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Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy

JHOP - December 2013 VOL 3, NO 4 - From the Literature
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PD-1 Inhibitor Lambrolizumab Is Safe, Shows Durable Responses in Patients with Advanced Melanoma

Background: Lambrolizumab (previously known as MK-3475) is a humanized monoclonal immunoglobulin G4 antibody that blocks the programmed death-1 (PD-1) receptor and reactivates an immune response to the cancer cells. The PD-1 receptor limits the body’s immune response against cancer. Researchers have set out to investigate the safety and antitumor activity of 3 dosing regimens of lambrolizumab in a cohort of patients with advanced melanoma.

Methods: This multi-institutional, international, phase 1 expansion study included 135 patients with advanced melanoma. Some of the patients enrolled had received treatment with the checkpoint inhibitor ipilim- umab and some had not received such treatment. All patients were administered the intravenous PD-1 inhibitor lambrolizumab at 10-mg/kg dosing every 2 or 3 weeks or 2-mg/kg dosing every 3 weeks. Tumor responses were assessed every 12 weeks.

Results: The confirmed response rate across the 3 dose cohorts was 38% (95% confidence interval [CI], 25-44), with the highest confirmed response rate observed in the patients receiving the 10-mg/kg dose of lambrolizumab every 2 weeks (52%; 95% CI, 38-66). Previous therapy with ipilimumab did not affect the response to lambroliz- umab. The response rate among patients who were previously treated with ipilimumab was 38% (95% CI, 23-55) compared with 37% (95% CI, 26-49) among those who had not received treatment previously. Response rates were durable in the majority of patients who had experienced response at a median follow-up of 11 months; 81% of patients with a response were still continuing treatment as of March 2013. The overall median progression-free survival among the 135 patients was longer than 7 months. The most common adverse events reported with lambrolizumab in this study were fatigue, rash, pruritus, and diarrhea; most of the adverse events were low grade. Drug-related adverse events of any grade were reported by 79% of the patients, with grade 3 or 4 adverse events reported by 13%. The highest incidence of overall treatment-related adverse events was seen among patients receiving the lambrolizumab dose of 10 mg/kg every 2 weeks compared with patients receiving the 10-mg/kg dose every 3 weeks and those receiving 2 mg/kg every 3 weeks (23% vs 4% and 9%, respectively).

Source: Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti–PD-1) in melanoma. N Engl J Med. 2013;369:134-144.


In this phase 1 study by Hamid and colleagues, lambrolizumab given in a dose of 10 mg/kg intravenously every 2 weeks showed the highest response rate (52% as measured by Response Evaluation Criteria in Solid Tumors, and 57% as measured by an immune-mediated response) in patients with metastatic melanoma. Of the 52 responders, 42 were still receiving the drug at the time of response analysis. Twelve patients achieved a complete response. It is notable that responses were similar in the patients who had received previous ipilimumab therapy. The majority of responses were seen after the first imaging at 12 weeks, but several more responses were seen subsequently. At 11 months of follow-up, the median duration of response had not been reached. Only 10 responders had discontinued therapy at 11 months of follow-up; 5 of these were a result of grade 3 or 4 toxicity. Other common adverse effects included diarrhea, hypothyroidism, rash and pruritus, and fatigue. This degree of toxicity is reasonable for monoclonal antibody therapy. The US Food and Drug Administration designated lambrolizumab (MK-3475) as a breakthrough therapy for the treatment of patients with advanced melanoma. In a similar phase 1 study of nivolumab and ipilimumab in advanced melanoma, Wolchok and colleagues (Wolchok JD, et al. N Engl J Med. 2013;369:122-133) reported that nivolumab, another PD-1 inhibitor, combined with the cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor ipilimumab, was no more toxic than either agent given alone. In addition, Wolchok and colleagues also found that at the maximum tolerated dose, 53% of patients with advanced, treatment-resistant melanoma had objective tumor responses, with tumor regression of at least 80% in every patient who had a response. These studies suggest that combination antibody therapy against PD-1 and CTLA-4 may offer an exciting new approach to treating tumors that are dependent on these tumor signaling receptor proteins.

Denosumab Improves Bone Metastasis–Free Survival in Patients with Nonmetastatic Castration-Resistant Prostate Cancer

Background: In a recently reported phase 3 trial of men with nonmetastatic castration-resistant prostate cancer (CRPC) and high risk for disease progression based on baseline prostate-specific antigen (PSA) ≥8 ng/mL and/or PSA doubling time of 10 months or less, denosumab—an anti-RANK ligand monoclonal antibody—significantly increased bone metastasis–free survival (BMFS) and delayed time to first metastasis, but did not improve overall survival (OS) or progression-free survival compared with placebo. In a new exploratory analysis of the study, researchers evaluated the relationship between PSA doubling time and BMFS, time to first bone metastasis, and OS in recipients of denosumab and placebo.

Methods: This randomized, phase 3, double-blind, placebo-controlled study included 1432 men with nonmetastatic CRPC. The patients were randomized in a 1:1 ratio to monthly subcutaneous denosumab 120 mg or to placebo. The time of survival without bone metastasis was analyzed according to PSA doubling times of ≤10 months, ≤6 months, and ≤4 months. At baseline, median PSA was 12.3 ng/mL, PSA doubling time was 5.1 months, and doubling duration time was 47.1 months.

Results: An analysis of the placebo arm demonstrated a shorter BMFS time as PSA doubling time decreased to less than 8 months. Compared with placebo, treatment with denosumab was associated with median BMFS increases of 6 months (28.4 months vs 22.6 months, respectively; hazard ratio [HR], 0.84) in patients with a PSA doubling time of ≤10 months, 7.2 months (25.9 months vs 18.7 months; HR, 0.77) among patients with a PSA doubling time of ≤6 months, and 7.5 months (25.8 months vs 18.3 months; HR, 0.71) in patients with a doubling time of ≤4 months. The median time to first bone metastasis was significantly reduced with denosumab in patients with a PSA doubling time of ≤6 months (26.5 months vs 22.1 months, respectively; HR, 0.80) and ≤4 months (26.4 months vs 18.5 months; HR, 0.71). No difference was found in OS between the 2 treatment arms for the overall study population or for PSA doubling time subsets. These findings demonstrate that faster PSA doubling time is associated with a shorter BMFS in this patient population. Denosumab significantly increased BMFS time and time to first bone metastasis in the overall study population, and the drug has shown the greatest treatment effects in men who are at high risk for disease progression.

Source: Smith MR, Saad F, Oudard S, et al. Denosumab and bone metastasis–free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostate-specific antigen doubling time. J Clin Oncol. 2013;31:3800-3806.


In this study, denosumab was shown to effectively delay the onset of first bone metastases and to increase bone metastases disease-free survival in patients with high-risk prostate cancer, with the best outcomes observed in patients with a PSA doubling time of <6 months. In other studies, denosumab has also been shown to be more effective than zoledronic acid in preventing further skeletal-related events in prostate cancer metastatic to bone, and both drugs are approved by the US Food and Drug Administration (FDA) for this indication. Unfortunately, the beneficial effects of denosumab have not translated into either increased OS or improved control of bone pain, and, as a result, the FDA has not approved the drug for the prevention of bone metastases in patients with high-risk prostate cancer. The FDA was also concerned about the expected long-term use of denosumab in the setting of preventive treatment and the risk of serious toxicities, especially osteonecrosis of the jaw.

The most important finding in the study by Smith and colleagues is that a short PSA doubling time was strongly associated with shorter BMFS. This is the first study to show this relationship, and it suggests that new strategies should be investigated that combine rational therapeutics with personalized medicine to treat advanced prostate cancer.

The role of denosumab in this setting remains in doubt until it can demonstrate substantially better survival outcomes, improved quality of life, or a safer toxicity profile with long-term use.

Gemcitabine Increases Survival for Patients with Resected Pancreatic Cancer

Background: The prognosis for patients with pancreatic cancer is poor, even for patients with surgically resectable tumors. Gemcitabine (Gemzar) is the standard chemotherapy for advanced pancreatic cancer. Despite the lack of a clear consensus, gemcitabine has also become the mainstay of adjuvant treatment for this deadly disease, even though its effects on survival after surgery have not been demonstrated. Now, findings from the extended follow-up of the Charité Onkologie 001 (CONKO-001) trial of patients with pancreatic cancer who underwent surgery provides support for the use of gemcitabine in the adjuvant setting.

Methods: CONKO-001 was a multicenter, open- label, parallel-group, randomized, phase 3 trial that compared gemcitabine with observation alone in the adjuvant setting in 368 adults who had undergone complete, curative-intent resection of pancreatic cancer at 88 medical centers in Germany and Austria. In the intent-to-treat analysis, the investigators randomized 354 eligible patients to adjuvant gemcita- bine (N = 179) or to observation alone (N = 175). Gemcitabine was administered at 1 g/m2 on days 1, 8, and 15 every 4 weeks for 6 months. The enrollment period ran from July 1998 to December 2004, and the follow-up period ended September 2012. During a median follow-up of 11 years, pancreatic cancer recurred in 308 patients—145 in the gemcitabine group and 163 in the observation group. The primary end point was disease-free survival (DFS). The secondary end points included overall survival (OS).

Results: The results show that the median DFS was significantly greater with gemcitabine than with observation alone (13.4 months vs 6.7 months, respectively). Furthermore, the rates of DFS were significantly better with gemcitabine than with observation at 5 years (16.6% vs 7.0%, respectively) and 10 years (14.3% vs 5.8%, respectively). At the end of the follow-up, 316 of the 354 (89.3%) patients had died. The median OS was 22.8 months in the gemcitabine group versus 20.2 months in the observation group. The difference in OS between the 2 groups was significant. OS in the gemcitabine group at 5 years was 20.7% versus 10.4% in the observation group, and at 10 years was 12.2% versus 7.7%, respectively. These treatment benefits occurred across all subgroups of patients, regardless of tumor stage and nodal status at the time of resection. These findings are likely to be representative of general clinical practice in other countries, because CONKO-001 was a community-based trial that involved academic centers and community-based oncologists without uniform standards for surgery.

Source: Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer. The CONKO-001 randomized trial. JAMA. 2013;310:1473-1481.


This large, randomized phase 3 study showed that adjuvant gemcitabine compared with observation doubled the OS rate at 5-year follow-up and increased OS by 58% at year 10, which was a 25% improvement in the risk of mortality. This study establishes gemcitabine as one of the mainstay agents in the adjuvant treatment of pancreatic cancer. According to Sinn and colleagues, who recently reported on the long-term survival (>5 years) of patients with pancreatic cancer (Sinn M, et al. J Surg Oncol. 2013;108:398-402), the benefit of adjuvant gemcitabine was seen regardless of surgical margin outcomes. In the 54 patients (median age, 60.5 years) who were classified as long-term survivors, 53 had a confirmed histologic diagnosis of adenocarcinoma of the pancreas. Furthermore, the researchers also confirmed that the long-term survival rate was 15% at 11.3 years of follow-up. Sinn and colleagues were unable to detect any new biologic tumor markers associated with long-term survival. Although the study by Oettle and colleagues showed the benefit of gemcitabine in the adjuvant setting, pancreatic cancer remains a complex disease and requires further research to determine if other therapies will improve long-term survival in this poor-prognosis cancer.

Long-Term Treatment with Cetuximab Linked to Early Tumor Shrinkage in Patients with Colorectal Cancer

Background: Although colorectal tumors with a mutation in the KRAS gene generally do not benefit from epidermal growth factor receptor (EGFR)-targeted therapy such as cetuximab, there are no current biomarkers to select patients who are more likely to respond to EGFR therapy. In a new study, researchers analyzed data from 2 trials to determine if early tumor shrinkage was associated with long-term outcomes in patients with colorectal cancer receiving first-line treatment with cetuximab.

Methods: The researchers combined data from the Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) and Oxaliplatin and Cetuximab in First-Line Treatment of Metastatic Colorectal Cancer (OPUS) trials that accrued patients between 2004 and 2006. CRYSTAL was a randomized, open-label, multicenter, phase 3 trial comparing fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus cetuximab with FOLFIRI alone. OPUS was a randomized, open-label, multicenter, phase 2 trial comparing fluorouracil, leucovorin, and oxaliplatin (FOLFOX-4) plus cetuximab with FOLFOX-4 alone. The analysis included 1289 patients whose tumors could be analyzed for KRAS mutation status. Patients were followed for a median of 45 months and 32 months in the CRYSTAL and OPUS trials, respectively. Response was assessed every 8 weeks until disease progression or withdrawal.

Results: Both trials showed that a more robust tumor response at 8 weeks after the start of therapy was associated with improved progression-free survival (PFS) and overall survival (OS) in patients with KRAS wild-type tumors. The researchers determined that early tumor shrinkage of 20% or more could identify patients who were receiving chemotherapy plus cetuximab with longer PFS and OS. In the CRYSTAL and OPUS trials, respectively, the cutoff value of early tumor shrinkage of ≥20% versus <20% for median PFS was 14.1 months versus 7.3 months and 11.9 months versus 5.7 months, and median survival was 30 months versus 18.6 months and 26 months versus 15.7 months. The interaction between early tumor shrinkage and the treatment group (with cetuximab) was significantly associated with PFS (P = .027 and P = .004 for CRYSTAL and OPUS data, respectively), but not for survival (P = .573 and
P = .546, respectively). These results suggest that tumor shrinkage can be used as a prognostic biomarker.

Source: Piessevaux H, Buyse M, Schlichting M, et al. Use of early tumor shrinkage to predict long-term outcome in metastatic colorectal cancer treated with cetuximab. J Clin Oncol. 2013;31:3764-3775.


This study uses a biometric model to calculate response to treatment and to compare early tumor shrinkage with a threshold of >20% at 8 weeks in patients with wild-type or mutated KRAS who were receiving cetuximab therapy. The theory is that rapid tumor response equates to greater drug sensitivity, especially in patients with a sensitive biomarker. Thus, patients with a >20% rapid tumor shrinkage is predictive of a better PFS. In contrast, patients who had <20% tumor shrinkage have a worse prognosis, suggesting that there was no benefit with the addition of cetuximab to chemotherapy. This study provides the clinician with a rational decision-making option based on a tumor biologic response (ie, rapid responders vs poor or slow responders), with the latter being switched to an alternative chemotherapy regimen.

In an accompanying editorial, Oxnard and Schwartz state that the study suggests that a patient’s “response phenotype” can help guide treatment strategy (Oxnard GR, Schwartz LH. J Clin Oncol. 2013;31:3739-3741). Using a biologic response that can be accurately measured, as was done by Piessevaux and colleagues, can be a predictive marker for survival. Oxnard and Schwartz describe other biometric approaches for non–small-cell lung and esophageal cancers that use other methods for biologic response rather than the traditional objective response criteria. Oxnard and Schwartz also suggest that the work of Piessevaux and colleagues lends evidence that a biologic agent can cause tumor shrinkage as opposed to the older idea that these therapies are static in their antitumor effects.

In summary, biometric methodologies that measure a response phenotype may expand our strategies for treating cancer.

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