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Over the past twenty years, a number of pharmaceutical and biotechnology companies have invested in cancer research and brought new drug therapies to the market. Between its founding in 1991 and its sale to Takeda Pharmaceuticals (and incorporation into Takeda Oncology), ARIAD Pharmaceuticals brought a number of innovative medicines through clinical research. These drugs have improved the prognosis for patients diagnosed with difficult-to-treat cancers, including non-small cell lung cancer (NSCLC) and multiple forms of leukemia.

Recent Advances in the Treatment of Cancer

Below I discuss a number of advances in treatments for difficult-to-treat cancers. This is not an exhaustive list of all treatment options for these cancer types and patients should discuss all treatment options with their doctor before deciding on the best path for them.

ALK-positive non-small cell lung cancer 

According to the American Lung Association, the five-year survival rate for lung cancer patients is 18.6%. The American Cancer Society claims that patients with NSCLC have a 23% 5-year survival rate.

One of the top reasons these numbers are so low, particularly in ALK+ cases, is because tumors can develop a resistance to the medications used to treat them.[1] ALK+ (anaplastic lymphoma kinase positive) NSCLC causes a mutation of the ALK protein, which is involved in cell reproduction.

    • Brigatinib

A preliminary study by ARIAD in 2010 found that Brigatinib was able to overcome tumor resistance to ALK inhibitors in a laboratory setting.[2] In 2016, ARIAD performed a Phase I/II trial of Brigatinib to determine its efficacy against ALK+ NSCLC, named ALTA.[3]

According to the 2017 ALTA report, the study involved two groups and showed positive results. Group A received 90 mg of Brigatinib daily and Group B received 180 mg of Brigatinib daily, after a 7-day lead in of 90 mg per day.[4]

The one-year overall survival rate was 70% for Group A and 80% for Group B.[5] Following this study, the FDA approved Brigatinib under their Accelerated Approval regulations and allowed it to be brought to market.[6] Results from a Phase III trial comparing Brigatinib to Crizotinib in patients with ALK+ NSCLC were released in 2018 and showed that treatment with Brigatinib resulted in longer progression-free survival for patients.[7]

    • Lorlatinib

Another medication that was recently approved to treat ALK+ NSCLC is Lorlatinib, produced by Pfizer. Similar to Brigatinib, Lorlatinib is capable of overcoming resistances that occur in ALK+ NSCLC tumors and was granted accelerated approval in November 2018 following a phase 2 trial in patients with ALK+ or ROS1+ advanced NSCLC.[8]

The study enrolled 276 patients in six different cohorts.[9] The majority of patients in the trial had been treated previously with chemotherapy or another tyrosine kinase inhibitor (TKI), including Crizotinib.[10]

For patients without a history of disease treatment, 90% had an objective response.[11] In patients who had been treated with at least one ALK TKI, objective responses were achieved in 47% of patients.[12] Patients who had only been treated before with crizotinib had an objective response rate of 69.5%.[13]

The results led to the conclusion that lorlatinib showed positive activity in patients with ALK+ NSCLC, whether they were treatment naive or had been treated with up to three ALK TKIs, and led to its approval by the FDA.[14]

Late Stage NSCLC

According to the American Cancer Society, the five-year survival rate for patients diagnosed with Stage IIIB NSCLC is 26%, Stage IVA is 10% and Stage IVB is less than 1%.[15] There aren’t many treatment options for patients diagnosed with late-stage NSCLC, but research in this area has grown in the past few years.

    • Osimertinib

For example, in 2017, the FDA approved osimertinib, produced by AstraZeneca, for the treatment of epidermal growth factor receptor (EGFR) T790M mutation-positive NSCLC after results from phase 3 clinical trial.[16] The trial consisted of 419 patients who had T790M-positive advanced NSCLC and had suffered disease progression after receiving first-line EGFR-TKI therapy.[17]

Patients were separated into three groups, with one receiving osimertinib and the others receiving intravenous pemetrexed that was either mixed with carboplatin or cisplatin.[18] Results showed that patients who received osimertinib had a longer median duration of PFS than patients who received pemetrexed, 10.1 months compared to 4.4 months.[19]

The following year, the FDA expanded osimertinib’s indication to be a first-line treatment for NSCLC patients whose tumors had EGFR exon 19 deletions or exon 21 L858R mutations.[20] The drug’s increased indication was based on a double-blind, phase three trial of 556 patients who had untreated EGFR mutation-positive advanced NSCLC.[21]

Patients either received osimertinib or a standard EGFR-TKI and the median PFS was significantly longer in the osimertinib group at 18.9 months, compared to 10.2 months in the other group.[22]

    • TAK-788

TAK-788 is another TKI that is currently undergoing a Phase I/II study, sponsored by Millennium Pharmaceuticals and Takeda Oncology, to determine its efficacy against advanced NSCLC tumors. It is currently being tested on tumors that contain an EGFR or human epidermal growth factor 2 (HER2) mutation.[23]

The drug is also being tested on patients with solid tumors that aren’t NSCLC but contain the same genetic mutations.[24] It involves three phases, a dose escalation phase, an expansion phase, and an extension phase and there are seven groups involved in the study.[25]The goal of this study is to determine if TAK-788 is effective in combating these tumors and improving patients survival rates.[26]

TAK-788 works by inhibiting mutant forms of EGFR and HER2.[27] It binds to the mutant forms and inhibits their ability to send signals and causes the death of these cells.[28] These cell types are important in tumor cell growth and vascularization, so TAK-788’s ability to kill them slows or stops the growth of the tumor cells.[29]

The trial is still recruiting participants to help determine the proper dosing for this medication to ensure patients achieve the maximum clinical effect with minimal side effects.[30] The study also hopes to determine the drug’s effectiveness against locally advanced metastatic NSCLC harboring EGFR inframe exon 20 insertion mutations.[31]

Philadelphia chromosome-positive leukemia

Philadelphia chromosome-positive (Ph+) accounts for approximately 25% of acute lymphoblastic leukemia (ALL) cases in adults and 3% of cases in children, according to the Leukemia & Lymphoma society.

The Philadelphia chromosome contains an abnormal gene, called BCR-ABL, which helps leukemia cells grow. This disease is treated with TKIs, which block the abnormal protein and stop the cells from growing. The introduction of TKIs in the early 2000s began improving the survival rate for patients with Ph+ leukemias.[32]

    • Nilotinib

Nilotinib, created by Novartis Pharmaceuticals, is a second-generation TKI that was developed to treat Ph+ Leukemias, a disease which has an overall survival rate of less than 20% when treated with only chemotherapy.[33]

In October 2007, the FDA granted accelerated approval to nilotinib, after a Phase 2 clinical trial showed the drug was effective and safe.[34] The study consisted of 232 Ph+ CML patients who had shown resistance to imatinib, a first-generation TKI. The study showed that 40% of the observable patients had a major cytogenetic response following treatment with nilotinib.[35]

According to the American Cancer Society, a cytogenetic response means that cells with the Philadelphia Chromosome are being reduced.[36] A major cytogenetic response means less than 35% of cells still have the Philadelphia Chromosome; a complete response means none of the cells have it.[37] A major molecular response means the amount of the BCR-ABL gene is 1/1000th or less of what would be expected in a person who had untreated CML.[38]

Three years later, nilotinib was tested against imatinib in a phase 3 trial consisting of 846 patients.[39] After 12 months, 44% of patients receiving nilotinib had a major molecular response, compared to 22% of patients receiving imatinib.[40] The rates of complete cytogenetic responses were also higher for nilotinib, coming in at 80% compared to 65% of imatinib.[41] These results led researchers to conclude that nilotinib was a more effective treatment method for dealing with Ph+ leukemia.[42]

    • Ponatinib

A few years after the trial comparing nilotinib and imatinib, ARIAD released results of a Phase 2 trial of Ponatinib, a third-generation TKI, that showed it was also effective in treating Ph+ CML.[43] The study showed positive rates of major cytogenetic responses, complete cytogenetic responses, and major molecular responses in patients treated with Ponatinib. Based on these results, the FDA approved Ponatinib to treat CML and Ph+ ALL.[44] 

The study concluded in 2018, and updated data was released showing that Ponatinib continued to be an effective treatment option for patients with Ph+ ALL and CML when other TKIs had failed. A major cytogenetic response was seen 60% of participants and 54% of participants achieved a complete cytogenetic response.[45] The probability of maintaining a major cytogenetic response for five years was 82% and the estimated 5-year overall survival rate was 73%.[46]

In a comparison study in 2018, Ponatinib was shown to be a better line of treatment than other TKIs, namely Dasatinib, Nilotinib and Imatinib, in treating Ph+ ALL when combined with chemotherapy.[47] The study showed a complete molecular response (CMR) rate of 79% and a three-year survival rate of 79%.[48] The CMR for the other three TKIs was 34% and the three-year survival rate was 50%.[49]

Sarcoma Treatment 

    • Trabectedin

The 5-year survival rate for patients who are diagnosed with sarcomas at the metastatic stage is only 16%.[50] There are few treatments available for these advanced sarcomas, but a couple medications have recently been approved. One of these drugs is Trabectedin, manufactured by Janssen Pharmaceuticals. A phase 3 trial in 2015 showed that trabectedin was more effective in controlling advanced sarcomas than dacarbazine after prior chemotherapy had failed.[51]

This trial involved 518 heavily pre-treated sarcoma patients who were treated with either trabectedin or dacarbazine.[52] Results showed that patients who received trabectedin had a 45% reduction in risk of disease progression or death compared to dacarbazine.[53] The median PFS in the trabectedin arm was 4.2 months compared to 1.5 months in the dacarbazine arm.[54] The study’s results confirmed earlier trial results that trabectedin was capable of controlling advanced soft tissue sarcomas after previous cytotoxic chemotherapy had failed.[55]

    • Ridaforolimus

Another recent development in sarcoma treatment was the development of Ridaforolimus a drug that inhibits rapamycin, a component of the phosphatidyl 3-kinase/AKT signaling pathway.[56] In a phase 2 trial, it was tested on patients with subtypes of advanced sarcomas to determine its efficacy against these solid tumors.[57] The results were positive, with a CBR rate of 28.8%, with a higher incidence of women responding better than men.[58] The patients involved in the trial had been treated before for their diseases and the median PFS for them were superior than other treatment protocols.[59]

Ridaforolimus has also been shown to be effective in treating coronary artery disease when used with a drug-eluting stent.[60] In a 2017 study, Medinol’s ridaforolimus-eluting stents were shown to be equally effective to zotarolimus-eluting stents.[61] Medinol, a biotechnology company that specializes in cardiovascular health, uses Ridaforolimus as a coating for its coronary stent system, which is used to treat narrowed or blocked arteries in patients with CAD.[62] Ridaforolimus helps the blood vessel remain open and stops it from narrowing again.[63]

The discovery that Ridaforolimus is capable of both combating cancer as well as treating CAD shows that it’s important for drug sponsors to follow the data and use medications to fight any disease they prove effective against, regardless if it was for their original intended use. 

Immunotherapies

Immunotherapy has become a more common area of disease research over the past few decades, particularly for cancer patients as chemotherapies are known to damage healthy cells, whereas immunotherapy drugs assist the body’s immune system in combating the cancer without damaging normal cells.

There are multiple forms of Immunotherapies according to the American Society of Clinical Oncology, including CAR-T cell therapy, checkpoint inhibitors and cancer vaccines. CAR-T cell therapies involve modifying a person’s T-cells in the laboratory in a way that allows them to better fight off cancer cells. Checkpoint inhibitors are medications that are block proteins in cancer cells to prevent them from growing and reproducing. Cancer vaccines are similar to traditional vaccines, like the flu shot; they expose the body to an antigen, which triggers an immune response.

    • Tisagenlecleucel

In 2018, the FDA approved tisagenlecleucel, produced by Novartis, a form of CAR-T Cell therapy that showed efficacy against ALL.[64] The trial results showed that 12 months after receiving the drug, 76% of patients were alive.[65] Tisagenlecleucel contains a 4-1BB domain which is believed to improve the persistence of CAR T cells through the process of killing cancer cells.[66]

    • Keytruda

Keytruda is one of the most well-known checkpoint inhibitors. Produced by Merck, Keytruda was approved by the FDA in 2014 to treat patients with advanced melanoma.[67] This approval was based on the results of the Trial P001 study involving 173 patients with unresectable or metastatic melanoma.[68] The ORR was 24% and one patient had a complete response.

These results led the FDA to grant accelerated approval to Keytruda under the requirement that Merck conduct a multicenter randomized trial comparing Keytruda to the standard therapy.[69] Since its approval in 2014, Keytruda’s indications have been expanded to include NSCLC, head and neck cancer and Hodgkin’s lymphoma.[70]

    • Rimiducid

Rimiducid is an activator agent that is used in combination with immunotherapies to treat advanced cancers.[71] It works in a similar way to anti-rejection medications used by patients after an organ transplant by allowing the immunotherapy medication to bind with human cells and activate a receptor on them, which causes the immune system to attack cancer cells.[72]

In a clinical trial where Rimiducid was used in combination with the BPX101 cancer vaccine to treat patients with advanced prostate cancer, immune upregulation and anti-tumor activity was observed, as well as prostate-specific antigen declines, objective tumor regressions and robust efficacy of post-trial therapy, all of which suggest this combination was a favorable treatment method.[73]

Conclusion

As cancer research has progressed, researchers have found that a personalized approach to treatment is important and that treating cancer based on the mutations present often offers a more positive outcome. But in order for more treatments to become available, trials need to have an adequate number of participants.

For cancer patients who aren’t benefiting from standard treatment options, it is prudent to seek out studies related to the disease for a chance at getting healthy. 

Other articles in this series:

Difficult-to-treat Cancers: Part 1 – What Now?  
Difficult-to-treat Cancers: Part 2 – The Drug Discovery Process

Reference Numbers

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3 – Source 11
4 – Source 22
5 – Source 22
6 – Source 22
7 – Source 4
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65 –  Source 19
66 – Source 19
67– Source 10
68 – Source 10
69 – Source 10
70 – Source 18
71 –  Source 25
72 –  Source 25
73 – Source 29

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Harvey Berger, MD
Dr. Harvey Berger founded ARIAD Pharmaceuticals, Inc. in 1991 and served as Chairman and Chief Executive Officer of the company until 2015. Today, he acts as the company’s Founder, Chairman and CEO Emeritus, in addition to his duties as the governing trustee at the Dana-Farber Cancer Institute. From 2017 to 2018, he served as the Executive Chairman at Medinol, Inc. Dr. Berger earned his A.B. degree in Biology at Colgate University and his medical degree from the Yale School of Medicine. He completed additional medical training at Yale-New Haven Hospital and Massachusetts General Hospital. Before founding ARIAD, Dr. Harvey Berger developed new medicines for various diseases, including lung cancer and Crohn’s Disease, and led the Research and Development Division at Centocor, Inc. from 1986 to 1991. He has also held teaching positions at Emory University, Yale University and the University of Pennsylvania. In 2013, he was awarded the Ernst & Young Entrepreneur of the Year Award in New England and the Gold Stevie Award for Executive of the Year, Pharmaceuticals. Dr. Berger currently resides in Palm Beach with his wife and two daughters.

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