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Immune therapy in a Clinical Trial of Anti-PD-1 It Can be Good to be Anti

Dr. Suzanne Topalian, professor of surgery and oncology at Johns Hopkins Sydney Kimmel Cancer Center presented a paper at a recent ASCO meeting which caused quite a stir in the kidney cancer community.  Her short talk is in the link below, with the transcription to follow.Topalian and Title

What’s the good news about being anti?  The complex interplay of our immune system and the manner by which cancer escapes its notice is a challenge to the researchers, but this trial shows that there are many ways to interrupt the growth of cancer cells.  This trial and another mentioned offer new hope to patients who have already exhausted earlier options.

Not only did this trial show that this drug could provide relief to some patients with kidney cancer, lung cancer and melanoma, the presence of this anti-body may serve as a biomarker, and may predict which patients might respond to the drug treatment.  Another step forward and more hope for all of us.

Anti PD-1 (BMS-936558, MDX-1106)


Today I would like to describe do the clinical activity the safety and potential biomarker of clinical response to the drug PD-1, which is an anti-body therapy. PD-1 or Programmed Death-1 is a molecule that is expressed on the surface of activated immune cells it plays a very important role in suppressing the tumor by suppressing antitumor immunity.

1 role of PD-1 in suppressing antitumor immunity

In order to understand how anti-PD one works you need to understand a little bit how the immune system works, and how it can fight cancer. T-cells are a central cell type in the immune system that fight cancer. T cell function is regulated by two different signals. Signal one is a specificity signal, whereby the T cell recognizes its target and here we are talking about the targets being components of tumor Cell., but then you need a second signal to tell, the T Cells what to do, a regulatory signals.  That signal can be either positive or negative.

If the signal is positive or stimulatory,  t he T-cells become activated. They secrete cytokines. They can kill tumor cells. They proliferate; they percolate throughout the body, seeking out and destroying tumor cells.  All of that is what we want to see.

But after activation, T-cells naturally begin to express the molecule PD-1 on their surface. This is will turn the T-cells off.  If they encounter the partner molecule PD-L1 or PD ligand 1, tumors cells can express PD-L1. So the interaction between these two molecules becomes a protective shield, that shields the molecule from immune attack. Even if the T-cell can recognize the tumor and they can get to the tumor, once they get there and they are expressing PD-1, if the tumor is expressing PD-L 1, the T-cells will be turned off. The anti-PD-1 antibody is a blocking antibody to PD-1. It interrupts this interaction and functions to rescue exhausted T-cells and to enhance anti- tumor immunity.

The phase 1 trial of anti-PD-1 that I’m describing today is a multi-dose regimen in which something is given the outpatient in the outpatient clinic once every two weeks. Patients were treated for a cycle of four treatments over eight weeks. At the end of which, they were restaged. Patients were eligible for these trials if they had advanced metastatic melanoma, kidney cancer, lung cancer, prostate cancer, colorectal cancer with progressive disease after having had at least one prior systemic therapy.

But they were allowed to have up to five of the therapies. Generally these patients who came on this trial had good performance tab status. But they were heavily pre-treated. Approximately half of them had at least three prior therapies be before they came onto the trial.

After the first cycle of treatment if patients had rapid continuation of disease or clinical deterioration, they went off study. If they had unacceptable side effects, the patient remained on study. They did not receive any more drug, but they continued under observation. If the patient demonstrated tumor regression or stable disease or even if they  had some progressive disease, but were clinically stable, we continued to treat those patients until we saw confirmed Complete response, worsening or progressive disease or unacceptable toxicity.  We could treat patients on this trial continuously for two years. After, they went into a follow up phase.

3 BMS-936558 related Adverse Events Here I’m showing you the drug-related adverse events are side effects that occurred in at least 5% of 296 patients which was the total patient population on this trial You can see that serious side effects were encountered in 14% of the patients. The most common side effects are listed here (fatigue, rash diarrhea, pruritis, etc.) There other side effects that are not listed here because they occurred less frequently. Many of the side effects were consisted with the side effects with over immune related causality as you might expected if you release the brakes on immune responses. As we are seeing anti tumor responses, you might also see immune-related sided effects.

We did see three treatment related deaths on this study. This was in 1% of the patient population due to pneumonitis, or lung inflammation which we’ve believe has an immune-related etiology. Over the course of time we developed better ways to identify people who are at risk for the side effect and also better ways to detect it early on and to treat it aggressively.

Also note that only 5% of all patients treated on this trial had to discontinue treatment, due to related side effects so in general the treatment was well tolerated in an outpatient setting, and in general the side effects were manageable.

4 Clinical Activity of BMS-9356558

This is showing the clinical activity of anti-PD-1 antibody in three different types of cancer across a wide range of doses. (Showing doses (mg/kg) of 0.1-10 for melanoma, 1-10 for lung cancer, and 1 or 10 in RCC). The largest number of patients in this treatment population of 236 patients who had at least six months of follow-up were 94 with melanoma.  We had 26 patients (28%) who had objective responses. An objective response means either a complete response or a significant partial regression of cancer.

We also saw stable disease that lasted at least six months in another 6% of patients. Among lung cancer patients we saw patients with squamous as well as non-squamous subtypes we saw a CR plus PR of 18%, and with a patient population of 76 and again 6% with stable disease, with another group of patients with stable disease (referencing 7% of lung cancer patients.)

Finally in kidney cancer (33 patients), 27% had a response rate and 27% who had prolonged stable disease.  There were 31 patients on this trial who had a response that occurred at least one year ago and among those 31 patients, two thirds of them had a response that persisted for more than one year. One of the remarkable features about this therapy is that it can induce very durable responses in otherwise treatment-refractory patients with advanced disease.  We did not reserve any objective responses in 19 colon cancer patients or 13 prostate cancer patients.

Finally I’d like to draw your attention to a possible molecular marker that would allow us to predict which patients are most likely to respond to therapy.

In a subset of 42 patients on this trial, we examined pre-treatment tumor biopsies for presence of PD-L1—and again this is the partner molecule to the PD-1 that is expressed on tumor cells. What we found was a correlation between the expression of PDL-1 on tumor cells and here I am showing you the pre-treatment staining biopsies.

I am showing you with its ringed expression an example of melanoma, kidney and cancer in a sample of lung cancer. When we saw this kind of expression in that group of patients we had a 36% objective response rate.  If we did not see that expression on the surface of tumor cells we did not had no responders. I would stress that these are very preliminary data but give us an important lead for further investigations and potential biomarker development.

In conclusion anti-PD-1 antibody–BMS 936558– can be administered safely in an outpatient setting for heavily pretreated patients with durable clinical benefit for patients with lung cancer, melanoma and kidney cancer.

6 Conclusions

These results will be released tomorrow, as you know in the New England Journal of Medicine, which is under embargo until early tomorrow morning. At the same time in the New England Journal, there’s a companion paper with the blocking antibody against PDL-1. The lead author of that paper here is Dr. Julie Braemar of Johns Hopkins and shall be available to answer questions at the end of session.

We found responses also in melanoma and lung cancer and kidney cancer with a blocking antibody against PD-L1, so we feel these two studies are in a sense bookends to point up the point the importance of the PD-1 pathway in cancer therapy across multiple histologies.

The preliminary data correlating PDL-1 expression in pretreatment tumor biopsies with outcomes needs to be further explored and that’s an area of active investigation.  Finally controlled clinical registration trials of this drug with patients with the three types of cancer that seem to respond are planned. Thank you for your attention.





Filed under Biological Systemic, Clinical Trials, Immune Therapies Old & New

A Second Opinion: How the Heck Do I Do That? And What If?

Second opinion? How do I  dare ask my doctor?  He seems so nice, he helped my mother, what makes me think he is wrong, what if he gets mad at me, how will it affect my care, what if the other doctor says the same?  All this goes through your head when you question the diagnosis or treatment plan you have just been given.  But the failure to ask for that second opinion will always haunt you, and may cost you a better treatment, or your life.

Nothing is more frightening than a cancer diagnosis–except perhaps the fear that you do not have the best advice or the best doctor. At minimum we want options and some control. You mayonder if your doctor really knows what he is talking about–you certainly have no way to judge, except to judge how he handles your request for a second opinion.

If the doctor proclaims that only he is qualified to treat you, and that no one else could possibly offer you anything else, the decision is easy.  Just stand up and walk out, getting all your records as you exit.  Your records are yours legally, of course, and should be in hand even when you work wonderfully with your doctor.

You may value your doctor’s advice, but know that your disease is rare and difficult, and that new information may have relevance to your case.  Can your doctor possibly have all the latest information at his finger tips?  And what about that article which you read on the internet or that your friend sent you from his hospital?

First of all, your doctor cannot possibly be up-to-date on all aspects of care and research into your disease.  One doctor estimated that if read two medical journal articles per evening, by the end of the year, he would be only 400 years behind!  And that was several years ago.

One patient friend through ACOR and its kidney cancer list serv has shared his approach, which has been effective and let him work closely with his doctor, while pursuing questions and potential treatments not readily available through his doctor in Australia.  I have made tiny changes to his letter, as it follows.  Good advice and the results, all relevant to us.

Tony starts: ” I’ll  outline how I start “delicate” discussions and get involvement from the likes of the hospital pharmacist. After working out exactly the treatment I want, I kick-start with a simple email, usually to my (general) oncologist. Importantly, I always attach one only medical study –  which is either current or past year.

My request for a treatment is always based on the conclusion in my cited study. I never offer my own opinion or view. I always keep the email short, logical and free of any argumentative material. This leaves the oncologist in the position of having to either (1) meet my request or (2) find grounds to reject the study itself or (3) to call in experts from other disciplines.

  I  learned that the medical decision making process mirrors life outside the medical profession where business managers and bureaucrats want that proverbial piece of paper in case something goes wrong – in this case it’s the well selected medical study (but finding exactly the right study can sometimes involve a lot of work). I find that
these general non-RCC specialists do respect precise RCC studies as they have no hope of keeping up with everything in every cancer type. Simple logic on basis of a reasonably current medical study is the art.

My simultaneous important method is little known fine print I found in our Oz hospital system where every patient is entitled to a second opinion from every relevant discipline. (Tony is in Australia.)

So where, an issue is complex, I respectfully ask for my med-onc’s opinion on whether we should get a second opinion. That gets a much wider team involved where the med-onc doesn’t want sole responsibility for decision making. All just normal human stuff where it’s not smart to make a decision contrary to a current medical study.

So far, I have pulled off four little feats:

The first was getting the urology department to reverse their initial decision to not neph me (they wanted to try to “reduce” my 10cm tumour with systemic drugs and otherwise reckoned I was at risk of karking it on the table).

Then, I got a thoracic surgeon involved with agreement for a rib resection that would have made me disease free (but surgery was called off the day before the scheduled date for sudden emergence of liver and lung mets).

Then, I got the hospital itself to pay for a shot of the very important zoledronic acid (Zometa) – Unbelievably, it is not on our PBS for RCC unless the patient has high blood Ca. Discussion continues on whether they will pay for the shot.
More recently, after one week into first Sutent round, I discovered from doing my own due diligence that another drug I must take for an unrelated condition dilutes the efficacy of the Sutent by about 50% which is unacceptable. My now well practised email / study / second opinion request procedure got the ball rolling resulting in an embarrassment of riches in a big team my med-onc pulled together.

Next week, for the first time I meet with a further member of my expanded team – an oncology radiation expert.”


Tony is obviously engaged in his own treatment, comfortable and motivated to read through medical articles, and choosing those which have impact on his treatment options.  He has done his homework  carefully and backs up the request with the medical article, i.e., in the physician’s language.  Tony puts himself in the equation, by asking if “we” should get a second opinion from an expert, partnering with his doctor in this request.  He has wisely calculated the needs of the doctor, and the system requirements. His results speak for themselves, and can have impact for the next patient the doctor sees!

You may think that this is a laborious process, and one which should not be necessary, but the reality is that it is both necessary and effective.  Getting the best possible treatment and making sure that your doctor supports you in this quest may save your life.

As a friend said, doing these kinds of things may save you someday from waking up dead…


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Filed under Clinical Trials, Making a Plan