Breathing New Life Into Chemotherapy

Bruce A. Feinberg, DO

Although the development of chemotherapy-free regimens is a major thrust of oncology research, improvements to traditional cytotoxic therapy are actively being explored, with a focus on new formulations and delivery methods for agents that have been used for decades.

Strategies in development include oral formulations that may provide greater efficacy with less toxicity than the intravenous (IV) versions, such as oral paclitaxel for metastatic breast cancer (mBC). Investigators are working to create new antibody-drug conjugates (ADCs) and nanotherapies that include familiar cytotoxic components. At least 1 new chemotherapy, a platinum drug, is also in clinical trials.

Several products that may be described as cytotoxic chemotherapy have been approved in the past few years. These include new formulations of older medicines, such as calaspargase pegol-mknl (Asparlas) for acute lymphoblastic leukemia. Other types of nonspecific cell-killing agents have also been approved, such as immunotoxins and CDK 4/6 inhibitors, although some experts dispute their classification as chemotherapy.

Chemotherapies have proved their effectiveness over decades, are particularly useful for rapidly reducing tumor volume and eliminating remaining cancer cells after surgery, and can be given to a wide range of patients rather than the relatively small number who respond to a molecularly targeted drug.

Despite these advantages, advances in immunotherapy and targeted therapies have led to declarations that the era of chemotherapy is nearing its end. A prominent turning point was the finding that pembrolizumab (Keytruda), a PD-1 immune checkpoint inhibitor, provides a longer survival benefit than standard chemotherapy in some patients with non—small cell lung cancer (NSCLC), said Bruce A. Feinberg, DO, vice president and chief medical officer of Cardinal Health Specialty Solutions.

However, in a recent analysis of systemic treatments for breast cancer, the most common type of cancer, Feinberg and colleagues pointed out that chemotherapy remains a “foundational” therapy at all stages of the disease.¹ They also found that nearly half of current trials involving mBC include a chemotherapy component, often combined with a novel agent. Given that the “aging platform” of chemotherapy remains central to treatment and drug development, Feinberg said research is needed to create more effective and patientfriendly chemotherapies.

“It looks like there’s still going to be a lot of chemotherapy in the cancer patient’s future, in the years and possibly decades to come,” Feinberg said in an interview with OncologyLive®. “If we would take some of that same research zeal that we have for that which is new and refine that which is old to make it better, to make it less toxic, to make it more effective, [and] to make it less burdensome in terms of mechanisms of delivery for patients, then maybe we would be doing something that was very much in the immediate benefit of patients.”

Oral Formulations in the Works

The world of innovative chemotherapy research is small, but a few companies are making new products, according to Feinberg. He cited the example of Athenex, a biopharmaceutical company with laboratories in Hong Kong and Buffalo, New York. The company is testing oral formulations of paclitaxel, docetaxel, irinotecan, topotecan, and eribulin in combination with encequidar, a p-glycoprotein (P-gp) pump inhibitor that promotes absorption into the bloodstream.

In phase III trial results presented at last year’s San Antonio Breast Cancer Symposium (2019 SABCS) in December, patients with mBC who received the oral paclitaxel with encequidar (OPE) formulation had higher rates of confirmed tumor response, overall survival (OS), and progression-free survival (PFS).²

In all, 402 patients with mBC were randomly assigned in a 2:1 ratio to either 205 mg/m² of oral paclitaxel plus encequidar for 3 days a week or 175 mg/m² of IV paclitaxel every 3 weeks. The primary end point was radiologically confirmed tumor response rate at 2 consecutive timepoints; secondary end points were PFS and OS.

The response rate in the modified intent-to-treat population was 40.4% among those who received OPE (n = 235) including a 1.3% complete response (CR) rate and a 39.1% partial response (PR) rate. In the IV paclitaxel arm (n = 125), the response rate was 25.6%, including 0.8% CR and 24.8% PR. The findings showed a statistically significant improvement with OPE (P = .005).

The estimated median PFS was 9.3 months with OPE versus 8.3 months with the IV format, a trend favoring OPE that was not statistically significant (P = .0773). Similarly, the median OS also was favoring OPE at 27.9 months compared with 16.9 months for IV paclitaxel (P = .0353).

Patients in the OPE arm also reported lower incidence and severity of grade ≥2 with OPE for neuropathy at 7.6% overall (1.5%, grade 3) compared with 31.1% overall (14.8%, grade 3) for standard paclitaxel, as well as for pain at 14.8% overall (2.3%, grade 3) versus 33.3% overall (3.7%, grade 3), respectively. The incidence of alopecia also was lower for OPE than for IV paclitaxel (all grade 2, 28.8% vs 48.1%).

However, the rate and severity were higher in the OPE arm for neutropenia grade ≥2 for OPE at 38.3% (14.8%, grade 4) than for IV paclitaxel at 33.3% (8.9%, grade 4); anemia at 19.7% (2.3%, grade 3) versus 10.4% (all grade 2), respectively; urinary tract infection at 18.9% (3.4%, grade 3) versus 11.9% (all grade 2); and diarrhea at 24.2% (4.9%, grade 3) versus 8.1% (1.5%, grade 3).

Oral chemotherapy is attractive because it allows patients to take their medicine at home and because using it metronomically, in frequently scheduled low doses, can result in fewer toxic effects, said Howard A. “Skip” Burris III, MD, FASCO, FACP, president of clinical operations and chief medical officer at Sarah Cannon in Nashville, Tennessee. A Giants of Cancer Care^® award winner for drug development, Burris is serving as president of the American Society of Clinical Oncology.

“The biggest reason to look at developing oral [chemotherapy] is the ability to give drugs at a lower dose chronically and avoid the higher peak concentrations, which are often contributing to the toxicity,” Burris said. “Much like a metronome, you’re consistently hitting the tumor every day or every other day, and so you’re chipping away at it, avoiding the toxicities but continuing to pound the target at a low dose.”

Burris noted the potential of the oral taxane tesetaxel, which has activity against P-gp and has been studied for more than 15 years in different cancers. In the phase II TOB203 trial (NCT01221870) for first-line treatment of patients with HER2-negative, hormone receptor (HR)—positive mBC (n = 38), tesetaxel monotherapy produced a 45% confirmed response rate (95% CI, 29%-62%).³

Median duration of response was 10.9 months (95% CI, 4.3-13.6) and median PFS was 5.4 months (95% CI, 3.8-9.8). In the 24 patients receiving 27 mg/m² without dose escalation, the most common grade ≥3 AE was neutropenia, which occurred in 25% of patients (febrile neutropenia, 4%). In this group, there was 1 case of grade 3 neuropathy.

The phase III CONTESSA study (NCT03326674) is testing tesetaxel plus a reduced dose of capecitabine (825 mg/ m²) versus the approved dose (1250 mg/ m²) in patients with HER2-negative, HR-positive, locally advanced or metastatic breast cancer previously treated with a taxane in the neoadjuvant or adjuvant setting.

The metronomic principle is driving research on S-1 (Teysuno), another chemotherapy for breast cancer. It combines tegafur, a 5-fluorouracil prodrug; gimeracil, which promotes tegafur activity; and oteracil, which prevents gastrointestinal (GI) toxicity, said Masakazu Toi, MD, PhD, professor of breast surgery at Kyoto University Hospital in Japan.

According to phase III POTENT trial findings that Toi presented at 2019 SABCS, adding S-1 to adjuvant endocrine therapy significantly improved invasive disease-free survival (iDFS) for Japanese patients with HR-positive, HER2-negative breast cancer.⁴

The study recruited patients with stage I to III HR-positive, HER2-negative breast cancer with intermediate or higher risk of recurrence. The median follow-up after treatment was 51.4 months. In the S-1 plus endocrine arm, 101 of 957 patients (10.6%) had disease recurrence (iDFS events) compared with 155 of the 973 patients (15.9%) in the endocrine-only arm. The estimated 5-year iDFS was 86.9% in the S-1 arm compared with 81.6% in the control arm, for a hazard ratio favoring S-1 therapy of 0.63 (95% CI, 0.49-0.81; P <.001).

Toi said S-1 was well tolerated, with associated major toxicities that included signs of bone marrow suppression such as decreased neutrophil counts, GI toxicities such as nausea and diarrhea, hyperpigmentation, and fatigue. S-1 is used in parts of Europe and Asia but has not been approved by the FDA.

New Formats for Older Drugs

S-1’s manufacturer, Taiho Pharmaceutical, has received FDA approval for its oral chemotherapy drug TAS-102 (Lonsurf). The agent is composed of a fixed combination of trifluridine, a nucleoside metabolic inhibitor, and tipiracil, a thymidine phosphorylase inhibitor that increases the bioavailability of trifluridine. Burris described it as a variation of capecitabine.

In 2019, TAS-102 was approved for adults with metastatic gastric or gastroesophageal junction adenocarcinoma previously treated with at least 2 lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and, if appropriate, HER2-targeted therapy. The drug initially was approved in 2015 for patients with metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan- based chemotherapy; an anti-VEGF biological therapy; and, if RAS wild type, an anti-EGFR therapy.⁵

In gastric cancer, approval was based on the phase III TAGS trial (NCT02500043), in which patients received TAS-102 at 35 mg/ m² orally twice daily on days 1 to 5 and 8 to 12 of each 28-day cycle with best supportive care (BSC) or a matching placebo with BSC, until disease progression or unacceptable toxicity. Median OS was 5.7 months (95% CI, 4.8-6.2) for patients receiving TAS-102 and 3.6 months (95% CI, 3.1-4.1) for those receiving placebo (hazard ratio, 0.69; 95% CI, 0.56-0.85; P = .0006). PFS was also longer in the patients who took TAS-102 (hazard ratio, 0.56; 95% CI, 0.46-0.68; P <.0001).⁵

In mCRC, the indication is based on findings from the phase III RECOURSE trial (NCT01607957), in which the same dose of TAS-102 plus BSC was evaluated against matching placebo plus BSC. The median OS with TAS-102 was 7.1 months (95% CI, 6.5-7.8) versus 5.3 months (95% CI, 4.6-6.0) with placebo (hazard ratio, 0.68; 95% CI, 0.58-0.81; P <.001).⁵

In terms of adverse events (AEs), the drug’s label takes note of severe myelosuppression. Across both pivotal studies, TAS-102 therapy involving 868 patients was associated with grade 3/4 anemia (18%), neutropenia (38%), thrombocytopenia (5%), and febrile neutropenia (3%). Two patients (0.2%) died because of neutropenic infection/ sepsis and 4 others (0.5%) died because of septic shock.⁵

Another recently approved chemotherapy is calaspargase pegol, a novel formulation of L-asparaginase used as part of multiagent chemotherapeutic regimen for acute lymphoblastic leukemia in pediatric and young adult patients aged 1 month to 21 years.⁶ The new product is administered intravenously and designed to provide a longer interval between doses compared with other available pegaspargase products.

Are New Cytotoxics Chemotherapy?

Some other drugs that entered the market in the past 2 years could be described as chemotherapy because they are cytotoxic and can be given generally to patients without targeting. For example, in 2018 the FDA approved the CD22-directed agent moxetumomab pasudotox- tdfk (Lumoxiti), which is used to treat patients with relapsed/refractory hairy cell leukemia by delivering a bacterial immunotoxin that inhibits protein synthesis and causes cell death.⁷

The term chemotherapy is applied to various types of agents, ranging from any anticancer drug to only older types of chemotherapy that prevent cell division or directly kill cells, such as taxanes, platinums, and anthracyclines. In the case of moxetumomab pasudotox, the drug resembles chemotherapy and is “very much a cytotoxic,” Burris said, but is different enough from traditional chemotherapy that it can be confusing to classify it that way.

CDK 4/6 inhibitors such as palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio) work by interfering in the cell cycle and have toxicities similar to those of conventional chemotherapies, so some oncologists characterize them as “nothing but chemotherapy but with a different target,” Burris said.

Yet the CDK inhibitors’ distinct mechanism of action means they are not usually referred to as chemotherapy, said Howard S. Hochster, MD, FACP, associate director for clinical research and director of GI oncology at Rutgers Cancer Institute of New Jersey in New Brunswick.

“It’s not like you test the breast cancer to see what their CDK expression is, but I would consider those more targeted therapies because we know they react on this 1 CDK protein,” he said.

Debate also surrounds whether ADCs such as the breast cancer drug ado-trastuzumab emtansine (T-DM1; Kadcyla) should be considered chemotherapy, because they are distinguished by their use of monoclonal antibodies to target specific tumor antigens and bypass other cells.

Hochster said he considers ADCs to be targeted drugs. However, ADCs also contain cytotoxins, often a familiar chemotherapy agent or close variation, so they may be considered chemotherapy delivery systems rather than a separate class of drug. ADCs are a major focus of drug development, with 7 approved oncology products8 and more than 100 active trials listed on the ClinicalTrials.gov website.

Potential for Nanomedicines

Research on nanoparticle delivery systems is also booming, with hundreds of trials under way of products that use liposomes or other nanoscale materials to take antineoplastics into cells. Burris noted, for example, that Fujifilm’s drug division has 2 liposome-encapsulated chemotherapies in phase I trials for treatment of advanced solid tumors: FF-10832 with gemcitabine (NCT03440450) and FF-10850 with topotecan (NCT04047251). Thirteen nanomedicines for cancer have been approved, most recently daunorubicin and cytarabine liposome for injection (Vyxeos) for acute myeloid leukemia in 2017.^9,10

The interest in nanocarriers illustrates a divide in drug development between those who dismiss chemotherapy as insufficiently effective or too toxic, and others—including many older, experienced oncologists—who understand and are exploring its continued potential, said Alan P. Venook, MD. He is the Shorenstein Associate Director for Program Development at the University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center and a 2019 Giants of Cancer Care^® award winner in GI cancer.

“With this belief that targeted therapies and immunotherapies are so much better than anything else, there are companies that have abandoned a lot of their chemotherapy drugs. There are a number of companies that are looking to repurpose them,” Venook said, adding that nab-paclitaxel (Abraxane), which is paclitaxel formulated as albumin-bound nanoparticles, is the “best example” of repurposing.

“It turns out repackaging [paclitaxel] made a world of difference,” he said. “I wouldn’t have thought it, but it is true that sometimes you can take these medications and get much more bang for your buck if you can change the toxicity profile.”

The misconception that all chemotherapies are very toxic and that targeted therapies are not helps explain the disputes over what to call some of the newer types of drugs, he said.

“If you were to look at the current portfolio of most pharmaceutical companies, there’s really very little interest in ‘conventional chemotherapies.’ Even if they are chemotherapies, people are trying to label them as targeted therapies. If imatinib [Gleevec] is not a chemotherapy, then maybe we’re developing a whole new class of drugs. But why wouldn’t it be a chemotherapy, just a different kind of chemotherapy? It’s a semantic argument to some extent,” Venook said.

Burris noted that, amid all the old agents in different packaging, some research on new, unmistakably chemotherapeutic agents is still occurring. Sarah Cannon is among several centers participating in phase I trials of PT-112, a novel phosphaplatin and immunogenic cell death inducer manufactured by Phosplatin Therapeutics.

In an all-comer phase I dose-escalation study of PT-112 in advanced solid tumors, the drug resulted in beneficial activity at a range of doses and was well tolerated.11 No significant acute neurotoxicity was reported after 533 infusions. Grade 1/2 peripheral neuropathy was observed in 8 of 62 patients (13%) and grade 3 in 2 patients (3%) with cumulative doses of 3.1 and 4.3 g/m². Neutropenia (6 patients) and thrombocytopenia (8 patients) were limited, with no infections or bleeding.

At the 2020 Genitourinary Cancers Symposium, investigators reported that PT-112 induced reductions in target lesions for patients with metastatic castrationresistant prostate cancer (CRPC) as monotherapy or in combination with avelumab (Bavencio), a PD-L1 inhibitor. Notably, investigators said the “nearly universal” decline of serum alkaline phosphatase reductions suggested activity against bone metastases.¹²

PT-112 has an FDA orphan drug designation for treatment of patients with thymoma and thymic carcinoma and is being tested in mBC, CRPC, NSCLC, multiple myeloma, and other cancers.

“The platinums are tough, so we’ve always looked at trying to have a better platinum,” Burris said. He noted, however, that finding funding for such studies is a struggle for small biotechs.

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References

1. Feinberg B, Kish J, Dokubo I, Wojtynek J, Lord K. Reports of the demise of chemotherapy have been greatly exaggerated. Am J Manag Care. 2019;25(6):270-272.
2. Umanzor G, Rugo HS, Cutler DL, et al. Oral paclitaxel with encequidar (OPE): the first orally administered paclitaxel shown to be superior to IV paclitaxel on confirmed response and survival with less neuropathy: a phase III clinical study in metastatic breast cancer. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract GS6-01. ir.athenex.com/static-files/46927288-0f89-401d-9f90-29c1ae9eb438.
3. Seidman AD, Schwartzberg LS, Gudena VK, et al. Activity of tesetaxel, an oral taxane, given as a single-agent in patients (Pts) with HER2-, hormone receptor + (HR+) locally advanced or metastatic breast cancer (MBC) in a phase 2 study. J Clin Oncol. 2018;36(suppl 15; abstr 1042). doi: 10.1200/JCO.2018.36.15_suppl.1042.
4. Addition of S-1 to post-operative endocrine therapy improves outcomes for patients with hormone receptor-positive, HER2-negative breast cancer [news release]. San Antonio, TX: San Antonio Breast Cancer Symposium; December 11, 2019. bit.ly/37ACHUi. Accessed February 17, 2020.
5. Lonsurf [prescribing information]. Tokyo, Japan: Taiho Pharmaceutical Co, Ltd; 2019. www.accessdata.fda.gov/drugsatfda_docs/label/2019/207981s008lbl.pdf. Accessed February 17, 2020.
6. FDA approves longer-acting calaspargase pegol-mknl for ALL. FDA website. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-longer-acting-calaspargase-pegol-mknl-all. Updated December 26, 2018. Accessed January 17, 2020.
7. Nobre CF, Newman MJ, DeLisa A, Newman P. Moxetumomab pasudotox&#8209;tdfk for relapsed/refractory hairy cell leukemia: a review of clinical considerations. Cancer Chemother Pharmacol. 2019;84(2):255-263. doi: 10.1007/s00280-019-03875-6.
8. Antibody therapeutics approved or in regulatory review in the EU or US. The Antibody Society website. antibodysociety.org/resources/approved-antibodies. Accessed February 17, 2020.
9. Current nanotechnology treatments. National Cancer Institute website. cancer.gov/nano/cancer-nanotechnology/current-treatments. Updated August 8, 2017. Accessed February 17, 2020.
10. Patra JK, Das G, Fraceto LF, et al. Nano based drug delivery systems: recent developments and future prospects. J Nanobiotechnol. 2018;16:71. doi: 10.1186/s12951-018-0392-8.
11. Karp DD, Camidge DR, Infante JR, Ames T, Jimeno JM, Bryce AH. PT-112: a well-tolerated novel immunogenic cell death (ICD) inducer with activity in advanced solid tumors. Annals Oncol. 2018;29(suppl 8; abstr 437P). doi: 10.1093/annonc/mdy279.424.
12. Bryce AH, Dronca RS, Costello BA, et al. PT-112 in advanced metastatic castrate-resistant prostate cancer (mCRPC), as monotherapy or in combination with PD-L1 inhibitor avelumab: findings from two phase I studies. J Clin Oncol. 2020;38(suppl 6; abstr 83). meetinglibrary.asco.org/record/183583/abstract.

In addition to falling out of favor with investors and pharmaceutical companies, chemotherapy development is limited by the short list of targets that cause DNA damage and cell death without killing too many normal cells or causing other unwanted effects, he said. There are only about a dozen types of traditional chemotherapies but a much larger number of mutational and molecular targets against which new drugs can be designed, he said.