immune system with drugs that are targeting the pathways that drive cancer cells to grow.”

Building on this, AstraZeneca presented data from MEDI4736 in combination with Tafinlar and Mekinist, demonstrating partial response rates in 69% of patients, as well as data from a trial combining AZD9291 with MEDI4736 that showed that AZD9291 has a tolerable safety profile that facilitates its use in the combination.

In chronic lymphocytic leukaemia (CLL), immunotherapy Arzerra (ofatumumab) from Novartis and targeted treatment Zydelig (idelalisib) from Gilead, together demonstrated a 73% reduction in the risk of disease progression or death and a median PFS of 16.3 months (compared to 8.0 months in Arzerra alone) in Phase III data on show at the conference.

Meanwhile, Roche’s Gazyvaro (obinutuzumab), takes a two-pronged approach in one treatment, causing ‘enemy’ cells to self-destruct and harnessing the immune system to remove the cell. Findings presented at ASCO showed that the drug in combination with bendamustine chemotherapy, followed by Gazyvaro alone, reduced the risk of non-Hodgkin lymphoma worsening or death by 45% in patients, compared with bendamustine alone.

Though ASCO’s focus on successes over failures inevitably provides an unbalanced view of current cancer trials, it’s hard to not be optimistic when exciting areas of treatment begin to deliver on their promises.

At the rate oncology medicine is developing, it’s almost impossible to say what the landscape will look like by the time ASCO 2016 comes around – but if 2015 is anything to go by the year ahead could be very interesting indeed.

Other ASCO data presented

Adaptamune’s T-cell therapy NY-ESO-T demonstrated robust clinical responses in solid and hematologic tumours, including a 60% confirmed response rate in synovial sarcoma, and a 59% response rate in myeloma in the context of autologous stem cell transplant.

Janssen’s targeted CLL drug Imbruvica (ibrutinib) combined with bendamustine and Roche’s MabThera (rituximab) increased progression-free survival, with overall response rates at 82.7% compared to 67.8% for bendamustine, MabThera and placebo.

Phase III data from Roche showed a median progression-free survival of 12.3 months for melanoma patients using MEK inhibitor cobimetinib plus BRAF inhibitor Zelboraf (vemurafenib).

BMS’ investigational multiple myeloma treatment Elotuzumab reduced risk of disease progression by 30% – and had a two-year progression-free survival rate of 41% when added to standard treatments Revlimid (lenalidomide) from Celgene and dexamethasone.