Patients with unresectable hepatocellular carcinoma (HCC) continue to show statistically significant improvement in overall survival (OS) with second-line regorafenib (Stivarga) treatment, according to updated results from the RESORCE trial presented at the 2017 annual World Gastrointestinal (WGI) cancer conference.

In addition, researchers noted during the trial that there is a strong correlation between regorafenib activity and the occurrence of hand-foot skin reaction (HFSR), which suggests that HFSR is can aid in gauging patient response.

Jordi Bruix MD, head of the Barcelona Clinic Liver Cancer (BCLC) at the University of Barcelona, presented an updated analysis of OS at approximately 1 year after the primary analysis.

“The phase III RESORCE trial met the primary endpoint: regorafenib improved OS versus placebo in patients with unresectable HCC who progressed during sorafenib (Nexavar) treatment,” said Bruix. “The results of this updated analysis of data from the RESORCE trial confirm the primary OS results.”

The RESORCE trial is an ongoing randomized, double-blind, placebo-controlled, multicenter phase III study of regorafenib in patients with HCC. The trial enrolled 573 patients with HCC and documented radiological progression after treatment with sorafenib. Patients were randomized to receive regorafenib at 160 mg once daily (n = 379), for 3 weeks on/1 week off, or placebo (n = 194). The primary endpoint of the study was OS, and secondary efficacy endpoints were time to progression, progression-free survival, objective response rate, and disease control rate.

Patient characteristics were balanced between the treatment arms: 88% of patients were male in both arms and the median age in the regorafenib arm was 64 (range, 54-71) years compared with 62 (range, 55-68) years in the placebo arm. Hepatitis B infection was reported in 38% and hepatitis C infection in 21% of patients in both groups. Microvascular invasion occurred in 29% versus 28% of patients in the respective groups and extrahepatic disease in 70% versus 76%. Cirrhosis was present in 74.5% of patients.

The updated analysis revealed OS was slightly improved over the primary analysis. Updated OS was a median 10.7 months (95% CI, 9.1-12.2) with regorafenib versus 7.9 months (95% CI, 6.4-9.0) with placebo (HR, 0.61; 95% CI, 0.50-0.75; 

 <.0001). In the primary analysis, median OS was 10.6 versus 7.8 months with regorafenib versus placebo (HR, 0.63; 95% CI, 0.50-0.79; 

Part of the significance of the updated results is that they more clearly show the effects of prolonged treatment with regorafenib, Bruix said. Using a Swimmer plot to illustrate, she explained “What you see here is that all of the events have shifted farther to the regorafenib side, demonstrating that any subgroup events of OS that were borderline in the primary analysis now firmly favor regorafenib.”

The updated safety profile was similar to that reported in the primary analysis, with an interesting update regarding HFSR, which causes redness, numbness, sensitivity, and sometimes blistering on the palms of the hands and soles of the feet and is a commonly reported adverse event with regorafenib. The incidence of any grade HFSR with regorafenib was 53% versus 8% with placebo; grade 3 HFSR incidence was 13% versus 1%, respectively. The median time to first occurrence was 14 days. A review of baseline characteristics revealed the HFSR was more like to occur following regorafenib in Asian patients and in patients infected with the hepatitis B virus.

A subgroup analysis of OS by occurrence of HFSR at any time during regorafenib treatment suggested that HFSR may be a marker for regorafenib activity. OS was significantly prolonged in patients developing HFSR. They demonstrated median OS of 14.1 months (95% CI, 11.7-16.5) over those who did not, who had median OS of 6.6 months (95% CI, 5.0-8.5).

“Although a retrospective analysis suggests that HFSR is associated with better OS with regorafenib, this analysis may be confounded by baseline or other unknown factors, and further evaluation is needed,“ said Bruix.

An analysis of OS in patients developing HFSR early on, during the first regorafenib treatment cycle revealed patients with HFSR had median OS of 13.2 months (95% CI, 10.6-15.5) versus patients with no HFSR, whose median OS was 8.2 months (95% CI, 7.0-10.0).

“Regorafenib is an effective treatment option for patients with unresectable hepatocellular carcinoma who progress on prior sorafenib,” Bruix concluded, adding that "effective treatment options are urgently needed for patients with unresectable liver cancer."

The RESORCE trial was supported by Bayer.

Bruix J, Merle P, Granito A, et al. Updated overall survival (OS) analysis from the international, phase 3, randomized, placebo-controlled RESORCE trial of regorafenib for patients with hepatocellular carcinoma (HCC) who progressed on sorafenib treatment. 

 2017;28(suppl 3): mdx262.008. doi.org/10.1093/annonc/mdx262.008. Accessed June 30, 2017.

Articles

The occurence of hand-foot skin response could signal regorafenib activity in hepatocellular cancer.

Hand-Foot Skin Reaction May Signal Regorafenib Efficacy in Hepatocellular Carcinoma

The first known trial of combined ublituximab (TG-1101), ibrutinib (Imbruvica), and umbralisib (TGR-1202) showed that the combination was well tolerated and had activity across heavily pretreated patients with high-risk B-cell malignancies, investigators reported during the 2017 European Hematology Association (EHA) Congress in Madrid, Spain.

Objective response rates (ORR) of 100% were demonstrated across 3 disease subtypes: chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL).

 Nineteen patients with CLL/SLL showed 100% ORR, which included 6 patients showing complete response (CR) and 13 with partial responses (PR). Four patients with MCL demonstrated ORR of 100%, with 2 patients each having CR and PR, and an ORR of 100% was also demonstrated in 2 patients with MZL with 1 patient achieving CR and 1 achieving PR.

The ORR was 80% in 5 patients with follicular lymphoma, which included 1 CR and 4 PR. In diffuse large B-cell lymphoma (DLBCL), only 1 out of the 6 patients in the cohort showed a PR, for an ORR of 17%. The ORR was 83% across 36 patients who were evaluable for efficacy, out of the total 38 patients enrolled in the trial.

The best percent change from baseline demonstrated a 100% reduction in disease burden for 10 patients, and 75% or greater reduction in all but 9 patients. Responses were durable, with 81% of responding patients remaining on study for more than 6 months. The median time of study was 11.1 months (range, 0.4-30+ months).

“Many patients continued on therapy, with approximately half of the patients continuing beyond 1 year,” said Loretta J. Nastoupil, MD, associate professor at the Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center.

This phase I trial explored targeting multiple pathways with ublituximab, a novel glycoengineered monoclonal antibody against a unique epitope on the CD20 antigen, the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, and the next-generation PI3K-delta inhibitor umbralisib in patients with advanced CLL or B-cell non-Hodgkin lymphoma (NHL).

“We know from this study that the triplet appears to be safe, but the mechanism and whether synergy is present are still unknown,” Nastoupil said. “Single agent activity has been observed with ublituximab in rituximab [Rituxan]-refractory patients.” The median patient age was 65 years (range, 32-85). The 29 male and 9 female patients had received a median of 3 prior regimens (range, 0-6). All but the 3 treatment-naïve CLL patients were relapsed or refractory to prior treatment, which included 39% of patients who were refractory to rituximab. In all, 55% of patients had received ≥3 prior regimens.

The study had a dose escalation component for umbralisib; both ibrutinib (420 mg in patients with CLL or 560&thinsp;mg in NHL) and umbralisib (400 mg, 600 mg, and 800 mg) were administered once daily, and ublituximab was given at 900&thinsp;mg IV. Response was evaluated by scans at week 8 and every 12 weeks thereafter.

In the cohort of patients with CLL, 50% had 17p and/or 11q deletions, and 3 patients were refractory to BTK or PI3K-delta inhibitors, including 1 patient who failed both idelalisib (Zydelig) and ibrutinib. Of patients with follicular lymphoma, 2 had received prior autologous stem cell transplants, 1 was refractory to ibrutinib, and 1 patient had received 5 prior lines of rituximab. Patients with DLBCL, who showed the lowest response, had received a median of 4 prior therapies; the sole responder had germ cell B-cell subtype disease.

“The safety profile of this novel combination was favorable, suggesting that umbralisib may be safely combined with targeted agents to overcome mechanisms of resistance,” noted Nastoupil. “The majority of patients in this study were either high risk, heavily pre-treated or both.”

At the time of data cutoff, all 38 patients were evaluable for safety. The majority of adverse events (AEs) were grades 1/2, including diarrhea, which occurred in 45% of patients. Grade 3/4 AEs included neutropenia in 18% of patients, pneumonia in 11%, thrombocytopenia in 8%, as well as rash, pyrexia, dyspnea, stomatitis, diarrhea and dizziness, which each occurred in 3% of patients. Two patients discontinued the study due to AEs of sepsis and pneumonia.

Just 1 dose limiting toxicity occurred in the 400 mg umbralisib CLL cohort, which was unrelated to treatment.

“Correlative studies are planned to understand the potential synergism of this combination and to identify the optimal subtype to pursue for additional study,” Nastoupil said. Additionally, the combination of ublituximab plus umbralisib is currently being evaluated in registration directed studies for CLL and NHL in the UNITY-CLL and UNITY NHL trials.

Nastoupil L, Lunning MA, Vose JM, et al. Chemo-free triplet combination of TGR-1202, ublituximab, and ibrutinib is well tolerated and highly active in patients with advanced CLL and NHL. Abstract presented at: 2017 EHA Congress; June 22-25, 2017; Madrid, Spain. Abstract S772. https://learningcenter.ehaweb.org/eha/2017/22nd/182059/loretta.nastoupil.chemo-free.triplet.combination.of.tgr-1202.ublituximab.and.html.

Lunning MA, Vose J, Fowler N, et al. Ublituximab + TGR-1202 demonstrates activity and a favorable safety profile in relapsed/refractory B-cell NHL and high-risk CLL: phase I results. Abstract presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 1538.

A trial testing the combination of ublituximab, ibrutinib, and umbralisib showed that the combination was well tolerated and had activity across patients with high-risk B-cell malignancies.

Non-Chemo Regimen Impresses in Lymphoma

Ribociclib, an orally bioavailable, selective cyclin-dependent kinase 4/6 inhibitor, demonstrated similar clinical benefits and safety profiles for both elderly and younger patients with hormone-receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced breast cancer, according to findings from a pre-planned subgroup analysis of data from the MONALEESA-2 trial.

These data point to a shift in paradigm for the future management of these patients, from the current standard of care, letrozole (Femara), to a combination regimen of letrozole plus ribociclib. These results were presented at the 19th European Cancer Congress (ECCO 2017).

"At some point, all breast cancers become resistant to endocrine therapy. The addition of targeted agents may extend the treatment benefit derived from endocrine therapy and delay disease progression,” according to Gabe S. Sonke MD, PhD, of the Netherlands Cancer Institute and BOOG Study Center in the Netherlands.

MONALEESA-2 is a randomized international, double blind phase III trial of ribociclib plus the aromatase inhibitor letrozole. The study demonstrated improved progression-free survival (PFS) over letrozole alone in treatment-naïve post-menopausal women with advanced HR+ metastatic breast cancer.

In the overall population of patients, a 44% improvement in PFS was demonstrated with ribociclib plus letrozole as a frontline therapy over placebo/letrozole. The median PFS was not reached in the study arm at data cutoff, compared to 14.7 months in the placebo arm. In patients with measurable disease who received ribociclib, the overall response rate (ORR) was 52.7%, compared to 37.1% in those receiving letrozole alone.

In the subgroup of 295 MONALEESA-2 patients aged 65 or more years having a median age of 71 years (range, 65-91), 150 patients received 2.5 mg daily of ribociclib plus 2.5 mg daily of letrozole and 145 patients received placebo plus 2.5 mg daily of letrozole (n&thinsp;=&thinsp;145). PFS by RESIST was the primary endpoint.

The subgroup analysis showed that the elderly cohort demonstrated similar responses and tolerability to the overall population.

At data cutoff on January 29, 2016, treatment was ongoing in 90 (60%) patients receiving ribociclib/letrozole and in 77 (53%) patients on placebo/letrozole. Median PFS was not reached (95%CI, 19.3 months — NR) with ribociclib/letrozole versus 18.4 months (95%CI, 15.0 months – NR) with placebo/letrozole, HR = 0.608 (95%CI, 0.394 – 0.937). The ORR in the elderly receiving ribociclib/letrozole versus placebo/letrozole was 37% versus 31%, respectively.

The median duration of study treatment exposure in elderly patients was 13.1 with ribociclib/letrozole and 12.5 months with placebo/letrozole. In the elderly cohort, 40% versus 47% of patients receiving ribociclib/letrozole versus placebo/letrozole, respectively, discontinued treatment. The most common reasons for discontinuation were disease progression in 33 (22%) versus 51 (35%) patients and adverse events (AEs) in 13 (9%) versus 5 (3%) patients in the ribociclib/letrozole versus placebo/letrozole arms, respectively. One death occurred in the ribociclib combination arm.

“The elderly patients had a slower rate of disease progression in both treatment arms, representing more stabilization of disease,” said Sonke. He also noted in his presentation that over 40% of patients diagnosed with breast cancer are aged 65 years or older, and physiologic functioning, comorbidities, or concomitant medications may impact their tolerability of combination regimens.

The rates of AEs in elderly patients were similar to those experienced by the younger patients; AEs that occurred more than 10% more frequently with ribociclib/letrozole than with sole letrozole included neutropenia (74% percent versus 5%), leukopenia (31% versus 4%), fatigue ( 37% versus 24%), alopecia (33% versus 17%), diarrhea (41% versus 26%), and vomiting (35% versus 19%).

“The rates of dose reduction or interruption due to an AE were similar in both treatment arms in elderly and younger patients, despite a higher proportion of elderly patients with ECOG performance status 1,” Sonke pointed out.

Most AEs could be managed through dose interruption; dose interruptions due to an AE occurred in 13% versus 13% in the ribociclib/letrozole versus placebo/letrozole arms, respectively, and no dose reductions due to an AE were made in either arm.

The Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for ribociclib in August 2016 and has also accepted a New Drug Application (NDA) and granted priority review for ribociclib as firstline treatment of postmenopausal women with HR+/HER2- advanced or metastatic breast cancer in combination with letrozole. The NDA was based in part on results of the MONALEESA-2 trial, which was presented at the European Society for Medical Oncology (ESMO) 2016 Congress and published simultaneously in the New England Journal of Medicine.

Sonke, G.S.,Hart, L.L., Campone M, et al. Efficacy and safety of ribociclib (LEE011) + letrozole in elderly patients with hormone receptor-positive (HR+), HER2-negative (HER2˗) advanced breast cancer (ABC) in MONALEESA-2. Abstract presented at: 2017 European Cancer Congress; January 27-30, 2017; Amsterdam. Abstract 2LBA.

The clinical benefits and safety profiles for ribociclib remained consistent when treating both younger and elderly patients with hormone-receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced breast cancer.

Ribociclib Emerges as Option for Elderly Patients with HR+/HER2- Breast Cancer

Findings from the phase III RESORCE trial of regorafenib (Stivarga) as second-line treatment in patients with previously treated hepatocellular carcinoma (HCC) show that the oral multikinase inhibitor has the potential to become the standard of care among those who are unsuitable for loco-regional therapy and have progressed on sorafenib.

Regorafenib improved overall survival (OS), the trial’s primary endpoint, by nearly 3 months over placebo and demonstrated improved progression-free survival (PFS) and time to progression (TTP), according to Jordi Bruix, MD, of the Liver Unit Hospital Clinic, University of Barcelona, Spain, presenting them at the recent ESMO 2016 Cancer Conference in Copenhagen.

Median OS was 10.6 months with regorafenib versus 7.8 months with placebo. Regorafenib patients had a 37% reduction in the risk of death and a 54% reduction in the risk of progression compared with placebo.

Significantly prolonged median PFS of 3.1 months was observed in patients treated with regorafenib compared with 1.5 months in patients receiving placebo, (HR, 0.46; 

 <.001). Similarly, median TTP was 3.2 and 1.5 months, respectively, (HR, 0.44; 

"We had a higher response rate and we doubled the disease control rate in late stage hepatocellular carcinoma, a difficult cancer to treat," Bruix explained. “Regorafenib has the potential to become the new standard or care for patients with hepatocellular carcinoma who progress on sorafenib.”

Patients receiving regorafenib demonstrated a higher disease control rate of 65.2% compared with 36.1% with placebo (

 <.001), and 10.6% of patients receiving regorafenib showed either complete or partial response versus 4.1% of placebo patients (

Bruix and colleagues enrolled 573 patients from centers in 21 countries who were stratified by geographic location of Asia or non-Asia, the presence/absence of microvascular invasion or extrahepatic disease, Eastern Cooperative Oncology Group performance of 0 versus 1, and alpha-fetoprotein less than 400 ng/mL versus 400 ng/mL or greater. All patients had Barcelona Clinic Liver Cancer (BCLC) stage B or C designated HCC plus documented radiologic progression after a minimum of 20 days of sorafenib at 400 mg or more per day.

Baseline characteristics were balanced between the regorafenib and placebo arms. The patients’ median age was 63 years, 88% were male, and 87% of patients had BCLC stage C disease.

The patients were randomized 2:1 to oral regorafenib at 160 mg or placebo once daily for 1 to 3 weeks of a 4-week cycle. The median treatment duration was 3.6 (range: 0.03 to 29) months for regorafenib versus 1.9 (range: 0.2 to 27) months for placebo.

Treatment-emergent adverse events (TEAEs) leading to treatment interruption occurred in 58% of patients in the regorafenib arm versus 29% of patients on placebo. Drug-related TEAEs leading to treatment interruption occurred in 42% versus 8% of patients in the respective arms.

The most commonly reported grade adverse events ≥3 were hypertension (15.2% vs 4.7%), hand/foot skin reactions (12.8% vs 0.5%), fatigue (9.1% vs 4.7%), and diarrhea (3.2% vs 0.0%) with regorafenib versus placebo, respectively.

Bruix also reported on quality-of-life data that was collected using the EQ-50 index, EQ-50 VAS, Fact-G, FACT-Hep total, and Trial Outcome scales. Significant differences among patients receiving regorafenib and placebo were seen only on the last 2 scales; the difference between the groups was -8.85 on the FACT-Hep total, and -4.05 on the Trial Outcome Index (both 

Session co-chair Florian Lordick, MD, PhD, of the University Cancer Center in Leipzig, Germany, discussed whether regorafenib would become the new standard of care and summarized: “Maybe, yes, because regorafenib significantly improved overall survival over placebo, but there are no clinically meaningful differences in patient-reported outcomes, and there was a high rate of treatment interruption due to adverse events, suggesting that regorafenib was not well-tolerated.”

Bruix responded to this comment by pointing out that regorafenib actually was well tolerated in this cohort: “Nearly 50% of patients received the full dose and the tolerance was similar to the tolerance reported in patients with GIST [gastrointestinal stromal tumor].”

Regorafenib received FDA approval in 2013 for treatment of patients with advanced GIST who are not candidates for surgery and do not respond to imatinib and sunitinib.

 Bruix, J. Efficacy, safety, and health-related quality of life (HRQoL) of regorafenib in patients with hepatocellular carcinoma (HCC) progressing on sorafenib: Results of the international, double-blind phase 3 RESORCE trial. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. LBA28.

Regorafenib was found to improve overall survival by nearly 3 months for patients with previously treated hepatocellular carcinoma.

Regorafenib Benefits Patients With Liver Cancer Who Progress on Sorafenib

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), according to new research reported at the recent 2015 World Congress on GI Cancer.

“Contrary to our hypothesis, patients who had the lowest BMI were at risk for having the shortest survival,” said lead author Yousuf Zafar, MD, 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 IV 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 6128 patients in the United States 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

 (interquartile range [IQR], 22.6-28.7). BMI was divided into five categories: <20 (n = 532); 20 to 24 (n = 2328); 25 to 29 (n = 2119); 30 to 35 (n = 821); and ≥35 kg/m

 (328). The majority of patients (n = 5554) 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%) had undergone surgical resection.

Although PFS was similar across baseline BMI categories, investigators found a difference in OS. Patients with BMIs <25, 25 to 29, 30 to 35, and ≥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 (hazard ratio [HR] = 0.911; 95% CI, 0.879-0.944).

For those with a BMI <20 versus <25, the HR was 1.18. For <20 in comparison with >25, the HR was 1.32. In those with a BMI of >25 kg/m

, the HR compared with <20 was 1.12. Using BMI as a categorical variable and adjusting for hypertension at baseline showed a similar pattern across the respective categories.

“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 (<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 is associated with a higher risk for colorectal cancer, patients who are thinner may not do as well after treatment for metastatic colorectal cancer.

Virginia Powers, PhD

Articles

Hand-Foot Skin Reaction May Signal Regorafenib Efficacy in Hepatocellular Carcinoma

Non-Chemo Regimen Impresses in Lymphoma

Ribociclib Emerges as Option for Elderly Patients with HR+/HER2- Breast Cancer

Regorafenib Benefits Patients With Liver Cancer Who Progress on Sorafenib

Study Finds Shorter Survival for Thin Patients With Colorectal Cancer