By Chase Doyle
For the first time in a few years, immunotherapy did not take center stage at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting. Although hundreds of abstracts featuring combinations of immunotherapy agents were presented, no groundbreaking novel immunotherapeutic topped the news.
Rather, the predominant storyline was the positioning of previously established drugs, mostly pathway inhibitors, into new tumor types and treatment settings. This year, it was back to the topic of “precision medicine,” meaning hitting the right target, in the right patient, at the right time.
Success: The Definitions Varied
APHINITY Trial Results: More Lackluster Than “Significant”
The robust overall survival (OS) benefit achieved by adding Perjeta (pertuzumab, Roche) to Herceptin (trastuzumab, Roche) in the CLEOPATRA trial of metastatic breast cancer, and a doubling of pathologic complete response rates with the combo in the neoadjuvant setting, set the stage for the adjuvant APHINITY trial.
The results were highly anticipated—and were met with some degree of disappointment by breast cancer experts at ASCO, who noted that the small “bang” delivered by dual HER2 blockade is probably not worth the bucks.
APHINITY randomized 4,805 HER2-positive patients to chemotherapy with Herceptin and Perjeta or placebo. The triplet did meet its primary endpoint by showing a significant improvement in invasive disease-free survival (IDFS) at 3 years, but a less than 1% difference was questionable from a clinical standpoint.
Three-year IDFS was 94.1% with Perjeta plus Herceptin versus 93.2% with Herceptin alone (HR: 0.81; P=.045). At 4 years, the difference widened a bit to 92.3% vs 90.6%, respectively.
The researchers emphasized that the benefit was greater in high-risk patients. In node-positive and estrogen receptor–negative cohorts, the absolute benefits were 1.8% (P=.019) and 1.6% (P=.085), respectively. Distant recurrence-free interval and overall survival were not improved.
Breast cancer experts agreed that the use of both agents in the adjuvant setting, therefore, should be limited to patients with node-positive or estrogen receptor-positive disease.
The questionable magnitude of benefit led many breast cancer experts to question the utility of this combination altogether. Among listeners commenting after the ASCO presentation was breast cancer researcher, medical oncologist, and surgeon William Sikov, MD, of Women & Infants Hospital in Rhode Island. “The problem is that we don’t live in utopia where treatments have no financial or toxicity costs,” he remarked.
“To treat 100 patients with pertuzumab on top of standard therapy would cost $10 million dollars,” he figured. “With a 2% improvement, this means paying $5 million for each patient who does not recur, and there will never be a survival advantage. I can think of a lot better things to do with $5 million.”
- Will physicians, who are increasingly concerned about value, believe the data justify an additional $100,000 to a course of adjuvant therapy for women who are already at low risk for recurrence?
- If Perjeta is used in the adjuvant setting, will it retain efficacy if used after recurrence? Will this lead physicians to reserve it for advanced disease?
- In early-stage HER2-positive breast cancer, neratinib has produced a slightly greater, though still modest benefit. Will it prove a competitor to Perjeta?
MONARCH 2 Adds to a Growing List of CDK4/6 Inhibitors
The phase III MONARCH 2 study evaluated abemaciclib (Eli Lilly and Company) in 669 hormone-receptor-positive, HER2-negative metastatic breast cancer patients, in combination with Faslodex (fulvestrant, AstraZeneca) versus Faslodex alone. Abemaciclib is the third CDK4/6 inhibitor to be evaluated in a large breast cancer trial.
Risk of progression for patients in the combination arm was reduced by 45%. Median progression-free survival (PFS) was 16.4 months in the combination arm compared with 9.3 months for patients in the fulvestrant alone arm (HR: 0.553; P<.0000001). The response rate was 48.1% in the combination arm vs 21.3% in the fulvestrant alone arm (P<.001).
“This response rate appears to be the highest recorded in an endocrine-resistant population,” said lead investigator George W. Sledge, MD.
The encouraging results were tempered somewhat by an incidence of diarrhea (86.4%) which was greater than what has been seen with Ibrance (palbociclib, Pfizer) and Kisqali (ribociclib, Novartis), which are approved in the metastatic setting.
An amendment to the MONARCH 2 protocol, however, resulted in less diarrhea, the investigators noted. Nevertheless, the potential for this side effect and the need for continuous dosing (vs every-3-week dosing for the CDK4/6 inhibitors), may be drawbacks to this agent.
Ingrid Mayer, MD, of Vanderbilt-Ingram Cancer, Nashville, maintained that while all CDK4/6 inhibitors “may not be created equal,” they are all “similar,” as the trials’ hazard ratios are comparable.
Mature overall data from additional MONARCH trials, from the PALOMA-2 for Ibrance trial, and from MONALEESA-2 for Kisqali will help determine which agent physicians will opt for, she said.
Meanwhile, Dr. Mayer concluded, “We should absolutely incorporate CDK4/6 inhibitors and endocrine therapy at some point in the treatment of estrogen receptor-positive metastatic breast cancer.”
- If approved, will clinicians make room for abemaciclib as a third CDK4/6 inhibitor, since they are already familiar with Ibrance and Kisqali?
- Will concern for diarrhea and need for continuous dosing be viewed as drawbacks by physicians?
- Will this and the other CDK4/6 inhibitors prove effective in the adjuvant setting?
First Positive Data for PARP Inhibitor in Breast Cancer
Results from the phase III OLYMPIAD trial were presented at the ASCO Plenary Session, reflecting the excitement that, for the first time, positive data for a PARP inhibitor was shown in metastatic breast cancer.
While the improvement in PFS in patients treated with Lynparza (olaparib, AstraZeneca) by many accounts was modest, it may have a practice-changing impact on the management of HER2-negative tumors that harbor BRCA mutations. Breast cancer specialists expressed excitement over a potential new therapeutic option in this challenging tumor type.
Patients treated with Lynparza had a median PFS of 7.0 months as compared with 4.2 months for patients receiving standard chemotherapy (HR: 0.58; P=0.0009). Response rates were almost doubled with Lynparza (59.9% vs 28.8%), time to second progression was prolonged (HR: 0.57), and tolerability was also better than with chemotherapy. Triple-negative patients had the most reduction in risk (HR: 0.43).
Lynparza is the first approved PARP inhibitor. The efficacy of this and other PARP inhibitors in BRCA-mutant ovarian cancer provided the rationale for studying them in other tumors associated with DNA-repair defects, which PARP inhibitors target.
“This is the first phase III study to show an advantage of a PARP inhibitor over standard-of-care chemotherapy in breast cancer patients with a BRCA mutation,” said lead investigator Dr. Mark Robson, of Memorial Sloan Kettering Cancer Center in New York City. “It is our opinion that olaparib could be an effective treatment option for women with BRCA mutations and metastatic HER2-negative breast cancer, including, importantly, women with BRCA mutations in triple-negative disease.”
ASCO president and breast cancer specialist Daniel Hayes, MD, of the University of Michigan, called the findings a major advance. “For patients whose cancers are negative for those two things, we’ve had chemotherapy, which is not very precise,” he said.
But he cautioned against the broad application of these findings, noting that Lynparza worked in women with BRCA mutations and not the general population of breast cancer. It is also not clear whether blocking DNA repair—which is how PARP inhibitors work—could have deleterious long-term effects on normal cells, where DNA repair is a good thing, he said.
In addition, the study found no difference in OS (median, 19 months), which is always a concern with expensive drugs.
“Even when the drugs worked, the survival curves ultimately came back together again. This goes back to using the drugs in different ways, perhaps combining them with other therapies. But I do believe this is a really big step forward in breast cancer,” Dr. Hayes said in a press briefing.
Study discussant Allison Kurian, MD, of Stanford University, called the results “practice-changing,” especially since “toxicity and quality of life were better for olaparib,” though she noted that the choices for the chemotherapy arm were not typical and “may have set a lower bar for comparative efficacy.”
- Will the small magnitude of the PFS benefit (3 months difference) and lack of overall survival benefit raise questions by oncologists as to the clinical meaningfulness of using Lynparza instead of chemotherapy, which is far less expensive?
- Will clinicians reserve this drug for the triple-negative subset, for whom benefit was apparently greater?
- How will Lynparza compare with other PARP inhibitors in BRCA-associated breast cancer?
- Can correlative biomarker studies identify which patients will benefit most?
- Will combination therapy be better than single-agent PARP inhibition?
Shifting LATITUDE in Prostate Cancer Landscape
In the first-line treatment of advanced prostate cancer, findings from two studies of abiraterone (Zytiga, Janssen) could shift upfront treatment “practically overnight,” propelling Zytiga into first-line use, according to Dr. Richard Schilsky, MD, chief medical officer at ASCO, and other prostate cancer experts at ASCO.
Commenting on the LATITUDE trial—which was presented at the ASCO Plenary Session—Dr. Eric Small, MD, of the University of California, San Francisco, called the results “profoundly positive,” while ASCO spokesperson Sumanta Pal, MD, of City of Hope Comprehensive Cancer Center, indicated they “should change the treatment paradigm” in newly diagnosed disease.
In other words, abiraterone could largely displace chemotherapy from the current paradigm, the experts suggested.
At present, the drug is approved for use after failure of androgen deprivation therapy (ADT), but the new data show substantial benefit when used earlier in the disease and in combination with ADT.
The global phase III LATITUDE trial randomized 1,199 newly-diagnosed, high-risk metastatic patients who are hormone-naïve to either Zytiga/prednisone/ADT or placebo/ADT.
The Zytiga/prednisone/ADT therapy produced a 38% reduction in risk of death. Overall survival was not reached but was 34.7 months in the control am (HR: 0.62; P<.0001). All other endpoints were also improved, and all subgroups derived benefit.
Zytiga patients had a 70% reduced risk of time to PSA progression (33.2 vs 7.4 months, HR: 0.30; P<.0001). The results led to early termination of the trial.
Similarly, Zytiga upped the benefit of ADT vs ADT alone in the STAMPEDE trial of high-risk locally advanced/metastatic prostate cancer nearly diagnosed or relapsed, which is a broader patient population.
“These data should reshape our model for treating metastatic prostate cancer,” said Dr. Pal, but he cautioned the benefit is not clear in non-metastatic disease where the confidence interval “straddles 1.0,” and further study is needed.
- Standard treatment with docetaxel may have more side effects but it is cheaper and has a much shorter treatment duration than Zytiga. How will physicians view these very different options?
- Will clinicians be tempted to use Zytiga in low-risk metastatic disease, too?
- If used early-on, can Zytiga be effective if used to re-treat?
Could Lenvima Unseat Nexavar in First-Line Hepatocellular Carcinoma?
The first-line treatment of advanced hepatocellular carcinoma (HCC) has long included Nexavar (sorafenib, Bayer), as clinical trials of potential competitors have failed to unseat it. At ASCO, Lenvima (lenvatinib, Eisai) was compared upfront with this standard of care in the global non-inferiority REFLECT trial of 954 unresectable HCC patients.
Lenvima is a multi-targeted tyrosine kinase inhibitor (TKI) that is approved as monotherapy in differentiated thyroid cancer and in combination with Afinitor (everolimus, Novartis) for advanced renal cell carcinoma following one prior anti-angiogenic therapy.
REFLECT met its primary endpoint as Lenvima proved non-inferior in OS. Median OS was 13.6 months with Lenvima vs 12.3 months with Nexavar (HR: 0.92). It proved statistically superior to Nexavar in numerous other endpoints. Median progression-free survival time was doubled (7.4 vs 3.7 months; HR: 0.66; P<.00001) and response rates were tripled with Lenvima (24% vs. 9%; OR: 3.13; P<.00001).
While efficacy was similar, so was toxicity. This is important because a concern with TKIs in HCC has been tolerability, since many patients have compromised liver function. Grade ≥3 treatment-related adverse events were observed in 57% of the Lenvima arm and 49% of the Nexavar arm. The two Grade 3/4 toxicities of note were hypertension (23% vs 14%) and palmar-plantar erythrodysesthsia (3% vs 11%).
Based on REFLECT data, Eisai announced plans to submit for regulatory approval later this year. Whether Lenvima can overtake the well-established Nexavar in this space is uncertain. Non-inferiority trials typically aim to show benefits in terms of toxicity, cost, or ease of administration—a bar not surpassed in REFLECT.
- With Nexavar entrenched in this setting, will Lenvima, which may not be more tolerable, find a niche?
- With Stivarga (regorafenib, Bayer) approved as well, and with Opdivo (nivolumab, Bristol Myers Squibb / Ono Pharmaceuticals) just around the corner, how will oncologists shuffle these cards in sequencing treatment?