Cancer immunology: Marketplace of hope


Are these new drugs living up to their initial promise?

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Previously we discussed some of the concerns about direct-to-consumer (DTC) advertising for cancer immunology drugs. It is probably sufficient for our purposes to set-aside the question of whether DTC is ultimately good or bad, and simply acknowledge that DTC advertising is deeply entrenched in the U.S. market, and very unlikely to change anytime soon.

But what about the drugs themselves? Are the new cancer immunology drugs living up to their initial promise?

Clinical landscape for immunology

Immunotherapy is a new type of cancer treatment. Conventional chemotherapy drugs act directly to attack tumors with toxic chemicals. While these can be effective, they are hard to control in a targeted way; also, they can also cause debilitating side-effects.1 Immunotherapies like Keytruda and Opdivo are called checkpoint inhibitors. They work by inhibiting a natural process in our immune system. Inhibiting that natural process allows the immune system to do its job by seeking and destroying cancerous cells.2

Our bodies typically do attack tumors using the immune system using special cells that kill tumors (called T-cells). T-cells come equipped with spots called checkpoints. When activated, the checkpoints tell the T-cells when to stop attacking in order to prevent them from damaging healthy tissues.3

Some forms of cancer can effectively “trick” the immune system by secreting immune-suppressing proteins that bond to the PD-1 spots. One is called PD-L1. By bonding to the PD-1 spots, the PD-L1 proteins produce a sort of masking effect, where the T-cells see cancer cells as healthy cells. Being masked from the T-cells means tumors are free to grow and reproduce.4

Immunotherapies like Keytruda and Opdivo work by blocking, or, inhibiting the PD-1/PD-L1 connection.5


Protecting the PD-1 receptor sites allows an effective immune response to develop, so the immune system can recognize and kill cancer cells:


Clinical landscape for immunology

Checkpoint inhibitors may not be enough in the fight against cancer. Media reports from an international cancer immunotherapy conference held in the fall of 2016 highlighted several speakers who urged caution regarding the new therapies.6 Some of the leading researchers in immunology warned that that “immuno-oncology will not be as simple as stimulating T-cells to attack tumors;” and that they are seeing relapses despite having a fully activated T-cell response.6

When immunotherapy works, the result can be spectacular. Many of us remember the example when former President Jimmy Carter recently experienced a complete remission of his melanoma.

Some caution is in order here regarding terminology. “Remission” means that the signs and symptoms of cancer are reduced. Remission can be partial or complete. Generally one must remain in complete remission for five years or more, before doctors may say that you are cured.7

But the newest concerns have nothing to do with the technical distinctions between remission and cure. Now researchers are asking whether immunotherapy will ever become a widespread cancer treatment. As of now, only a tiny minority of patients expected to die from cancer will benefit from immunotherapy.8

As this graph illustrates, fully two-thirds (68.8%) of Americans predicted to die of cancer will die of one that currently has no FDA-approved immunotherapy options. Looking just at the cancers for which immunotherapy has been approved, fewer than 30% of all cancer types are potentially treatable as of February 2017. [* See note below.]


Another way to look at the impact of immunology is to ask how many can expect to benefit from these drugs. This graph shows that, when we consider all of the patients dying of cancer in the U.S. this year, fewer than 10% might benefit from a checkpoint inhibitor drug:


Side effects are also a very real concern that can get overlooked. For the most part, immunotherapy is fairly well-tolerated. Unlike chemotherapy and radiation, immunotherapy leaves healthy cells intact. 3

But sometimes the immune system overreacts, which can be dangerous. A severe immune system overreaction is potentially fatal.3

A wide range of adverse events (side effects) are observed with immunotherapy agents. These include severe and potentially life-threatening inflammation of the lungs, colitis, autoimmune thyroid disease, inflammation of the pituitary gland, and vitiligo (a disease that causes the loss of skin color in blotches).9 More recent studies have found new-onset rheumatologic and musculoskeletal adverse events following treatment with immune checkpoint inhibitors.9

The combination of a relatively small pool of treatment candidates, plus the real possibility of severe side-effects makes accurate targeting for these drugs especially important. Unfortunately, this is still a very inexact science.

Genetic testing

Clearly, cancer immunotherapy is not a cure-all. The majority of patients don’t respond to checkpoint inhibitors, even when used on FDA-approved cancers.

But this is not exactly a novel situation. Consider the story of the breast cancer treatment Herceptin® (trastuzumab).

Besides skin cancer, breast cancer is the most commonly diagnosed cancer among American women. Over 40,000 women in the U.S. are expected to die in 2017 from breast cancer.10

In 2005 a study found that adding Herceptin to standard chemotherapy could result in improved outcomes for treating breast cancer. Other studies have shown overall survival with Herceptin improving overall 10-year survival rates from 75% to 84%. 11

But the important thing to know is that the women who were studied had a specific type of breast cancer known as HER2-positive. About 25% of people with metastatic cancer have tumors with too many copies of the HER2 gene, or too many HER2 receptors.12

Herceptin binds to HER2 receptors and blocks them from growing. At the same time, it stimulates the immune system to destroy cancer cells. That makes Herceptin a highly targeted treatment – it works best for HER2-positive cancers. 9

That’s a critical bit of information for two reasons:

  • First, it gives us the opportunity to deliver the precise medicine a patient needs and see optimum results.
  • Second, Herceptin is another extremely expensive immunotherapy – about $70,000 for a full year of weekly infusions – and there is little point in using it on someone who won’t properly respond.13

Consequently, it is now a broadly accepted clinical best-practice to request HER2 testing on every primary invasive breast cancer in order to properly guide the decision to pursue a HER2-targeted therapy like Herceptin.13 In addition, it is standard practice in the insurance world to make sure that no one can receive coverage for Herceptin, unless they have been tested HER2-positive.


Genetic role for checkpoint inhibitors?

Herceptin is a useful illustration because currently, there’s no way to know in advance which patients will benefit from PD-L1 inhibitor drugs. But that may be changing, as recent evidence suggests that there may be a genetic marker that points to superior response rates and better outcomes .

Both Keytruda and Opdivo are based on the same biochemical approach. But in recent clinical trials treating newly diagnosed non-small cell lung cancer (NSCLC) some critical differences emerged:

  • Keytruda showed far better outcomes compared to the standard chemotherapy.15
  • Opdivo showed no benefit at all compared to the standard chemotherapy.16

The critical point is that Keytruda was tested on patients who expressed the PD-L1 biomarker in at least 50% of their tumor cells. Opdivo tested against a much broader patient population that did not have the same level of PD-L1 expression.16


The presence of the PD-L1 biomarker appears to coincide with the increased effectiveness of Keytruda in attacking tumor cells:


Merck, the maker of Keytruda, was quick to incorporate this result into their advertising. Their commercials center on a patient who talks about the PD-L1 biomarker test she took. Her results allow her to receive Keytruda as a first line therapy over chemotherapy for her non-small cell lung cancer (NSCLC).16

These results seem like they ought to offer some guidance for treatment. Slightly fewer than 30% of patients with NSCLC have the minimum level (at least 50%) of PD-L1 expression.15 It would seem simple enough to make a PD-L1 expression test standard in order to proceed with checkpoint inhibitor therapy, thereby restricting the use of these expensive drugs to just those who can benefit from them.

However, unlike the situation with Herceptin and the HER-2 marker, it's not clear that PD-L1 expression is a definitive indicator that checkpoint inhibitor drugs will work.16 There is evidence that patients with high PD-L1 levels are more likely to respond, while those with little or no expression are not. The problem is that we don't know exactly where the response threshold begins and ends.16

Nevertheless, it seems safe to assume that treatment decisions for patients with previously untreated advanced NSCLC will need to take these results into account. Keytruda patients with high PD-L1 expression saw longer progression-free and overall survival rates, and fewer side effects versus chemotherapy.15

Looking ahead, Dr. David Chan, program director for oncology at Torrance Memorial Medical Center in California had some key observations regarding cancer immunotherapy. In his view, not every antibody is the same, and not every cancer is the same. In other words, we’re not likely to see a simple solution, as in a single way to treat cancer.3

Instead, Dr. Chan sees a long, difficult challenge of trying to identify, molecularly, which patients will benefit, and which won’t. This will require a tremendous amount of research, because "…we’ll have to figure it out cancer by cancer, and drug by drug."3


What can we say about the current state of cancer immunotherapy? On the one hand, it is clear that when immunotherapy works, the results are outstanding. Patients with otherwise life-threatening cancers live far longer than expected, and some may respond so well to treatment that their cancers appear to be in permanent remission.7 (As noted above, even a strong response is not the same as cure. None of the checkpoint inhibitors have yet been shown to cure cancer.)

On the other hand, at least today, very few patients can expect to experience such positive outcomes.

Looking ahead, the field continues to advance. One research group reckons that there are over 2,000 products currently in active development in the cancer immunotherapy pipeline – nearly 40% of the entire oncology pipeline.17

Hopefully, some of these drugs will be approved for more cancers, or they may work better in combination with other drugs. However, for several common cancers, like colon and breast cancer, we already know that checkpoint inhibitor drugs work poorly — this is why the first approvals were in cancers like melanoma. So it is unlikely that the percentage of people who benefit from cancer immunotherapy will grow significantly.7

The relatively small population that can benefit from these drugs is vastly mismatched by the massive advertising campaigns promoting them. All told, DTC advertising is pushing 80 drug ads every hour — some of which are, frankly, misleading.18

The percentage of people benefiting from cancer immunotherapy will not change greatly.

– Nathan Gay, MD; Vinay Prasad, MD

Fortunately, the evidence indicates that cancer patients remain relatively level-headed about the endless barrage of advertising aimed at promoting cancer cures. They understand perfectly well that drug makers have a vested interest in being as positive as possible, and that they need to trust their doctors to recommend the right treatments.19

Our role

At BriovaRx®, the OptumRx® specialty pharmacy, we provide much more than specialty medications. The BriovaRx oncology clinical management program offers members the resources, programs and clinical assistance they need to manage their oncology medications with confidence.

Our research has shown that oncology patients who received support from BriovaRx experienced improved medication adherence and quality of care along with reduced overall costs of care. Our designated specialty clinicians provide expert advice and disease-state education, plus targeted prescription adherence counseling.20, 21

Another service, BriovaCommunity provides targeted videos that can help oncology patients feel less isolated and more connected. These videos are sent to individual patients at key points in their treatment, with condition-specific information that helps educate them on their condition and on their medication regimen. They also address how to manage side-effects and provide other tips and advice.

By letting patients share their experiences with other real patients, BriovaCommunity can help patients stay on the path to better health.

At OptumRx, we can help people who are struggling with complex conditions like cancer. We’ll guide you through this difficult time of life with compassion, support, and accurate information.


*As this article was in final production, Merck announced that it had gained FDA approval to start marketing a combination of Keytruda with chemotherapy as a first-line therapy to treat non-small cell lung cancer (NSCLC). Keytruda was already approved as a stand-alone, first-line, therapy for advanced NSCLC, but only for patients who expressed a high level of the PD-L1 biomarker. That equals approximately 30% of NSCLC cases.22

The new approval permits the combination treatment regardless of level of PD-L1, which expands the indication to include about 75% of NSCLC cases. About 14% of all new cancers are lung cancers, and between 80% and 85% of lung cancers are NSCLC.23

Based on this development, we can expect that the percentages of cancers that can and cannot be treated with immunotherapy will change from the 70/30 split shown in the graphic above. However, the basic disparity will remain, which is the central point of the image.

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  2. National Cancer Institute. NCI Dictionary of Cancer Terms: immunotherapy. Accessed at: https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45729 on 04.14.2017.
  3. Healthline News. The Value and Cost of Immunotherapy Cancer Treatments. Oct. 12, 2016. Accessed at: http://www.healthline.com/health-news/value-and-cost-of-immunotherapy#2 on 05.05.2017.
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  10. Breastcancer.org. U.S. Breast Cancer Statistics. Last modified on March 10, 2017. Accessed at: http://www.breastcancer.org/symptoms/understand_bc/statistics on 05.05.2017.
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This article is directed solely to its intended audience about important developments affecting the pharmacy benefits business. It is not intended to promote the use of any drug mentioned in the article and neither the author nor OptumRx has accepted any form of compensation for the preparation or distribution of this article.