Virginia Powers

The addition of Onivyde (MM-398) to 5-fluorouracil (5-FU) and leucovorin significantly improved overall survival (OS) while having no negative impact on quality of life (QOL) for patients with metastatic pancreatic cancer, according to an analysis of the phase 3 NAPOLI-1 trial presented at the 2016 World Congress on Gastrointestinal (GI) Cancer, a gathering of oncology professionals from around the world in Barcelona, Spain.

"This quality of life analysis of the NAPOLI-1 data underscores the significant clinical benefit the Onivyde regimen provides to a patient population with few treatment options,” Richard Hubner, an investigator on the NAPOLI-1 trial and Consultant Medical Oncologist at Christie NHS Foundation Trust, said in a statement.

“Fluorouracil and leucovorin is recognized as a well-tolerated therapy for metastatic pancreatic cancer patients. The addition of Onivyde, a second chemotherapeutic agent, to this treatment regimen demonstrated significant improvement in median overall survival, progression-free survival, and overall response rate with little or no impact on baseline quality of life at 12 weeks, as shown in this analysis. This further supports the growing recognition that the Onivyde combination regimen is a clinically beneficial treatment option for metastatic pancreatic cancer patients who have progressed on gemcitabine-based therapy."

In October 2015, the FDA approved Onivyde in combination with 5-FU and leucovorin as a treatment for patients with metastatic pancreatic cancer following prior administration of a gemcitabine-based regimen, based on results from the NAPOLI-1 trial.

In the international trial, 417 patients with gemcitabine-refractory metastatic pancreatic cancer were randomized to Onivyde monotherapy, 5-FU with leucovorin (control) or Onivyde plus 5-FU and leucovorin. Per standard irinotecan protocols, dexamethasone and a 5-HT3 antagonist could be administered in the combination arms.

In the control, 5-FU was administered at 2000 mg/m

 weekly for four weeks followed by two weeks of rest (149 patients). In the combination arm, intravenous Onivyde was administered at 80 mg/m

 every two weeks (117 patients). In the monotherapy group, Onivyde was administered at 120 mg/m

The addition of Onivyde to 5-FU and leucovorin improved OS by 1.9 months. In the combination arm, the median OS was 6.1 months compared with 4.2 months with 5-FU and leucovorin alone.

QOL was among the NAPOLI-1 trial’s secondary endpoints. Hubner and colleagues assessed the impact of Onivyde on QOL and symptom burden in patients.

The QOL evaluation was done in 69 percent of patients in the intent to treat population receiving Onivyde plus fluorouracil/leucovorin and in 53 percent of patients receiving fluorouracil/leucovorin alone who also completed QOL assessments at baseline, every six weeks during treatment, and at 30 days after study completion.

Patients in both treatment groups demonstrated an observed median change from baseline in Global Health Status (GHS) score of 0 after 12 weeks on study. The observed median change included assessments on subscale scores regarding financial difficulties, physical, emotional, cognitive and social functioning, plus symptom subscores on pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, nausea and vomiting.

“Global health status and functional scale scores were not significantly different between treatment arms at baseline and showed no appreciable change over 12 weeks,” Hubner said when presenting the data at the World GI Congress.

Baseline median GHS scores were similar in both treatment groups and ranged from 0 to 33 points. Changed scores greater than 10 percent were categorized as 

, whereas patients who did not meet the improvement criteria and died or showed a score decrease greater than 10 percent were categorized as 

. Those patients meeting neither improved nor worsened criteria were deemed 

Pairwise treatment group comparison was done using the Cochran-Mantel-Haenszel test. A difference of 0 was observed in the subscale scores for global health status, and emotional, cognitive, social and role functioning. A change of -6.7 points in the physical functioning scale was below the 10-point threshold and determined as “no change.”

No substantial differences were seen in symptom scale scores between the treatment arms for nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation and diarrhea. Fatigue subscores increased from baseline at week 12 by 11 points, which corresponded to a “moderate” increase.

Although a manageable safety profile was demonstrated in the Onivyde group, grade 3/4 adverse events occurred more frequently in the Onivyde versus control arm, including fatigue (27 percent vs 1 percent), diarrhea (13 percent vs 4 percent) and vomiting (11 percent vs 3 percent).

One potential limitation of the analysis was the small number of patients assessed, Hubner noted.

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The addition of Onivyde to some chemotherapy regimens for pancreatic cancer improved survival and did not affect patients' quality of life. 

Addition of Onivyde to Standard Care Improves Survival, Does Not Worsen Quality of Life in Pancreatic Cancer

A new generation of TKIs are about to take the place of drugs such as as Tarceva (erlotinib), Gilotrif (afatinib) and Iressa (gefitinib), as the first-line targeted treatment of 

-mutated lung cancer, says David Planchard.

“Drug resistance limits the long-term success of even the most effective targeted therapies,” according to Planchard, Department of Cancer Medicine at the Institute Gustav Roussy in Villejuif, France, during the 2016 European Lung Cancer Conference (ELCC).

“Third-generation TKIs offer a higher level of selectivity towards 

 versus wild type, allowing a wider therapeutic range, and a better tolerability profile,” he said. “Expect a prolonged control of the disease compared to currently available TKIs.”

Planchard described the odyssey of treatments for patients with 

-mutated lung cancer who develop resistance to frontline TKIs, usually a result of acquired resistance through the T790M mutation. This has led to the development of third-generation TKIs that selectively bind to 

 T790M mutations, such as Tagrisso (osimertinib) and rociletinib. Pretreated patients with T790M-positive tumors have experienced a median progression-free survival (PFS) of 9.7 to 11 months with Tagrisso at 80 mg and 8.0 months with rociletinib at 625 mg.

Planchard offered the possibility that the best sequence may actually be to reverse these lines of therapy and to start with a third-generation TKI.

“Prevention or delay of resistance may be a better strategy than treating resistance,” he said and detailed a strategy of ‘hitting harder’ the 

 mutation target with third-generation TKIs.

Planchard proceeded to make a strong case for T790M inhibition in the first-line, explaining that this strategy inhibits mutant 

 with sensitizing mutation exon 19 or L858R, as well as dual mutant 

 having either de novo or secondary T790M resistance mutation. Third-generation TKIs have the advantage of greater selectivity, better tolerability and also allow for optimized brain penetration. They have demonstrated longer PFS and prolonged the development of resistance, according to Planchard.

With available EGFR first-generation TKIs, rash and diarrhea have been observed in approximately 80 percent of patients with grade 3/4 seen in nearly 20 percent of patients. In contrast, Tagrisso has shown low rates of all-cause adverse events (AEs) in phase 1 and 2 trials. Similar findings were seen with rociletinib, in which grade 1 or 2 diarrhea was noted in 20 percent of patients, with no reports of diarrhea of grade 3 or higher.

Third-generation TKIs show optimized brain penetration, and are therefore more likely to have activity in brain metastases, which develop within a year of treatment in many patients. Planchard also cited a case study from his practice demonstrating tumor shrinkage in the brain of a patient with lung cancer and said that phase 2 trial data have shown efficacy in patients with a history of brain metastases.

Tagrisso has been evaluated as first-line treatment in the AURA trial in patients with locally advanced or metastatic 

-mutated NSCLC. Thirty patients each received 80 mg per day and 160 mg per day in the first-line setting. At median follow-up of 16.6 months, the ORR was 77 percent. Median PFS was 19.3 months for the 160-mg dose and has not yet been reached for the 80 mg-dose.

Tagrisso was well tolerated at both dose levels, though at the recommended 80-mg dose, just 10 percent of patients required dose reduction and no grade 3 or higher AEs of rash, diarrhea, and other AEs were reported; there was one report of grade 3 nausea.

Planchard pointed out that first-line Tagrisso will be evaluated in the FLAURA study and the phase 3 SOLAR study (NCT02588261). He also noted that the clinical development of rociletinib is ongoing in the TIGER-X, -1, -2, and -3 trials.

Possible pitfalls of first-line third-generation TKIs could be the type of resistance that develops. The C797S mutation is known to impact the sensitivity of these treatment strategies, as it blocks the binding site of Tagrisso. Also, the magnitude of PFS and overall survival response is unknown.

“Tumor heterogeneity has important clinical implications and may also enter into the equation,” Planchard commented.

Combination treatment may be the way forward to counter this pitfall. Tagrisso in combination or alternating with Iressa as first-line in patients with 

-mutant lung cancer is currently being evaluated. Co-targeting EGFR and MEK has shown prolonged time to the development of resistance.

Another strategy being tested is the inhibition of anti-apototic factors BCL-xL and BCL-2.

Other combination strategies have shown promising activity, as in the TATTON trial of Tagrisso plus durvalumab, a high-affinity human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80. This study was conducted in patients with confirmed T790M mutations but was offset by elevated incidence of pneumonitis.

With all these new options and possibilities for combinations, Planchard said, toxicity must remain top-of-mind for physicians and researchers alike.

“Toxicity represents another pitfall of new treatment strategies and must be minimized in treating patients.”

The first-line treatment paradigm for lung cancer is shifting. 

New Class of Agents Moves to Frontline in Lung Cancer

Though having a high body mass index (BMI) is associated with a higher risk for colorectal cancer, patients who are thinner may not do as well after treatment for metastatic colorectal cancer (mCRC). This research was reported at the recent 2015 European Society for Medical Oncology (ESMO) 17th World Congress on Gastrointestinal Cancer.

“Contrary to our hypothesis, patients who had the lowest BMI were at risk for having the shortest survival,” says lead author Yousuf Zafar, associate professor of medicine at Duke Medicine. “In this case, patients with the lowest body weight — people who had metastatic colon cancer and a BMI of less than 25 &mdash; were at the highest risk.

"This effect persisted after adjusting for study, age, ECOG performance status, gender, and hypertension. We did not see any relationship between BMI and progression-free survival.”

The results surprised researchers, who expected obese patients to respond more poorly to treatments for stage 4 colorectal cancer due to their increased risk of developing the disease and having it come back. Additionally, there is some evidence that many obese patients also receive less-than-optimal doses of cancer drugs, or have other health problems that complicate recovery.

According to guidelines, a healthy adult’s BMI ranges from 18.5 to 24, whereas a BMI below 18.5 is considered underweight.

Researchers examined data pooled from 6,128 patients in the U.S. and Europe who had previously been untreated for their mCRC and who were included in four different registry studies. Their average BMI at the start of cancer treatment was 25.3, considered slightly overweight, and all patients received bevacizumab with chemotherapy in their treatment.

The study’s primary endpoints were overall survival (OS) and progression-free survival (PFS).

Median BMI for all patients was 25.3 kg/m

. BMI was divided into five categories: less than 20 (532 patients); 20-24 (2,328 patients); 25-29 (2,119 patients); 30-35 (821 patients); and at least 35 kg/m

 (328 patients). The majority of patients (5,554) had an ECOG performance status of 0 or 1 and the site of the primary tumor was the colon, rectum, rectum and colon, and recto-sigmoid. Nearly all patients (86 percent) had undergone surgical resection.

Although PFS was similar across baseline BMI categories, investigators found a difference in OS. Patients with BMIs less than 25, 25-29, 30-35, and at least 35 kg/m

 demonstrated a median PFS of 10.0, 10.6, 10.5, and 10.9 months, respectively. The median OS in the same four respective BMI ranges was 21.1, 23.5, 24.0, and 23.7 months.

“Proportional hazards models confirmed that low BMI was associated with shortened OS after adjusting for potential differences in baseline characteristics,” commented Zafar.

According to a proportional hazard model using BMI as a continuous variable, a BMI increase of 5 kg/m

 was associated with a decrease in the risk of death.

“I see this study as hypothesis-generating and a basis for a randomized, controlled study,” said Zafar during a question and answer session.

The role of high BMI has only recently been evaluated in mCRC, revealing obesity as a risk factor for developing colon cancer. Also, patients with BMI at both the lowest (less than 18.5 kg/m

) levels have been shown to be at higher risk for earlier disease recurrence following adjuvant chemotherapy for colon cancer.

“Although high BMI has been associated with increased risk of colorectal cancer, little is known about how BMI impacts outcomes for patients already diagnosed with mCRC,” remarked Zafar.

“It’s possible that the lowest weight patients may receive adequate first-line treatment but then are too sick to receive subsequent lines of therapy. That may be where we can focus more attention on improving their outcomes.”

Zafar Y, Hubbard J, Van Cutsem E, et al. Survival outcomes according to body mass index (BMI): results from a pooled analysis of 5 observational or phase IV studies of bevacizumab in metastatic colorectal cancer (mCRC). Presented at: 17th World Congress on Gastrointestinal Cancer; July 1-4, 2015; Barcelona, Spain. Abstract LBA-01. 

Though having a high body mass index (BMI) is associated with a higher risk for colorectal cancer, patients who are thinner may not do as well after treatment for metastatic colorectal cancer (mCRC).

Virginia Powers

Addition of Onivyde to Standard Care Improves Survival, Does Not Worsen Quality of Life in Pancreatic Cancer

New Class of Agents Moves to Frontline in Lung Cancer

New Study Shows Shorter Survival for Thin Patients With Colorectal Cancer

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