Why Chemotherapy Remains Vital in an Era of Targeted Agents and Immunotherapies

Franco Muggia, MD

When Franco Muggia, MD, was a freshly minted oncologist 50 years ago, his new colleagues warned him not to waste much time learning about a drug like fluorouracil. After all, they suggested, the chemotherapy agent would soon be a thing of the past.

“They were wrong—it’s still around,” Muggia, professor of Medicine (Oncology) at the NYU School of Medicine in New York City and medical director of the Chemotherapy Foundation, says now. “It does have some special features that make it particularly selective against GI cancers, which are a breed of their own.”

The drug’s persistence is a prime example of the continuing role of chemotherapies as a backbone of cancer management, even as novel targeted drugs and immunotherapies are increasingly introduced into treatment paradigms for a variety of tumor types, said Muggia. In fact, he noted, a number of new chemotherapies have been introduced within the last 10 to 15 years, several of them practice changing.

Among Muggia and his colleagues, the expectation is that these new drugs, as well as older chemotherapy standbys, will be used into the foreseeable future, whether alone, in combination, or sequenced with novel targeted agents or immunotherapies. So an important goal, they told OncologyLive, is to find safer, more targeted ways of delivering chemotherapy.

A method that’s gathering speed is the development of antibody-drug conjugates (ADCs), which pair extremely strong chemotherapy drugs with antibodies that target cancer cells.

Recent Innovations in Modality

One important chemotherapy that emerged about a decade ago is oxaliplatin (Eloxatin), whose approval as a frontline treatment in 2004 “totally changed the results in colorectal cancer,” Muggia pointed out. Approved in 2008, bendamustine hydrochloride (Treanda), which is “revolutionizing the treatment of some lymphomas,” is a new formulation of the first chemotherapy ever, nitrogen mustard, proving that it’s an oversimplification to consider chemotherapy outdated, he said.

Muggia added that chemotherapy regimens are “making a dent” in extremely difficult-to-treat pancreatic cancers, and that single-agent chemotherapies (cisplatin and methotrexate, respectively) can cure testicular cancer and choriocarcinoma.

“Certainly, treatment is multidisciplinary,” said Muggia. “When used by itself, it’s a tall order to expect a chemotherapy to eliminate every single cancer cell in somebody who presents with very advanced disease. So when using systemic therapies, we often have to work with surgery, with radiation, and, more and more nowadays, the great advances being made in immunology. No one area should be emphasized or de-emphasized. Those involved in the study of human disease and its treatment don’t get hung up on the semantics of what a class of therapy is called, but follow what are the best leads.”

Debu Tripathy, MD

In fact, the difference between chemotherapies and targeted agents is not always clear cut, added Debu Tripathy, MD, professor of Medicine and co-leader of the Women’s Cancer Program at the USC Norris Comprehensive Cancer Center in Los Angeles.

“We tend to make a distinction between targeted and chemotherapy drugs, but the line that separates those is a little bit blurry,” he said. “Chemotherapy drugs have certain properties of biological drugs and can modulate cellular pathways, and, similarly, targeted drugs can cause injury to normal cells, so they have some properties of chemotherapy.”

A movement away from cytotoxic therapies is anticipated in hematologic malignancies. Chemotherapy has been eliminated from the standard regimen for chronic myeloid leukemia (CML), and promising experimental agents could make the same outcome possible in other blood cancers, said Bruce Cheson, MD, professor of Medicine at the Lombardi Comprehensive Cancer Center at Georgetown University in Washington, DC.

But chemotherapies are curative—and thus, for now, indispensable—in diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma, he noted. In breast, lung, and prostate cancers, leading oncologists not only rely on chemotherapy as a staple of treatment regimens, but also expect it to remain part of the armamentarium for the foreseeable future.

Among them is Naiyer Rizvi, MD, a lung cancer expert at Memorial Sloan Kettering Cancer Center in New York City.

“Even in the era of targeted therapy, most lung cancer patients do not have any ‘druggable’ targets and need chemotherapy. Even if they do have a targeted therapy option, invariably resistance to targeted therapy will occur and patients will need chemotherapy at some point in their illness,” Rizvi said. “So, chemotherapy for many patients will continue to be the mainstay therapy, whether it’s first- or second-line.”

With chemotherapy maintaining its stronghold, a major area of research is devoted to finding new ways to reduce its toxicities—in many cases through the creation of ADCs, some already approved by the FDA.

Breast Cancer

“The goal in cancer therapeutics is to eventually get rid of chemotherapy or to develop chemotherapy drugs that hone in on cancer cells so specifically that the side effects to normal tissue are as low as they could be,” Tripathy said. “We don’t want to eliminate them just for the sake of it; if they were engineered to be less toxic, that would be fine, as well. The bottom line is how effective these drugs are and how safe they are.”For patients with smaller tumors and negative lymph nodes, oncologists may sometimes recommend a chemotherapy—free regimen after surgery: hormonal therapy alone. But most often, according to Tripathy, chemotherapy remains a critical component of treatment for breast cancer, used in early-stage disease to lower the risk of recurrence; after cancer has spread to control or temporarily shrink it; and in combination with targeted agents trastuzumab (Herceptin) or pertuzumab (Perjeta) to improve outcomes in HER2-positive breast cancer. Triple-negative breast cancer is another subtype in which chemotherapy is a vital tool, Tripathy said.

Within the past five years or so, two new chemotherapies have become available for the treatment of breast cancer: eribulin (Halaven) for advanced metastatic disease following several other chemotherapy regimens, and ixabepilone (Ixempra) with or without capecitabine for patients resistant to an anthracycline, taxane, and/ or capecitabine. These microtubule inhibitors represent an advance in chemotherapy because they more effectively overcome drug resistance, allowing patients to live a few months longer on average, Tripathy said.

Another step forward came in 2013 with the approval of T-DM1, or ado-trastuzumab emtansine (Kadcyla), an ADC designed to better target cancer cells while sparing normal ones, for patients with HER2-positive, late-stage breast cancer, said Tripathy. Another approved conjugate is the nanotherapeutic nab-paclitaxel (Abraxane), paclitaxel bound to albumin, that is indicated in breast, nonsmall cell lung cancer (NSCLC), and pancreatic cancers. The drug is more soluble and thus more easily delivered to patients than paclitaxel alone, Tripathy said.

Still another modern chemotherapy delivery method involves wrapping systemic agents in a lipid droplet, which makes them less toxic.

Approved in this class is liposomal doxorubicin (Doxil), used in multiple myeloma and ovarian cancer. And still in clinical development is Irinophore C, a lipid formulation of the chemotherapy irinotecan being explored in various solid tumors. What has yet to be accomplished is to find methods for personalizing chemotherapy treatments in breast cancer, Tripathy said. Although the OncotypeDX test can help determine whether patients need chemotherapy in the first place, there are no assays that offer insights into which specific chemotherapy is best for a given patient, Tripathy said.

He added that, since chemotherapy is used so frequently, there is a need to establish methods of getting it across the blood/brain barrier.

“Sometimes we treat patients for breast cancer and they develop brain metastases because the brain is not being treated preventively,” he said. “Efforts are being made in clinical trials to develop chemotherapy drugs that are attached to substances that allow them to pass through the blood/brain barrier—such as ANG1005.”

According to its developer, Montreal-based Angiochem, ANG1005 is “a novel targeted taxane derivative (that) represents the first oncology product to leverage the LRP-1 pathway to cross the blood—brain barrier and enter cancer cells.”¹

Lung Cancer

Patients with nonsquamous disease have benefited the most from new developments in chemotherapy for lung cancer, with pemetrexed (Alimta) paired with cisplatin approved in 2008 as a first-line therapy, and then a year later as a maintenance therapy, according to Rizvi.

Pemetrexed “has an improved toxicity profile over more traditional taxane-based regimens with less myelosuppression, neuropathy, and alopecia,” Rizvi said. “It offers a similar survival benefit with a better safety profile.”

In addition, conventional systemic therapies carboplatin and paclitaxel found a new partner in the monoclonal antibody bevacizumab (Avastin) when it was approved as a first-line treatment for NSCLC in 2006.

Naiyer Rizvi, MD

Other than that, “there’s been pretty much a plateau in terms of chemotherapy options for lung cancer,” Rizvi said. “Old standbys like cisplatin and carboplatin continue to be the backbone of first-line chemotherapy. They’ve been around the longest and continue to be among the most active and frequently used.”

A new trend, however, is that novel paradigms have pushed chemotherapy into a later setting in specific subgroups of patients, Rizvi noted. “For patients with EGFR mutations or ALK rearrangements, we sometimes use targeted therapies first-line and then reserve chemotherapies as second-line therapies,” he said. “We have different pathways for therapy based on whether a tumor is mutated with EGFR or ALK, primarily, but we’re also identifying more and more targets in terms of mutations as we do that, so there may be more and more targeted therapies that could be options instead of chemo.”

Other questions being investigated in the clinic are which patients might benefit from stillexperimental immune checkpoint blockade agents, and how the effectiveness of those agents might compare with that of chemotherapy, Rizvi said. Currently, about 15% to 20% of patients with NSCLC respond to these agents, he said.

“There may be a subset of patients who may not ever get chemotherapy if they have a great, durable response to first-line immune checkpoint therapy,” Rizvi predicted.

As in other cancers, ADCs are also on the horizon as a potentially safer, more effective delivery system for chemotherapies in patients with lung cancer, Rizvi said.

In addition to the approved nab-paclitaxel, drug conjugate candidates are being studied in early-phase clinical trials. IMMU-132, which pairs the antibody RS7 with SN38, the active metabolite of irinotecan, is being tested in a phase I/II study in a variety of cancers, including NSCLC and small cell lung cancer (SCLC).2 Also in the clinic are IMGN388, the maytansinoid DM4 attached to an alpha-v integrin-targeting antibody for use in lung, breast, and prostate cancers; IMGN901, or lorvotuzumab mertansine, a CD56-targeting agent for SCLC, multiple myeloma, and other tumor types; and BAY 94-9343, which is targeted against the cancer antigen mesothelin.³

Prostate Cancer

Daniel P. Petrylak, MD

In 2004, docetaxel (Taxotere) changed practice when the FDA approved the taxane for the treatment of metastatic, hormone-refractory prostate cancer. Before that, “We had the palliative agents mitoxantrone and samarium, but none that improved survival in this disease state,” said Daniel P. Petrylak, MD, of the Smilow Cancer Hospital at Yale-New Haven in Connecticut. “This opened up and changed people’s thought process about whether something could be effective for these patients.”

A further improvement came in 2010 with the approval of cabazitaxel (Jevtana) in combination with prednisone, which generated a survival benefit for patients who had become resistant to docetaxel. “The thought is that these chemotherapy drugs work as antiandrogen agents by preventing the androgen receptor from translocating to the nucleus by interfering with tubulin,” Petrylak said. Looking ahead at chemotherapy’s future, Petrylak said the excitement about ADCs abounds as much in prostate cancer as in other tumor types. Petrylak is the principal investigator in a clinical trial of an antibody to prostate-specific membrane antigen (PSMA) linked to antitumor agent monomethyl auristatin E, or MMAE. In addition, he said, there are ongoing trials of the conjugate nab-docetaxel.

But in prostate cancer, the drug development process is marked by special concerns, he noted. “It’s difficult to find niches to fit these drugs in,” he said, “because so many drugs have been approved recently for this disease.” Since patients can receive so many different drugs, Petrylak explained, it becomes hard to gauge the survival benefits of new players added into the mix.

Even with the plethora of existing agents, it’s often difficult to plan a course of treatment, Petrylak added. “You now have four different approaches to treating prostate cancer: the chemotherapies docetaxel and cabazitaxel; hormonal, which may include those chemotherapies and abiraterone (Zytiga) or enzalutamide (Xtandi); the immune therapy Provenge (sipuleucel-T); and DNA damage approaches with isotopes (radium-223 [Xofigo]),” Petrylak said. “All these come into play at some point, so the real question is how you sequence them. What’s the best treatment to go forth with at a given time? It’s a complex issue.”

Hematologic Cancers

Despite the glowing promise of experimental therapies, chemotherapy is far from ready to take its final bow when it comes to treating hematologic malignancies. CML is currently the only blood cancer whose standard treatment does not include chemotherapy— although it can be used palliatively in the late stages of the disease. Therapy for the condition typically involves targeted agents starting with imatinib (Gleevec), and followed by stem cell transplant only if imatinib and other drugs fail.⁴

Meanwhile, conventional chemotherapies are still a go-to treatment in multiple myeloma, and they hold the relatively rare distinction of being able to cure two other blood-cancer types, Cheson said. DLBCL, the most common type of non-Hodgkin lymphoma (NHL), can be cured with either the R-CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) or with R-EPOCH (the same drugs plus etoposide). Those therapies include the monoclonal antibody rituximab (Rituxan).⁵

And Hodgkin lymphoma can, in most cases, be cured with the chemotherapy regimen ABVD (Adriamycin, bleomycin, vinblastine, and dacarbazine).⁶

Still, movement away from traditional chemotherapies is the aim in these diseases, and like in other cancers, Cheson said, there are ADCs available.

“Antibody-drug conjugates have revolutionized the management of Hodgkin lymphoma,” Cheson explained. “Brentuximab vedotin (Adcetris), in patients with Hodgkin lymphoma who have relapsed and then failed stem cell transplant, generates a response rate of 76%. Those with anaplastic large cell lymphoma who have failed initial therapies have a response rate of 85%. This drug is increasingly used in the relapsed setting instead of chemotherapy before stem cell transplant, and it’s also being evaluated as part of the initial treatment of Hodgkin lymphoma to see if it can replace some chemos.”

Another conjugate, pinatuzumab vedotin, is being evaluated in NHL, Cheson added. “For most of the other forms of lymphomas and chronic leukemias,” Cheson predicted, “chemotherapy will likely disappear.”

Strides have been made in follicular lymphoma with the development of experimental doublets of monoclonal antibodies and other targeted agents; phase II results with rituximab and lenalidomide (Revlimid) were so exciting that they led to the ongoing RELEVANCE trial of rituximab/lenalidomide versus rituximab/chemotherapy, Cheson said. Other breakthroughs in blood cancer over the past few years have involved the development of novel targeted agents including ibrutinib (Imbruvica), idelalisib, ABT-199, IPI-145, chimeric antigen receptor therapy, and drugs that target PD-1 and PDL-1, all for the treatment of B-cell lymphomas—primarily DLBCL, follicular, and mantle cell—or chronic lymphocytic leukemia (CLL). The agents are generally less toxic than chemotherapy and offer the advantages that come with oral, as opposed to intravenous, treatment regimens.

“There are a number of ongoing trials looking at replacing chemotherapy with these drugs,” Cheson said.

Cheson was among the researchers responsible for bringing the popular chemotherapy bendamustine to the United States, which the FDA approved in 2008 for diseases including CLL and indolent NHL. Still, Cheson anticipates that ibrutinib and idelalisib will soon eclipse the chemotherapy’s use.

In blood cancers, “No one cares a whit about new chemotherapies,” he said. “Bendamustine sneaked under the wire as kind of the last. Everyone cares more about what we’ve been doing for the last 10 years to develop a chemotherapy—free approach to cancer.”

Even with that goal in mind, there’s a possibility that novel treatment modalities may inadvertently create a new niche for chemotherapy, Cheson noted.

Targeted therapies “suppress disease as long as patients take them, but when they are stopped, the disease comes right back,” he said. “So, we have to figure out if cure is still the goal of therapy, or whether we should treat these now as chronic diseases, like diabetes or hypertension. Cure would be financially better, because these new drugs can cost around $130,000 a year. We have to determine how best to combine them with other agents so that we don’t have to give them indefinitely.”

Chemotherapies could be among the agents used to limit the duration of treatment with targeted agents, Cheson said, but only clinical trial results will establish that with certainty. “All this has happened in the last two or three years, and papers are just starting to come out,” he said. “There’s still a lot to be learned.”

References

1. ANG1005A—promising new targeted taxane derivative. Angiochem website. http://angiochem.com/grn1005. Accessed May 15, 2014.
2. NIH Clinical Trials Registry. www/ClinicalTrials.gov. NCT01631552.
3. Burris HA. Developments in the use of antibody-drug conjugates. Am Soc Clin Oncol Ed Book. http://meetinglibrary. asco.org/content/102-132. 2013.
4. Treatment of chronic myeloid leukemia by phase. American Cancer Society website. http://www.cancer.org/cancer/ leukemia-chronicmyeloidcml/overviewguide/leukemiacml- overview-treating-treatment-by-phase. Updated Fbruary10, 2014. Accessed May 15, 2014.
5. Diffuse large B-cell lymphoma (DLBCL): overview. Lymphoma Research Foundation website .http://www.lymphoma. org/site/pp.asp?c=bkLTKaOQLmK8E&b=6300153. Accessed May 15, 2014.
6. The cure of Hodgkin lymphoma. American Society of Hematology website. http://www.hematology.org/About/ History/50-Years/1528.aspx. Accessed May 15, 2014.