Breakthroughs in Lung Cancer

The newest treatments are extending life…

Timothy Burns, MD, PhD

December 1, 2018

Lung cancer kills more Americans—both smokers and nonsmokers—than colon, breast and prostate cancers combined. But the good news is, treatment options are now extending the lives of many people affected by this formidable disease.

Latest development: Recently announced treatment breakthroughs provide new hope for people with non-small cell lung cancer (NSCLC)—the type of malignancy responsible for 85% of all lung cancers.

THE NEW HEAVY HITTERS

• Immunotherapy. Some of the newest treatments for NSCLC are immune checkpoint inhibitors—drugs that energize the immune system to kill cancer cells by blocking one of two cancer-promoting proteins, PD-1 and PD-L1. These drugs include pembrolizumab (Keytruda), the immunotherapy treatment credited with saving the life of former President Jimmy Carter when melanoma spread to his brain…nivolumab (Opdivo)…atezolizumab (Tecentriq)…and durvalumab (Imfinzi).

Typically, these drugs are used only as second-line therapies for patients with advanced disease who haven’t responded to other types of treatments, such as chemotherapy. But several studies presented at the 2018 annual meeting of the American Association for Cancer Research show that immunotherapy can work as a first-line therapy for people with advanced NSCLC, improving survival.

New scientific findings: A combination of the immunotherapy drug pembrolizumab and chemotherapy worked better than chemo alone as a first-line treatment for patients with metastatic NSCLC—69% were still alive after one year in the combo group, with only 49% alive in the chemo-only group, according to a one-year study published in The New England Journal of Medicine.

In a similar one-year study, patients with stage IV lung cancer were given either chemotherapy or two immunotherapy drugs—nivolumab and ipilimumab (Yervoy), which blocks CTLA-4, a protein similar to PD-1. Those treated with immunotherapy were 42% less likely to have their disease progress than those who received other treatment.

Meanwhile, research focusing on the use of immunotherapy without chemotherapy as a first-line treatment—reported at a recent meeting of the American Society of Clinical Oncology—also delivered positive results. The stage IV NSCLC patients getting pembrolizumab lived four to eight months longer than those getting chemo. Only 18% of the immunotherapy patients suffered severe side effects, such as inflammation of the lung, liver or colon, versus 41% of those in the chemo group.

Takeaway: With the impressive results of these studies, first-line treatment with an immunotherapy drug with or without chemotherapy is now the standard-of-care for most cases of advanced NSCLC. If a test of your tumor tissue shows that you have a high PD-L1 activity—and one-third of patients with NSCLC do—then single-agent immunotherapy might be the best first treatment for you with or without chemotherapy. Patients whose tumor does not express high levels of this marker still benefit from the combination of immunotherapy with chemotherapy in the majority of cases. Talk to your oncologist.

• Gene-modulating drugs. This type of therapy uses drugs to turn off one of several genetic mutations (oncogenes) that can drive lung cancer. An estimated 10% to 20% of NSCLC patients have the epidermal growth factor receptor (EGFR) mutation, which is treated with drugs such as erlotinib (Tarceva), afatinib (Gilotrif), gefitinib (Iressa) and osimertinib (Tagrisso). An estimated 5% have the anaplastic lymphoma kinase (ALK) mutation, which is treated with drugs such as crizotinib (Xalkori), ceritinib (Zykadia), alectinib (Alecensa) and brigatinib (Alunbrig).

These oral drugs are so powerful that they can, in rare cases, extend life by five years or more. However, the newer and more effective of these drugs—such as alectinib for ALK—has been used as a second-line therapy. Now this treatment paradigm is changing.

New scientific findings: In a study published earlier this year, more than 500 NSCLC patients with an EGFR mutation got either osimertinib as a first-line treatment or the previous standard therapy (erlotinib or gefitinib). After 12 months, those taking osimertinib had a 54% lower risk for disease progression or death. In April of this year, the FDA approved osimertinib for first-line treatment of metastatic NSCLC.

In a study of more than 300 metastatic NSCLC patients with the ALK mutation, the disease progressed or death occurred in 41% of those receiving alectinib (a newer more effective drug) compared with 68% receiving crizotinib, an older drug, after about a year and a half. The alectinib group also had fewer side effects. Patients receiving alectinib had control of their tumors for almost three years, on average.

Takeaway: If you are diagnosed with NSCLC, get tested to find out if you have a genetic mutation driving the disease. If you do, talk to your oncologist about the best gene–targeting drug for you—patients with these mutations often do not benefit from immunotherapy.

THE LIQUID BIOPSY OPTION…

The gold standard for biopsies in NSCLC is a tissue biopsy—removing a portion of the tumor and testing it—to identify the specific type of cancer and genetic mutations that inform treatment decisions.

Problem: In many cases, a tissue biopsy isn’t possible—for example, the position of the tumor in the lung or other organ may make it too difficult to biopsy, or the patient may have emphysema.

Solution: A liquid (blood-based) biopsy can be used when a tissue biopsy is not an option. The FDA approved liquid biopsy for lung cancer in 2016. A recent study published in JAMA Oncology suggests that combining liquid biopsies with tumor biopsies can improve the chance of finding a targetable mutation. Ask your oncologist if this is right for you. FoundationOne and Guardant360 are the two most widely used liquid biopsies.

https://bottomlineinc.com/health/lung-cancer/what-it-means-when-your-doctor-finds-a-spot-on-your-lung

Immunotherapy drug could halt the return of the 'most aggressive form of breast cancer' and 'save thousands of lives'

• Women with triple negative breast cancer were given the drug Keytruda 
• Keytruda was taken alongside chemo to shrink tumours before surgery
• More than 60% of the patients showed no sign of cancer after the operation

By ALEXANDRA THOMPSON SENIOR HEALTH REPORTER FOR MAILONLINE

PUBLISHED: 10:27 BST, 30 September 2019 | UPDATED: 15:31 BST, 30 September 2019

An immunotherapy drug could prevent a 'particularly aggressive' form of breast cancer returning, research suggests.

Scientists gave more than 700 women with triple negative breast cancer Keytruda (pembrolizumab), a drug which has been shown to be effective in lung and skin forms of the disease.

The patients took Keytruda alongside chemotherapy to shrink their tumour, before having the malignant mass surgically removed. 

Some 64 per cent of the women showed no sign of cancer after going under the three-pronged treatment, the study found. This is compared to 51 per cent of those who had chemo and a placebo. 

Fifteen months later, the disease was 37 per cent less likely to return in the women who took Keytruda, the Queen Mary University of London researchers added.  

The scientists have called the results 'very promising', with the drug having the potential to 'cure more patients' and 'save thousands of lives'.

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Over 700 women with triple negative breast cancer were given Keytruda (pembrolizumab) 

'Triple-negative breast cancer is a particularly aggressive form of cancer with the potential to devastate lives,' lead author Professor Peter Schmid said.

'We have been desperately looking for better treatment options. These early results suggest the addition of immunotherapy to chemotherapy leads to a substantial reduction in recurrences in this form of breast cancer.

'These are preliminary results, but they are very promising. If we prevent the cancer from coming back, we cure more patients, but we need longer-term data to confirm this.'

He added, according to The Sun: 'The potential of this is massive — this approach could save thousands of lives.'

WHAT IS KEYTRUDA? AND IS IT AVAILABLE IN THE UK? 

Keytruda (pembrolizumab) is an IV immunotherapy that works with a cancer patient's immune system to help them fight the disease.

It does this by blocking PD-L1 on the surface of cancer cells. This takes the brakes off the immune system, setting it free to attack cancer cells.  

Keytruda, developed by Merck, has been approved by the FDA to treat the following cancers:

• Advanced melanoma
• Advanced non-small lung
• Head and neck squamos cell
• Classical Hodgkin lymphoma
• Primary mediastinal B-cell lymphoma
• Bladder and urinary tract 
• Advanced stomach
• Advanced cervical 
• Those with a 'DNA mismatch repair', which can include breast 

In the US, Keytruda - injected twice a week - can be used in adults or children with any of the above cancers that cannot be surgically removed or have progressed following treatment. 

In June 2018, NHS England announced the drug will be routinely available on the health service for patients with lung cancers that have spread. It can already be dished out for patients with melanoma or Hodgkin lymphoma.

Some patients have also chosen to have the treatment privately.  

Studies show the drug can shrink different types of tumours and boost a patient's response to other treatments.  

But Keytruda can also cause the immune system to attack healthy organs and tissue, which can be life threatening. Complications may include colitis, hepatitis or kidney failure. 

Source: Keytruda.com

One in eight women in the UK and US will develop breast cancer at some point in their lives, Cancer Research UK statistics show. 

In the UK, triple negative breast cancer makes up 15 per cent of cases of the disease - around 7,500 people each year.

And in the US, it is responsible for 10-to-20 per cent of breast cancers, according to Breastcancer.org

Triple negative tumours do not have receptors for the hormones oestrogen and progesterone or the HER2 protein.

As a result, hormone treatments and the HER2-binding drug trastuzumab (Herceptin) do not work. 

Patients are therefore usually forced to have chemotherapy and surgery.

Immunotherapy is increasingly being used to fight cancer by boosting the body's natural defences. 

To investigate its potential in triple negative breast cancer, the scientists tested Keytruda in 124 clinics across 21 countries between March 2017 and September last year.

Keytruda was given to 748 patients before and after surgery, while 390 women had chemo and a placebo.

After surgery, 64.8 per cent of the patients who received immunotherapy had no signs of cancer versus 51.2 per cent of those treated with chemo and a placebo.

Full results will be presented at the European Society for Medical Oncology (ESMO) 2019 Congress in Barcelona. 

'We know if cancer is completely gone out of the breast, they have a much better long-term survival, the cure rates are much higher,' Professor Schmid said.

'Whereas in patients where there is still cancer visible at the time that we do the operation, they have a higher risk of recurrence.' 

Fifteen months later, there was a 'favourable trend' towards the patients staying cancer-free, which Professor Schmid calls 'incredibly encouraging'.  

Keytruda is an ‘anti PD-1 inhibitor', which make cancer cells more ‘visible’ to the immune system. 

In recent years it has become widely available on the NHS for lung and skin cancer, and is used in some cases for types of bladder cancer and lymphoma. 

ESMO spokesman Professor Fabrice André, of the Institut Gustave Roussy in Villejuif, France, said: ‘Triple negative breast cancer represents an unmet medical need, since the only approved medical therapy at early stages of the disease is chemotherapy.

‘This study could have a major impact on treatment for these patients.’

Future research will track cancer recurrence in both Keytruda and placebo-treated groups over a long time, the scientists said. 

WHAT IS BREAST CANCER, HOW MANY PEOPLE DOES IT STRIKE AND WHAT ARE THE SYMPTOMS?

Breast cancer is one of the most common cancers in the world. Each year in the UK there are more than 55,000 new cases, and the disease claims the lives of 11,500 women. In the US, it strikes 266,000 each year and kills 40,000. But what causes it and how can it be treated?

What is breast cancer?

Breast cancer develops from a cancerous cell which develops in the lining of a duct or lobule in one of the breasts.

When the breast cancer has spread into surrounding breast tissue it is called an 'invasive' breast cancer. Some people are diagnosed with 'carcinoma in situ', where no cancer cells have grown beyond the duct or lobule.

Most cases develop in women over the age of 50 but younger women are sometimes affected. Breast cancer can develop in men though this is rare.

The cancerous cells are graded from stage one, which means a slow growth, up to stage four, which is the most aggressive.

What causes breast cancer?

A cancerous tumour starts from one abnormal cell. The exact reason why a cell becomes cancerous is unclear. It is thought that something damages or alters certain genes in the cell. This makes the cell abnormal and multiply 'out of control'.

Although breast cancer can develop for no apparent reason, there are some risk factors that can increase the chance of developing breast cancer, such as genetics.

What are the symptoms of breast cancer?

The usual first symptom is a painless lump in the breast, although most breast lumps are not cancerous and are fluid filled cysts, which are benign. 

The first place that breast cancer usually spreads to is the lymph nodes in the armpit. If this occurs you will develop a swelling or lump in an armpit.

How is breast cancer diagnosed?

• Initial assessment: A doctor examines the breasts and armpits. They may do tests such as a mammography, a special x-ray of the breast tissue which can indicate the possibility of tumours.
• Biopsy: A biopsy is when a small sample of tissue is removed from a part of the body. The sample is then examined under the microscope to look for abnormal cells. The sample can confirm or rule out cancer.

If you are confirmed to have breast cancer, further tests may be needed to assess if it has spread. For example, blood tests, an ultrasound scan of the liver or a chest x-ray.

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How is breast cancer treated?

Treatment options which may be considered include surgery, chemotherapy, radiotherapy and hormone treatment. Often a combination of two or more of these treatments are used.

• Surgery: Breast-conserving surgery or the removal of the affected breast depending on the size of the tumour.
• Radiotherapy: A treatment which uses high energy beams of radiation focussed on cancerous tissue. This kills cancer cells, or stops cancer cells from multiplying. It is mainly used in addition to surgery.
• Chemotherapy: A treatment of cancer by using anti-cancer drugs which kill cancer cells, or stop them from multiplying
• Hormone treatments: Some types of breast cancer are affected by the 'female' hormone oestrogen, which can stimulate the cancer cells to divide and multiply. Treatments which reduce the level of these hormones, or prevent them from working, are commonly used in people with breast cancer.

How successful is treatment?

The outlook is best in those who are diagnosed when the cancer is still small, and has not spread. Surgical removal of a tumour in an early stage may then give a good chance of cure.

The routine mammography offered to women between the ages of 50 and 70 mean more breast cancers are being diagnosed and treated at an early stage.

For more information visit breastcancercare.org.uk or www.cancerhelp.org.uk

https://www.dailymail.co.uk/health/article-7519901/Immunotherapy-drug-help-thousands-women-aggressive-form-breast-cancer.html

Immune therapy scores big win against lung cancer in study (Keytruda)

CHICAGO—For the first time, a treatment that boosts the immune system greatly improved survival in people newly diagnosed with the most common form of lung cancer. It's the biggest win so far for immunotherapy, which has had much of its success until now in less common cancers.

By Marilynn MarchioneThe Associated Press

Mon., April 16, 2018

In the study, Merck's Keytruda, given with standard chemotherapy, cut in half the risk of dying or having the cancer worsen, compared to chemo alone after nearly one year. The results are expected to quickly set a new standard of care for about 70,000 patients each year in the United States whose lung cancer has already spread by the time it's found.

Research released on April 16 suggests that many more lung cancer patients may benefit from treatments that boost the immune system, which have scored some of their biggest wins until now in less common cancer types. Using one of these drugs, like Keytruda (shown here), with usual chemotherapy extended survival for people newly diagnosed with the most common type of cancer that had spread beyond the lungs, one study found.  (MICHAEL LUND/MERCK / THE ASSOCIATED PRESS)

Another study found that an immunotherapy combo — the Bristol-Myers Squibb drugs Opdivo and Yervoy — worked better than chemo for delaying the time until cancer worsened in advanced lung cancer patients whose tumors have many gene flaws, as nearly half do. But the benefit lasted less than two months on average and it's too soon to know if the combo improves overall survival, as Keytruda did.

All of these immune therapy treatments worked for only about half of patients, but that's far better than chemo has done in the past.

"We're not nearly where we need to be yet," said Dr. Roy Herbst, a Yale Cancer Center lung expert who had no role in the studies.

Results were discussed Monday at an American Association for Cancer Research conference in Chicago and published by the New England Journal of Medicine. The studies were sponsored by the drugmakers, and many study leaders and Herbst consult for the companies.

ABOUT THE DRUGS

Keytruda, Yervoy and Opdivo are called checkpoint inhibitors. They remove a cloak that some cancer cells have that hides them from the immune system. The drugs are given through IVs and cost about $12,500 a month.

Keytruda was approved last year as an initial treatment with chemo for the most common form of advanced lung cancer, but doctors have been leery to use it because that was based on a small study that did not show whether it prolongs life.

The new study, led by Dr. Leena Gandhi of NYU's Perlmutter Cancer Center, gives that proof. In it, 616 patients were given chemo and some also received Keytruda. Those not given Keytruda were allowed to switch to it if their cancer worsened.

After one year, 69 per cent of people originally assigned to Keytruda were alive versus 49 per cent of the others — a result that experts called remarkable considering that the second group's survival was improved because half of them wound up switching.

How much it ultimately will extend life isn't known — more than half in the Keytruda group are still alive; median survival was just over 11 months for the others.

The Keytruda combo also delayed the time until cancer worsened — an average of nine months versus five months for the chemo-only group.

That's a big difference for such an advanced cancer, said Dr. Alice Shaw, a Massachusetts General Hospital lung cancer expert and one of the conference leaders. "This is really a pivotal study ... a new standard of care," said Shaw, who has no ties to the drugmakers.

Rates of serious side effects were similar, but twice as many in the Keytruda group dropped out because of them. More than 4 per cent of that group developed lung inflammation and three patients died of it.

THE COMPETITION

Dr. Matthew Hellmann of Memorial Sloan Kettering Cancer Center in New York led a study testing the Opdivo-Yervoy combo versus chemo in a slightly different group of newly diagnosed advanced lung cancer patients.

The study design was changed after it was underway to look at results according to patients' tumour mutation burden — a measure of how flawed their cancer genes are, according to a profiling test by Foundation Medicine. Medicare recently agreed to cover the $3,000 test for advanced cancers.

Of 679 patients, 299 had a high number of gene flaws in their tumors. In that group, survival without worsening of disease was 43 per cent after one year for those on the immunotherapy drugs versus 13 per cent of those on chemo. The immunotherapy drugs did not help people with fewer tumour gene flaws.

"We have a tool that helps us determine who are the patients that are most likely to benefit from this combination," Hellmann said.

The median time until cancer worsened was about 7 months on the immunotherapy drugs versus 5.5 months for chemo. Serious side effects were a little more common in the chemo group.

Another rival, Genentech, recently announced that its checkpoint inhibitor, Tecentriq, improved survival in a study similar to the one testing Keytruda. Details are expected in a couple months.

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Marilynn Marchione can be followed on Twitter: @MMarchioneAP

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The Associated Press Health & Science Department receives support from the Howard Hughes Medical Institute's Department of Science Education. The AP is solely responsible for all content.

https://www.thestar.com/life/health_wellness/2018/04/16/immune-therapy-scores-big-win-against-lung-cancer-in-study.html

Behind big pharma's race to develop the next wave of cancer therapy

Pharmaceutical companies are betting big on a new wave of innovative cancer therapies they believe will be more effective than existing treatments and move them a big step closer to finding a cure for the disease.

•  Iain Withers 

25 JUNE 2017 • 9:14PM

Staff working in Astrazeneca's Medimmune biologic laboratory in Cambridge CREDIT: DAVID PARKER/ANL/REX/SHUTTERSTOCK

The fast-emerging branch of therapies – immuno-oncology (IO) – works by equipping the body’s immune system with the tools to kill cancer cells.

Britain’s FTSE 100 giant AstraZeneca and rival pharma conglomerates, including America’s Merck & Co and Bristol-Myers Squibb (BMS), Switzerland’s Roche and Germany’s Merck KGaA are in a race to develop the most effective IO therapies.

When they work, the body learns to fend off cancer as it would a virus, developing a long-term memory for killing off tumours in the process.

They are already transforming lives, with tens of thousands of patients around the world benefiting from first generation IO treatments, which can extend lives for months or years longer than chemotherapy and radiotherapy with fewer debilitating side effects.

It’s this “long-term benefit” and “curative potential” that excites Stuart Farrow, director of biology at Cancer Research UK’s commercial arm Cancer Research Technology, which is partnering with industry on developing IO treatments. “It is the biggest breakthrough in oncology R&D for 20 years, possibly even since chemo,” he says.

Immuno-oncology is a huge opportunity for UK plc. We have an incredibly vibrant science community here.

As well as providing potential life-changing medical benefits, effective IO treatments bring big commercial rewards. IO drugs sales hit $8bn (£6.3bn) last year, led by blockbuster forerunners Keytruda and Opdivo, produced by Merck & Co and BMS respectively.

But analysts say the potential prize is much larger – a $50bn a year market if the future pipeline of IO drugs realise their full potential. That’s because there are still substantial gaps to plug in the market, both for Merck and BMS and its international rivals playing catch-up, including AstraZeneca. Only around 25-30pc of patients have been responsive to the early IO treatments. They also haven’t been approved for every type of cancer, with lung cancer remaining the largest – and largely unmet – potential market opportunity, worth up to an estimated $10bn a year. It is also the biggest cancer killer, responsible for more than 1.6m deaths each year.

So the race is on, with pharma companies increasingly turning to trials of combinations of drugs to try to boost response rates.

For AstraZeneca, Mystic can go a long way to validating CEO Pascal Soriot’s decision to rebuff Pfizer’s £69bn takeover approach CREDIT: CHRIS RATCLIFFE/BLOOMBERG

Two such closely watched trials are due to report by the end of the year – AstraZeneca’s Mystic this summer and BMS’s CM-227, both of which are phase three lung cancer trials that will go some way to demonstrating the medical and commercial potential of IO treatments.

They are also likely to be big market-movers. AstraZeneca investors expect a positive result in Mystic would lead to a 17pc jump in the company’s share price, while a negative result would send them crashing 12pc, according to an average of responses to a Credit Suisse survey.

David Cook, analyst at Panmure, cautions: “Everyone is watching Mystic to see what happens. If it’s a failure the reaction will likely be severe. With clinical trials the market tends to punish you when it goes wrong.”

Meanwhile, BMS shareholders will be hoping the company’s combination of Keytruda and Opdivo will garner positive results, after a failed lung cancer trial last August sent shares nosediving. They are still more than 20pc down since the news, slashing its market capitalisation by more than $30bn to $92bn.

For AstraZeneca, Mystic can go a long way to validating CEO Pascal Soriot’s decision three years ago to rebuff American rival Pfizer’s £69bn takeover approach in order to focus on its drugs pipeline, and on oncology R&D in particular. Since then AstraZeneca has doubled its spending on oncology R&D to around $2.6bn, almost half its total $6bn spend. A group of 1,118 patients in 17 countries are taking part in the Mystic trial, which combines IO drug durvalumab, commercially known as Imfinzi, with antibody tremelimumab.

For its part AstraZeneca insists Mystic should not be seen as the “binary” market event some investors are making it out to be.

Robert Iannone, head of IO at AstraZeneca, stresses “there’s quite a bit of optionality” built into the Mystic trial, as it will capture data for a variety of types of patients, as well as produce further “more robust” overall survival data in 2018.

AstraZeneca has seven late stage cancer drug trials underway, and another seven outside the cancer space

Nor is AstraZeneca a one-horse stable when it comes to cancer drug development. Mystic is one of seven late stage cancer drug trials the firm is working on, while it has another seven outside the cancer space.

Imfinzi has already generated positive headlines for AstraZeneca this year, boosting investor confidence ahead of Mystic, by winning US approval for use by some bladder cancer patients and producing positive trial results in a separate group of lung cancer sufferers.

Elsewhere, fellow FTSE 100 firm GSK has largely vacated the oncology market after selling its cancer drugs portfolio to Novartis in 2015, but it retains an oncology R&D operation that investors will want to keep an eye on.

Yet the IO drugs space is not just the domain of massive conglomerates. A whole host of innovative start-ups are investing in developing IO therapies, including UK firms working in partnership with Britain’s world-leading bioscience universities.

If it’s a failure the reaction will likely be severe. With clinical trials the market tends to punish you when it goes wrong

Smaller firms working in IO include Crescendo Biologics, Cell Medica, e-Therapeutics, F-star, Targovax, ANGLE, IGEM and Scancell.

“IO is a huge opportunity for UK plc,” says Cancer Research’s Mr Farrow. “We have an incredibly vibrant science community here.” The fierce race among big pharma companies to become IO market leaders means even small firms with limited clinical data can be candidates for takeovers or successful IPOs, industry insiders say.

But companies working in this cutting-edge field still face big challenges. IO drugs are known to produce significant side-effects for some patients, including the immune system mistakenly attacking normal organs and gut problems such as severe diarrhoea.

Then there’s the cost, put at around £150,000 a year per patient for a typical IO treatment. Will the NHS and other country’s health services be willing to pay this?

Scientists in the field say the potential for side-effects and the high costs make it more crucial than ever to identify which patients stand to get the best outcomes from particular treatments, by identifying biomarkers that make them most suitable and through more targeted treatments.

IO nonetheless offers up huge potential, with scientists estimating the approach may be able to address 60pc of all cancers through combinations of drugs within five years.

Dr David Berman, head of oncology innovative medicines at MedImmune, part of AstraZeneca, is bullish for the future of his field: “This is a golden age for patients and an exciting time.”

http://www.telegraph.co.uk/business/2017/06/25/behind-big-pharmas-race-develop-next-wave-cancer-therapy/