When we’re trying to fight against an adversary that is as strong and full of tricks as cancer, what we need to do is look for points of vulnerability – Achilles heels.   We all remember, of course, that the mother of Achilles dipped him in the River Styx when he was a tiny boy, so as to make him invulnerable.   She held him by the heel, which did not go into the water, and so, although Achilles was mostly invulnerable, one heel remained vulnerable.   And it was in that heel that Paris pierced Achilles with a spear and killed him.  

For a long time, the only Achilles heel in cancer that medical science was aware of was that cancer cells appeared to be greedier for nourishment than non-cancerous cells.   The cancer cells simply ingest a larger share of the nutrients that are present in the circulation than do the normal cells.   So if the fluid in the circulatory system contains a substance that is poisonous to cells – i.e., cytotoxic – the cancer cells will swallow more of it than their normal neighbors will.   The normal cells may experience some harm, but the cancer cells will have committed suicide.   That was the basis for chemotherapy for a considerable period.   At first, chemotherapy didn’t much resemble the spear that Paris wielded against Achilles, but a much cruder blunt instrument.

One of the oldest groups of chemotherapy drugs makes use of alkylating agents, which attach an alkyl group to the cell’s DNA, preventing the cell from replicating.   An alkylating agent, cyclophosphamide, continues to be widely used in cancer treatment, despite its toxicity to some normal cells such as those in bone marrow.   Cyclophosphamide and some related chemotherapy agents are derived from mustard gas.  Some alkylating agents that contain platinum, such as carboplatin and cisplatin, present a somewhat lower risk.

Drugs such as fluorouracil, gemcitabine, and methotrexate interfere with the normal metabolism of cells such that they stop growing.   Another group of drugs target an enzyme that signals the genetic material inside the cancer cell to divide and replicate.   These include bleomycin, daunorubicin, and doxorubicin.

Evolution of chemotherapy: Searching for another target

The obvious drawback in these chemotherapy agents is that they affect normal cells as well as cancer cells; the hope is that the effect on cancer cells is more pronounced than the effect on normal cells.   We need to remember that cancer cells are not all that different from the normal cells from which they originate.   The chief difference is that the cancer cells lack the genetic information that leads to programmed cell death, or apoptosis, in normal cells.   Apoptosis is an immensely valuable characteristic in normal cells.   It essentially leads to a population of normal cells that is relatively young and healthy, and makes room for beneficial evolutionary changes as those cells divide and reproduce.

Cancer cells arise when that reproductive process in normal cells goes off track.   This can happen due to an external stimulus – exposure to a carcinogen such as tobacco smoke or radiation – and it can also happen as the result of random errors in transcription.   Most of time, the results of those errors is meaningless, but if the error happens to eliminate the mechanism that brings about apoptosis, the cell will continue to replicate without limit.   What we then have is a colony of cancer cells.  

Targeted chemotherapy

A way of preventing the replication of cancer cells is by targeting the mechanisms that enable the cancer cells to replicate, or, as it is termed, mitosis.   Some of these drugs are based on plant alkaloids.   Among the most widely used are a group of drugs which come from vinca alkaloids.   (Readers of classic detective stories will recognize the term “alkaloid” as being the poison that crafty murderers would employ to dispatch their stingy wealthy uncles.)   Vinca is also known as periwinkle, and it is growing abundantly in my garden, and perhaps yours also.   These drugs, which interfere with the mitosis of cancer cells, include vincristine, vinblastine, and vinorelbine, which are available under a large variety of trade names and from many manufacturers.

More recently, several successful drugs were developed from the bark of the Pacific yew tree, botanical name taxus.   Thus the taxanes, which include paclitaxel (Taxol, Bristol-Myers Squibb), docetaxel (Taxotere, Sanofi-Aventis), and another formulation of paclitaxel (Abraxane, Celgene).   These are quite effective in preventing several types of cancer cell replication and are now widely used as first-line drugs.

Tyrosine kinase inhibitors

Chemotherapy drugs continue to be developed, even though the makers of these drugs shy away from the name “chemotherapy” due to the nasty side effects that some of the earlier chemo agents produced.   A group of drugs called tyrosine kinase inhibitors technically falls under the chemotherapy classification; however, these agents are much more narrowly targeted than the original chemo drugs.   Tyrosine kinase inhibitors specifically inhibit cancer cell replication.   Tyrosine kinase is an enzyme which can play a number of roles, including stimulating the growth of new blood vessels.   It is also active in cell replication.  In healthy cells, tyrosine kinase activates a kind of “on-off” switch that makes it possible for cells to reproduce, but in cancer cells, tyrosine kinase just turns the switch to the “on” position and keeps it there, so that cancer cells just keep reproducing without cease.   Imatinib (Gleevec, from Novartis) is a cancer-cell specific tyrosine kinase inhibitor which is used to treat one form of chronic myelogenous leukemia (CML) and also gastrointestinal stromal tumors (GIST).   CML median 5-year survival has nearly doubled since the approval of imatinib, to about 31% currently, and median survival in GIST is also currently about 5 years.

Inhibitors of vascularization

In order to survive and replicate, cancer cells require nourishment, and because of their innate avidness for nourishment (we might call it “greed”) they require more nourishment than their normal neighbors.   Nourishment is conveyed to normal cells and cancer cells alike by means of the network of blood vessels – the vasculature.   When cancer cells emerge through that process of mutation, one of the first things they do is induce the growth of blood vessels – i.e., angiogenesis.   In order to do this, they release vascular endothelial growth factor (VEGF) in far greater amounts than do normal cells.   A drug has been developed that takes aim at this mechanism.   The drug, bevacizumab (Avastin, from Genentech/Roche) binds to the VEGF molecule in such a way that VEGF cannot interact with its receptor on endothelial cells; thus blocking the growth of new blood vessels to nourish the cancer cells.   Avastin has been approved by the FDA for the treatment of a number of cancers including colon, kidney, brain, and lung cancer.   It was originally approved also for treating breast cancer, but the FDA has recommended that it no longer be used for breast cancer, since there are other options.

A similar mechanism is deployed against a particularly difficult breast cancer variant which uses another growth factor to induce vascularization.   The release of the factor, human epidermal growth factor type 2 (HER2), is triggered by tyrosine kinase in another of its cancer-related roles.   Drugs that have been developed to counter the effects of tyrosine in HER2-positive breast cancer include lapatinib (Tykerb, from Glaxo SmithKline), and trastuzumab (Herceptin, from Genentech/Roche).    

Both Avastin and Herceptin attained “blockbuster” status and have done exceedingly well for their parent; however, we need to note that those top rungs on the revenue ladder are a bit slippery.   Amgen and Allergan have just launched biosimilars to both bevacizumab/Avastin and trastuzumab/Herceptin, which will threaten the $5.9 billion in 2018 US sales of the originals – definitely not good news for Roche.   The advance of biosimilars is expected to be a recurring trend in the future, particularly as US pharmaceutical outfits, with their huge resources and deep scientific expertise, enter the biosimilar arena. 

Liberating T-cells to attack cancer: Checkpoint inhibitors

Every day, our immune system seeks out, identifies, and destroys harmful invaders, be they microbes, viruses, or simply foreign substances that don’t belong inside our bodies.   On the cellular level, the patrolling agents are T-cells, which are highly effective against a wide range of enemy agents.   T-cells are equipped with surface receptors that recognize our own healthy cells and instruct the T-cells to leave those alone.   These surface receptors, called immune checkpoints, act as brakes.   Cancer cells, with their own survival at stake, have developed high levels of proteins that attach to those checkpoints and deflect the attack from T-cells.   

Researchers spent about 25 years looking into this mechanism as a potential way to liberate T-cells to attack cancer cells before the approval of the first drug that addressed the checkpoints on T-cells.   That was ipilimumab (Yervoy, from Bristol-Myers Squibb), which got FDA approval in March 2011 for the treatment of malignant melanoma.    Yervoy targets the immune checkpoint protein CTLA-4, and was demonstrated to extend significantly the survival of patients with this deadly form of cancer.   The success of Yervoy was followed by the approval of five more checkpoint inhibitors in the next six years.   These targeted one of two other checkpoint proteins, labeled PD-1 and PD-L1.   Nivolumab (Opdivo, also from Bristol-Myers Squibb) and prembolizumab (Keytruda, from Merck) both target PD-1, while atezolizumab (Tecentriq, from Genentech), avelumab (Bavencio, from Pfizer), and durvalumab (Imfinzi, from AstraZeneca) target PD-L1.

Opdivo has garnered ten FDA indications, most recently in August 2018 for the treatment of patients with small cell lung cancer who have previously been non-responsive to other forms of chemotherapy.   The response rates will not seem highly impressive, with 11% of patients experiencing partial responses and 0.9% complete responses; however, any degree of response is considered by experts to be a notable success in patients with this form of cancer.   In patients who demonstrated any degree of response, the median duration of response was almost 18 months, with 62% of patients continuing to respond at 12 months and 39% still responding at 18 months.

Opdivo has previously received indications for the treatment of non-small-cell lung cancer in individuals who have not responded to previous treatment; also in melanoma; in advanced renal cell carcinoma; in recurrent or metastatic squamous cell carcinoma; and in liver, urothelial, and colorectal cancers as well as Hodgkin lymphoma. 

Another PD-1 inhibitor, Keytruda (pembrolizumab, Merck), also received FDA approval in August 2018 as a combination treatment for metastatic nonsquamous non-small-cell lung cancer (NSCLC).   It is to be used in combination with Eli Lilly’s Alimta (pemetrexed) and platinum chemotherapy for the first-line treatment in these patients, along with platinum chemotherapy.   At the American Society of Clinical Oncology meeting in June of this year, it was announced that 23.2% of patients with metastatic NSCLC were surviving five years after diagnosis.   Before this form of immunotherapy, long term survival was unheard of.

Imfinzi (durvalumab, AstraZeneca), a PD-L1 inhibitor, just recently registered a major success.   In patients with non-small-cell lung cancer, patients treated with this checkpoint inhibitor had a 32% lower risk of death than patients treated with what had been standard-of-care treatment.   Previously, Imfinzi had been demonstrated to ward off disease progression for almost a year longer than placebo.   It is projected that Imfinzi will become the standard treatment for patients with this form of lung cancer.   It is the only checkpoint inhibitor to date to prove a benefit in lung cancer maintenance.   Imfinzi is also approved for locally-advanced urothelial carcinoma in patients whose disease has progressed after chemotherapy with an agent containing platinum.

However, Imfinzi, acting either alone or in combination with an investigational agent failed to elicit any meaningful response in patients with a particularly lethal form of pancreatic cancer, metastatic pancreatic ductal adenocarcinoma.   The Phase 2 study, recently published in JAMA Oncology, points to the huge challenges to treating cancers that are particularly difficult to diagnose at early stages.  

These checkpoint inhibitors, as well as the agents that slow cancer growth by interfering with the mechanism through which cancer cells attract new blood vessels so that they can get nourishment, and those that inhibit replication, occupy a space somewhere between old-time chemotherapy and the projected cancer treatment forms of the future, which aim for much greater precision, targeting the precise cancer subtype as well as the precise genetic characteristics of the patient.   

Narrowing the focus of cancer treatment

The way medical research views cancer as an antagonist has definitely shifted.   No longer is cancer viewed as Achilles, the mighty warrior, whose vulnerability must be sought out and targeted.   Instead, cancer becomes plural, and the enemy is the large number of individual cancers, evolving separately and distinctly from normal human cells in every part of the body, and bearing only a superficial resemblance to each other.   Thus, the way to combat cancer is one at a time.   

The current approach in cancer drug development, therefore, is to take aim at a specific cancer for which effective treatment has proved elusive.   This approach has several advantages: 

One – there exists a population of cancer patients whose cancers have advanced despite having undergone courses of treatment with one or more established cancer drugs.   Such patients are more likely to willingly take part in a clinical trial in which they are given an experimental agent.   The patients know that they have already failed treatment with an established drug, and they may see the experimental drug as at least a chance.   Newly diagnosed patients, in contrast, are not likely to risk participating in a clinical trial where an experimental drug is going head-to-head with a drug with an established record.   Most newly diagnosed patients would opt for treatment with a drug where their chances of success are known rather than take a chance on a newcomer.

Two – a new drug that demonstrates some success in patients who have failed treatment with one or more established drugs has a reasonably good shot at FDA approval, perhaps only as a third-line drug.   But approval as a third-line drug opens the door for wider approval, if only a crack.   The new candidate drug may then be compared, on a head-to-head basis, with an established first- or second-line drug, and if the candidate demonstrates any advantage in any of a number of outcome measures, it is likely to gain FDA approval.

Three – once a drug has received FDA approval, even if it is for a narrowly specified condition or patient population, it can then be tested on a wider basis.   Many cancer drugs, having been first very narrowly approved, have gone on to win approval in other forms of cancer and in other patient populations.

Polivy (polatuzumab vedotin, Roche)

An example of this approach is the FDA’s approval in June of this year of Polivy in the treatment of diffuse large B-cell lymphoma (DBLCL) in patients who have failed two previous courses of treatment.   The drug is used in combination with Roche’s Rituxan and bendamustine, a chemo drug.   In this Phase 1b/2 trial, the combination that included Polivy produced a complete response in 40% of patients, compared with 18% of patients who were treated with Rituxan and bendamustine alone.   A Phase 3 trial as a first-line drug in DLBCL patients is scheduled for later this year.   Some analysts have projected that Polivy could reach $1 billion in sales.   This should help – at least a bit – to offset the huge loss in sales that Roche will suffer due to new generic competition to Avastin and Herceptin.          

Keytruda (prembolizumab, Merck)

Also this June the FDA approved Keytruda for previously untreated head and neck cancer patients.   That’s two approvals, and the really big news for Merck is that their star drug is now first-line treatment in those cancers.   It’s approved as monotherapy in patients with the checkpoint protein PD-L1 and in combination with a common chemo drug in other head and neck cancer patients.   The quick FDA green light was based on the performance of the drug compared to “standard of care” treatment.   In PD-L1-positive patients, Keytruda was demonstrated to lower the risk of death by 22%, and in other patients, the combination therapy including Keytruda lowered the risk of death by 23%.   Merck estimates that about 65,000 patients are diagnosed each year with cancer of the head or neck, and Keytruda is approved for use in these newly diagnosed patients, while Opdivo (nivolumab, from Bristol-Myers Squibb) is approved only in patients who have failed first line chemotherapy treatment.

Keytruda also received FDA approval in August 2018 as a combination treatment for metastatic nonsquamous non-small-cell lung cancer (NSCLC).   It is to be used in combination with Eli Lilly’s Alimta (pemetrexed) and platinum chemotherapy for the first-line treatment in these patients, along with platinum chemotherapy.   

At the ASCO meeting this June, Merck reported results of a trial in previously untreated NSCLC, demonstrating that 23.2% of the patients taking Keytruda were still living after five years of treatment.   (Note that the approval noted in the previous paragraph was for patients with metastatic NSCLC.)   Five-year survival of 23.2% may not sound like such good news, but historically, five year survival in lung cancer patients has hovered around the 5% marker.    

Also, in addition to the good news about Keytruda’s performance in lung cancer, just yesterday (as I am writing this), Merck announced interim results in a Phase 3 trial of a combination treatment using Keytruda and chemotherapy in patients with triple negative breast cancer.   In the ongoing study, KEYNOTE-522, the combined treatment met one of the dual-primary endpoints, pathological complete response, which is defined as a lack of all signs of cancer in tissue samples analyzed following completion of therapy.   The trial will continue in order to assess the other primary endpoint, which is event-free survival. 

These strongly positive results have added to the importance of Keytruda in Merck’s prospects.   Keytruda sales in the second quarter of 2019 have jumped to $2.63 billion, increasing 63% globally and 73% in the US.

Keytruda also has several indications in addition to those mentioned above.   It is indicated for advanced melanoma, squamous cell cancers of the head and neck, Hodgkin lymphoma, urothelial carcinomas, certain solid tumors that have metastasized or cannot be surgically removed, and cervical cancer.

Lynparza (olaparib, Merck, AstraZeneca

Merck is partnering with AstraZeneca on another drug, the PARP inhibitor Lynparza.   (PARP is an enzyme that repairs damaged DNA, a process that must take place in order for cells to replicate.   PARP inhibitors block that process, and since cell replication takes place much more often in cancer cells than in normal cells, PARP inhibitors are able to prevent cancer cell replication without having much effect on normal cells.)

In late July 2019, Phase 3 data on Lynparza were released, reporting that the drug decreased the risk of death or disease progression by 47% in patients with BRCA-mutated pancreatic cancer that had not progressed after an initial round of chemotherapy.   Patients treated with Lynparza went a median 7.4 months without cancer progression, compared with 3.8 months without progression in patients treated with placebo.   After one year of treatment, 34% of Lynparza-treated patients were cancer free, compared with 15% of placebo patients, and at the two-year mark, those percentages were 22% and 10% respectively.   Those rates may not appear to be impressive, but pancreatic cancer is one of the most difficult cancers to treat.   Only about 8% of patients diagnosed with pancreatic cancer make it to the five-year mark after diagnosis.   This is largely because pancreatic cancer is seldom diagnosed at an early stage.    We will see how many of the Lynparza-treated patients in this Phase 3 study are still alive after five years, but based on the two-year mark, there is reason to be optimistic. 

Kisqali (ribociclib, Novartis)

Another bit of good news for women with hormone receptor positive and human epidermal growth factor-negative (HR pos, HER2 neg) breast cancer was announced about six weeks ago.   Adding Kisqali to a hormone antagonist and either tamoxifen or an aromatose inhibitor reduced the risk of death in these patients by 29%.   After 42 months of treatment, 70.2% of the women treated with Kisqali were alive, compared with 46% of those receiving treatment with the endocrine-directed drugs alone.   Kisqali is an inhibitor of CKK 4/6, a cyclin-dependent kinase that promotes a phase of cancer cell division.   Cancer specialists pointed out that it was noteworthy that the subjects in the study were all younger women, premenopausal, and it is in that cohort that more aggressive cancers frequently emerge.   Thus the survival data were particularly impressive.

Xtandi (enzalutamide, Astellas/Pfizer)

Xtandi is an androgen-receptor inhibitor that acts on several different steps in the androgen signaling pathway, which is implicated in the progression of castration-resistant prostate cancer.   The growth of prostate cancer cells is greatly fueled by testosterone; thus, a means of inhibiting that growth is to deprive the cancer cells of testosterone, either through chemical castration (i.e., administration of a drug that interferes with testosterone secretion) or through surgical means (i.e., removal of the testicles).    

Xtandi was approved for the treatment of all patients with castration-resistant prostate cancer, whether metastatic or non-metastatic, in mid-2018.   In June of this year, it was announced that in the subset of patients with metastatic hormone-sensitive prostate cancer, Xtandi lowered the risk of death by 33% in comparison with other androgen-inhibitors. 

… and other new and recent entries

Erleada (apalutamide, Johnson & Johnson), another androgen-receptor inhibitor, already FDA-approved for the treatment of non-metastatic castration-resistant prostate cancer, has recently applied to the FDA for approval in metastatic castration-resistant prostate cancer.   And Nubega (darolutamide, Bayer/Orion) has also been given an FDA green light for non-metastatic castration-resistant prostate cancer, based on a 59% lowering of the risk of tumor metastasis or death in patients already on standard androgen-deprivation therapy.

This puts three major pharmaceutical companies in direct competition for the same subset of prostate cancer patients.   Because prostate cancer screening – and, thus, early detection – may be diminishing due to doubts about its effectiveness raised by the U. S. Preventive Services Task Force, the number of patients whose cancers are not susceptible to early treatment have grown.   As a result, the market potential for those three drugs may be on the increase.                                                                                                              

Blueprint Medicines’ RET inhibitor BLU-667 shrank tumors in 60% of a difficult-to-treat group of lung cancer patients, preparing for a 2020 filing in patients with RET-altered non-small cell lung cancer (NSCLC) who had already tried chemotherapy.   (RET is a form of kinase, which is active in fostering cancer cell replication.) 

Sanofi’s anti-CD38 antibody isatuximab, added to the standard of care for relapsed multiple myeloma, extended patients’ lives and nearly doubled the number of patients for whom the combined treatment worked. The Phase 3 data, presented at the recent ASCO meeting, showed that the isatuximab combination shrank tumors in 60% of patients compared to 35% of patients taking the standard of care alone.

Amgen’s KRAS inhibitor, AMG 510 shrank tumors in five of the ten evaluable non-small-cell lung cancer patients and shrank tumor growth in another four, demonstrating that it could likely control the disease in 90%of patients.   In colorectal cancer patients, about three-quarters of the evaluable patients achieved stable disease, meaning that their tumors had stopped growing.   (KRAS is one of a group of genes involved in a pathway called the epidermal growth factor receptor (EGFR) pathway.

Meanwhile, GlaxoSmithKline has more than doubled the number of oncology drugs in their pipeline, from about eight just a year ago to 17 at present.   GSK plans to launch a number of clinical trials in some of these candidate drugs starting this fall.

What does this say about the future of cancer care?

As you can see, Big Pharma is in the game big-time.   In this issue of the musings of Doc Gumshoe, 12 biggies have been mentioned – Bristol-Myers Squibb, Merck, Genentech, AstraZeneca, Roche, Novartis, Pfizer, J & J, Bayer, Sanofi, Amgen, and GlazoSmithKline.   The number of new candidate drugs vying for approval and recognition is staggering.   I wish the same thing could be said about antibiotic development. 

A principal reason for this is statistics: the number of new cancer diagnoses annually in the US alone is predicted to increase, from about 1,762,450 in 2019, to about 2,400,000 in 2035.   That’s not because cancers are getting worse.   It’s because more and more of us are surviving the numerous other diseases that tend to get us at an earlier point in our lives.   More than anything else, it’s a matter of demographics.   

But another reason is economics.   Pharmaceutical outfits may be reluctant to invest much money in the development of antibiotics, because new antibiotics are likely to be kept in reserve for cases in which the established antibiotics don’t work for reasons of resistance.    Also, new antibiotics may be quickly copied and sold as generics elsewhere in the world in defiance of US patent law, based on the needs of the population.

Cancer drugs are a different story.   If a drug gets regulatory approval, insurers have to cover it when prescribed within the indications.   I’m aware, of course, of the present battle over drug pricing, but I’m confident in predicting that when a pharmaceutical company develops a drug that works really well in any of a huge number of cancers, it will reap excellent profits.

A word about CAR-T treatment.   There have been a number of quasi-miracle cures using this technique, which involved harvesting the patient’s T-cells, tinkering with their DNA, letting the modified T-cells reproduce in great numbers, and then giving them back to the patient where the T-cells will do their job and kill all the cancer cells.   The problem with this form of treatment is that there is no way, based on what is known at present, to mass-produce it.   The process has to be repeated from the very beginning for each patient.   CAR-T treatment is not like drug development, where by far most of the cost is in the research phase; making the actual drug itself is cheap by comparison.   And don’t hold your breath for CAR-T treatment to become affordable.   That won’t happen anytime soon.

But I hope that it’s clear that many cancers that were once thought to be tantamount to death sentences can now be treated with at least some positive expectations.   The war is far from over, but some battles have gone our way.

* * * * * * *

Thanks for paying attention to all this complicated stuff!   Don’t worry, Doc Gumshoe is not going to subject you to a quiz.   In fact, if you want to subject Doc Gumshoe to a quiz, in the form of sharpish comments, do please go ahead.   My mother never dipped me in any river, let alone the River Styx, but I have a fairly tough hide.   Thanks to all, Michael Jorrin (aka Doc Gumshoe)