Moving Beyond Targeted Therapy Stalwarts: Experts Weigh In on Four Tumor Types

It has been nearly 18 years since the first molecularly targeted therapy, rituximab (Rituxan), was approved for the treatment of patients with B-cell non-Hodgkin lymphoma, a development that helped launch a new era in cancer care.

Today, as scientific advances propel the oncology field forward with novel strategies aimed at genomic aberrations and biological processes, the first generation of targeted agents continues to form the backbone of treatment for the tumor types in which they were initially approved and to fulfill expanded roles in other malignancies.

As the year opens on a fresh season of discovery, OncologyLive asked experts in lymphoma, chronic myeloid leukemia, breast cancer, and non—small cell lung cancer to discuss the impact that the first targeted agents have had on these malignancies and the prospects for new therapeutic approaches that might improve upon the impressive gains made during the past two decades.

Lymphomas: Tactics for Improving Rituximab Regimens Vary With Subtype

Andy Chen, MD, PhD

The introduction of rituximab to the treatment of patients with non-Hodgkin lymphoma (NHL) in 1997 has doubled median survival to 10 years for individuals newly diagnosed with high-risk, low-grade follicular lymphoma and also has made a significant, although not as dramatic, impact in aggressive lymphomas, according to Andy Chen, MD, PhD. Rituximab is a genetically engineered murine/human monoclonal antibody directed against the CD20 antigen expressed on the surface of pre-B and mature B-lymphocytes.

Chen, who leads the lymphoma research group for the Knight Cancer Institute at Oregon Health & Science University (OHSU) in Portland, said approaches to improve upon established rituximab-containing regimens vary according to lymphoma subtype— with different degrees of success thus far. For B-cell NHL, the standard regimen had been R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) until recent years.

In 2012, German researchers demonstrated that pairing bendamustine (Treanda) with rituximab significantly improved progression-free survival (PFS) over R-CHOP (69.5 months vs 31.2 months, respectively) as first-line therapy among patients with indolent NHL subtypes, including follicular and mantle cell lymphoma (MCL).¹ And in October 2014, the FDA approved bortezomib (Velcade) as part of a regimen that includes rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP) for patients with previously untreated MCL, the first such treatment specifically indicated for this setting, based on a phase III clinical trial demonstrating a 59% relative improvement in PFS over R-CHOP.²

“But this has all been progression-free survival so far,” said Chen. “There has been no overall survival benefit yet. It’s hard to show an overall survival (OS) benefit these days in low-grade lymphoma because the average survival of the high-risk patient in the rituximab era is over 10 years.”

In chronic lymphocytic leukemia (CLL), the emergence of the Bruton tyrosine kinase inhibitor ibrutinib (Imbruvica) and other targeted therapies has prompted efforts to combine a new agent with rituximab. Ibrutinib is approved for the treatment of patients with MCL or chronic lymphocytic leukemia (CLL) in relapse settings. Last year, the FDA also approved idelalisib (Zydelig), a PI3K-delta inhibitor, in CLL in combination with rituximab, and in relapsed follicular and small lymphocytic lymphoma.

“Low-grade lymphoid malignancies, particularly CLL, are further along in terms of novel and targeted therapies. A lot of those drugs that have worked well in low-grade lymphoma and CLL have not worked as effectively in aggressive lymphoma,” said Chen.

For aggressive lymphomas, researchers have had a more difficult time improving upon R-CHOP. Diffuse large B-cell lymphoma (DLBCL) is now divided molecularly into germinal center (GC) versus activated B-cell (ABC) subtypes, with significantly worse outcomes among patients with the ABC type who receive the standard R-CHOP therapy, Chen noted. He said researchers are experimenting with adding agents to the R-CHOP regimen such as ibrutinib, bortezomib, and lenalidomide (Revlimid) for ABC subtype DLBCL. Another approach involves seeking improvements to the chemotherapy component of the regimen, most notably dose-adjusted R-EPOCH (rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin).

Chen said there are indications that R-EPOCH may be more effective for some types of aggressive lymphomas than R-CHOP; a phase III clinical trial testing this hypothesis in DLBCL is currently under way.³ However, he said R-EPOCH is more cumbersome to administer in terms of dosing schedules and monitoring of blood counts, and therefore might not translate well into community settings. “We use it ourselves, but only for highly aggressive lymphomas like MYC-positive or double-hit lymphomas,” said Chen.

While most of these regimens remain anchored to rituximab, the possibility of a more potent replacement for targeting CD20 also is an important strategy under development. In 2013, the FDA approved obinutuzumab (Gazvya), a type II glycoengineered monoclonal antibody that selectively targets CD20, for the treatment of patients with previously untreated CLL in combination with chlorambucil after studies showed the regimen was superior to chlorambucil alone. In December, the label was updated to reflect results from the CLL11 trial indicating that obinutuzumab plus chlorambucil led to a median PFS of 26.7 months compared with 14.9 months with rituximab and chlorambucil (HR = 0.42; 95% CI, 0.33-0.54; P <.0001).⁴

In lymphomas, the question of whether obinutuzumab can replace rituximab in chemotherapy regimens likely will be answered by two phase III trials: the GALLIUM trial5 in patients with untreated advanced indolent NHL and the GOYA trial6 in patients with treatment-naïve DLBCL.

“Going forward, there will always be an anti-CD20 antibody involved in the B-cell NHL treatment,” said Chen. “If obinutuzumab is shown in multiple phase III studies to be better than rituximab, then I think you’ll see a movement toward it. In part, it will also depend on the cost difference between obinutuzumab and rituximab—or future biosimilar—and what the magnitude of benefit is.”

Regardless of the outcome of any particular study, the need for new therapies for patients suffering from aggressive disease remains pressing, Chen stressed.

“Yes, these days in the R-CHOP era, we cure over 50% of aggressive lymphoma,” said Chen. “But there’s still a significant number of patients who are not cured. Those patients tend to relapse early, and the majority do not respond to standard second-line therapy and transplant. We have very poor treatment options for them.”

Elias J. Jabbour MD

Chronic Myeloid Leukemia: Many Agents Follow Imatinib But Big Questions RemainThe development of imatinib (Gleevec) for patients with chronic myeloid leukemia (CML) is often considered one of the most important developments in the emergence of targeted therapies. The small molecule tyrosine kinase inhibitor (TKI), which Giants of Cancer Care award winner Brian L. Druker developed at OHSU, was approved in record time by the FDA in 2001 and now carries 10 indications in hematologic and other malignancies. In fact, oncology specialists last year ranked imatinib among the “Top 5 Advances in Modern Oncology” in an American Society of Clinical Oncology poll, not only because of its impact on the treatment of blood cancers but also because the agent helped point the way to attacking molecular mutations.⁷ Imatinib targets tyrosine kinases encoded by the BCR-ABL fusion gene, an abnormality known as the Philadelphia chromosome (Ph).

“Imatinib is an amazing model of a success story in cancer. In fact, before the era of imatinib, patients with CML used to live 6 to 7 years. They would get interferon and those who were lucky would get transplantation,” said Elias J. Jabbour, MD, an associate professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston. “With the era of imatinib, things have changed drastically. Today, somebody with CML can expect to have a normal lifespan on a drug.”

Today, clinicians have a field of BCR-ABL inhibitors from which to choose to treat patients with CML. The second-generation compounds dasatinib (Sprycel) and nilotinib (Tasigna) are both more potent BCR-ABL inhibitors than imatinib and are approved in frontline as well as relapse settings, Jabbour and colleagues noted in a recent review.8 In clinical trials, dasatinib has been more effective than imatinib in helping patients achieve complete cytogenetic response (CCyR), while nilotinib has outperformed imatinib in the rate of major molecular response. Bosutinib (Bosulif) and ponatinib (Iclusig) are second-line choices; ponatinib is designed to attack the BCR-ABL T315I point mutation, which promotes resistance to frontline TKIs. Although the newer frontline agents are more effective as upfront therapy, they have not outperformed imatinib in OS, Jabbour said.

“It’s hard to show improvement over imatinib therapy,” he said. “The question is, should we give everybody a new drug upfront? That is an unsolved question.”

Other important questions that remain unsettled include whether it is safe for patients who have achieved a CCyR to stop taking a TKI, how to address the resistance to therapy that develops in a significant proportion of patients, and financial problems that patients encounter in their ability to pay for daily imatinib and other TKIs.

Looking forward, Jabbour said researchers are focusing on targeting stem cells directly as a means of potentially effecting a cure for CML and of new combinations of imatinib with other agents such as the protein synthesizer omacetaxine mepesuccinate.

“All these are very important concepts but still far away,” Jabbour said. Meanwhile, Jabbour said clinicians treating patients with CML must remain vigilant even amid positive results. “While progress has been made, we should not underestimate [the disease],” he said. “We should not say, well patients are doing so great why not leave them on their own? We should really monitor them very carefully and make sure the patient is responding very well.”

HER2-Positive Breast Cancer: More Research Needed on Trastusumab, Novel Agents

Edith Perez, MD

In breast cancer therapy, improving upon the performance of trastuzumab (Herceptin) for HER2-positive tumors has proved to be a daunting challenge for researchers and drug developers. Since its initial approval in 1998, the humanized monoclonal antibody has substantially improved disease-free survival and OS in several treatment settings, and has transformed metastatic disease into a manageable chronic illness for many patients.⁹ T-DM1 (ado-trastuzumab emtansine; Kadcyla) was considered the likely successor to trastuzumab until drug developer Genentech announced in December10 that two regimens containing the agent failed to outperform the standard trastuzumab plus chemotherapy combination in the phase III MARIANNE trial.

T-DM1 is an antibody-drug conjugate that links trastuzumab with the microtubule inhibitor DM1, a maytansine derivative, to deliver both the anti- HER2 agent and chemotherapy directly to the cancer cells. In 2013, the FDA approved the drug as a single-agent treatment in the second-line setting for patients with HER2-positive metastatic breast cancer, and the MARIANNE trial was an attempt to move T-DM1 into a frontline setting for women with advanced, HER2-positive disease.

The disappointing results surprised Edith A. Perez, MD, the lead investigator in the MARIANNE trial, given the drug’s performance in preclinical studies and early clinical trials. In the three-arm trial, patients were randomized to T-DM1 plus or minus pertuzumab (Perjeta) or trastuzumab plus either docetaxel or paclitaxel. The novel therapeutic approaches resulted in PFS rates similar, but not superior, to the standard arm, according to Genentech. Specific findings have not yet been released.

“T-DM1 is an excellent drug in the portfolio of therapies for patients with HER2-positive metastatic breast cancer,” said Perez, deputy director at large for the Mayo Clinic Cancer in Florida. “It’s still there. Whether T-DM1 will substitute for trastuzumab and chemotherapy, I think it will require [us] to look at the data in detail to try to figure out the benefit ratio. Now we know there’s noninferiority, so there are other issues we’ll have to look at in detail.”

Overall, Perez said much more research is needed not only to further develop new therapies, but also to better elucidate trastuzumab. “We are trying to understand better how trastuzumab works,” Perez said. “Even though this drug has been available now for essentially 15 years, we’re still doing some work in identifying the real benefits of this drug and also identifying molecular markers to understand who benefits from trastuzumab.”

To that end, Perez has been investigating the correlation between levels of stromal tumor-infiltrating lymphocytes (S-TILs) and likelihood of disease recurrence among women with HER2-positive breast cancer treated with chemotherapy alone. Early analysis indicates that high TIL levels may function as a biomarker to identify patients for whom optimal treatment might be chemotherapy alone, without HER2-targeted therapy.¹¹

Similarly, Perez and colleagues have succeeded in confirming that adjuvant trastuzumab added to chemotherapy for 1 year should be the standard of care for women with early-stage HER2-positive breast cancer.12 The addition of trastuzumab led to a 37% relative improvement in OS and a 10-year OS rate of 84%.

“One of the critical issues related to the use of adjuvant therapy for patients with any cancer, including breast cancer, is whether the benefits we observe in the short term are maintained in the long term, especially related to survival,” said Perez. “We had demonstrated that in the short term, trastuzumab improved survival. Now we have 10-year data showing that the results are very solid.”

Another important study for the HER2-positive patient population is the phase III APHINITY trial, which is testing whether the combination of trastuzumab, pertuzumab, and a chemotherapy regimen, which was recently approved by the FDA for neoadjuvant therapy, will improve invasive disease-free survival in approximately 4800 patients who have undergone surgery for HER2-positive breast cancer. Results are expected in 2016. Meanwhile, Perez said improvements in the molecular targeting of HER2 through novel agents, such as bispecific antibodies, are an important goal.

“Many companies are trying to find better targeting of the HER2 protein and ways to modify the molecular structure to have these drugs that not only bind better to HER2 but also enhance the immune activation that is first associated with these monoclonal antibodies,” Perez said.

Non—Small Cell Lung Cancer: New EGFR Inhibitors Suggest Potential for Better Outcomes

Thomas J. Lynch Jr., MD

The recognition that abnormal epidermal growth factor receptor (EGFR) activity can promote non—small cell lung cancer (NSCLC) led to the FDA approval of two TKIs targeting the mutation: gefitinib (Iressa) in 2003 and erlotinib (Tarceva) in 2004.

The introduction of these agents meant a new paradigm for treating patients with NSCLC, particularly as understanding of EGFR mutations was refined, and helped pave the way for targeting other aberrations such as ALK and ROS1 translocations.

“EGFR inhibitors have really changed the way we treat EGFR-mutated lung cancer,” said Thomas J. Lynch Jr, MD, the director of Yale Cancer Center and a pioneer in the use of EGFR molecular testing. “For patients who have mutations—which is 13% of patients in North America—these drugs offer less toxicity and better activity than conventional chemotherapy offers.”

Erlotinib has demonstrated OS and PFS benefits in several treatment settings in NSCLC clinical trials, but AstraZeneca took gefitinib off the market in the United States in mid-2005 after the agent failed to reach those benchmarks in studies that followed its initial accelerated approval.13 In December, AstraZeneca announced that the FDA is reviewing the company’s new drug application for gefitinib as monotherapy for first-line treatment of advanced or metastatic EGFR-mutated NSCLC.

At the same time, the development of EGFR inhibitors continues to evolve with agents more specifically targeted to certain points of the mutation. In 2013, the FDA approved afatinib (Gilotrif) for first-line treatment of patients with metastatic NSCLC whose tumors harbor EGFR exon 19 deletions or exon 21 (L858R) mutations. The agent is an irreversible TKI.

Two promising novel agents in development are rociletinib (CO-1686) and AZD9291, EGFR inhibitors that selectively target the T790M resistance mutation. Both agents have gained the FDA’s breakthrough therapy designation.

Lynch said the emerging agents are designed to more specifically target the molecular mutation, resulting in fewer toxicities, such as the rash and diarrhea that are most bothersome to patients. “By being designed against a mutated receptor, you have fewer side effects because you have less inhibition of wild-type EGFR and you have greater activity against the EGFR-mutated receptor—more antitumor activity, less side effects,” he said. “It delivers a better drug to patients. The future is for the use of third-generation drugs in patients who are mutation-positive.”

The most pressing problem with EGFR-targeted therapies in NSCLC, however, remains the resistance that develops to therapy, Lynch said.

“Third-generation [agents] may be able to tackle resistance partially, but it’s not entirely clear that they would be able to overcome it completely,” he said. “We just don’t know yet.”

References

1. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent and mantle cell lymphomas (MCL): updated results from the StiL NHL1 study. J Clin Oncol. 2012;30(suppl; abstr 3).
2. FDA approves Velcade (bortezomib) for injection for previously untreated patients with mantle cell lymphoma [press release]. Cambridge, MA: Millennium: The Takeda Oncology Company; October 9, 2014.
3. NIH Clinical Trials Registry. www.ClinicalTrials.gov. NCT00118209.
4. FDA approves Gazyva (obinutuzumab) supplemental biologics license application with new data in previously untreated chronic lymphocytic leukemia [press release}. South San Francisco, CA: Genentech. December 24, 2014.
5. NIH Clinical Trials Registry. www.ClinicalTrials.gov. NCT01332968.
6. NIH Clinical Trials Registry. www.ClinicalTrials.gov. NCT01287741.
7. The top 5 advances in modern oncology. American Society of Clinical Oncology website. http://cancerprogress.net/ top-5-advances-modern-oncology. Accessed January 5, 2015.
8. Mathisen MS, Kantarjian HM, Cortes J, Jabbour EJ. Practical issues surrounding the explosion of tyrosine kinase inhibitors for the management of chronic myeloid leukemia [published online June 12, 2014]. Blood Rev. 2014;28(5):179-187.
9. Sledge GW, Mamounas EP, Hortobagyi GN, et al. Past, present, and future challenges in breast cancer treatment [published online June 2, 2014]. J Clin Oncol. 2014;32(19):1979-1986.
10. Genentech provides update on phase III MARIANNE study in people with previously untreated advanced HER2-positive breast cancer [press release}. South San Francisco, CA: Genentech. December 18, 2014.
11. Perez EA, Ballman KV, Anderson SK et al. Stromal tumorinfiltrating lymphocytes (S-TILs): in the Alliance N9831 trial S-TILs are associated with chemotherapy benefit but not associated with trastuzumab benefit. Presented at: 2014 SABCS; December 9-12, 2014; San Antonio, TX. Abstract S1-06.
12. Perez EA, Romond EH, Suman VJ, et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2—positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831 [published ahead of print October 20, 2014]. J Clin Oncol. 2014;32(33):3744-3752.
13. FDA approval for gefitinib. National Cancer Institute. http://www.cancer.gov/cancertopics/druginfo/fdagefitinib. Accessed January 5, 2015.