The FDA approved ivosedinib (Tibsovo) for the treatment of previously treated, locally advanced or metastatic cholangiocarcinoma with an 

 mutation, as detected by an FDA-approved test, in adult patients.

The regulatory decision is based on findings from the phase 3 ClarlDHy study, which showed a statistically meaningful improvement in progression-free survival (HR, 0.37; 95% CI, 0.25-0.54; 

 < .001), which was determined by an independent review committee. Six- and 12-month PFS was 32% and 22%, respectively, in the ivosedinib arm. In comparison, no patients on the placebo arm were free of progression at either of these time markers.

-mutated cholangiocarcinoma, especially those whose disease progresses following chemotherapy, are in urgent need of new treatment options," said Rachna T. Shroff, MD, associate professor of medicine, University of Arizona, and chief of GI medical oncology at the University of Arizona Cancer Center, in a press release. "In addition to an acceptable safety profile, Tibsovo demonstrated an impressive, significant benefit in progression-free survival, underscoring its importance as a new option for patients battling this aggressive cancer."

Notably, the study design allowed patients in the placebo cohort to switch to the experimental group if their disease progressed. The majority of patients (70.5%) in the placebo cohort ultimately switched to ivosedinib treatment. Overall survival (OS) was based on a final analysis 16 months after the first assessment of PFS. At 16 months, the median OS was 10.3 months in the experimental arm (95% CI, 7.8-12.4) and 7.5 months in the control arm (95% CI, 4.8-11.1).

Adverse events (AEs) were consistent with previously reported data. The most common AEs included fatigue, nausea, abdominal pain, diarrhea, cough, decreased appetite, ascites, vomiting, anemia, and rash. Over 15

The recommended dosage for ivosedinib is 500 mg orally once daily with or without food. Treatment should be stopped if disease progresses or if unacceptable toxicity occurs.

"Before today's approval of Tibsovo, there were no approved targeted therapies available to cholangiocarcinoma patients harboring the 

 mutation, and limited chemotherapy options available to patients with advanced disease," said Stacie Lindsey, Founder and CEO, Cholangiocarcinoma Foundation, in a press release. "This approval brings new hope to the cholangiocarcinoma community and we are excited that this much-needed new therapeutic option is being made available to patients."

Servier announces FDA approval of TIBSOVO® (ivosidenib tablets) in IDH1-Mutated cholangiocarcinoma. Cision. News release. Accessed August 25, 2021. https://www.prnewswire.com/news-releases/servier-announces-fda-approval-of-tibsovo-ivosidenib-tablets-in-idh1-mutated-cholangiocarcinoma-301363055.html

Articles

The FDA approved ivosedinib as the first targeted therapy to treat patients with previously treated IDH1-mutated cholangiocarcinoma. 

FDA Approves Ivosedinib to Treat Patients with IDH1-Mutated Liver Cancer

A novel triplet combination of chemotherapy as a first-line treatment has demonstrated better responses from patients with 

 V600-mutant metastatic colorectal cancer (CRC). Although doublet and triplet chemotherapy-based therapies are standard treatment options for patients with 

 V600­–mutant metastatic CRC, this population has traditionally demonstrated poor outcomes with chemotherapy-based regimens. Even so, BRAF inhibitors are not effective enough to overcome the feedback activation of EGFR.

Investigators of the ANCHOR-CRC trial (NCT03693170) hypothesized that targeting multiple nodes in the MAPK pathway may elicit better responses for patients and fill an urgent unmet need for patients whose disease harbors 

Specifically, the study was designed to examine the efficacy of the triplet combination of encorafenib (Braftovi), binimetinib (Mektovi), and cetuximab (Erbitux) in the first-line setting.

Updated data analysis presented at the 2021 European Society of Medical Oncology Virtual World Congress on Gastrointestinal Cancer demonstrated that the trial met its primary end point of observed confirmed objective response rate (cORR). In total 92 patients were evaluable and the investigator-assessed cORR was 47.8% (95% CI, 37.3%-58.5%); all responses were partial responses for a disease control rate of 88%. Progressive disease was reported in 5.4% of patients.

The analysis combined 41 patients enrolled to stage 1 of the study with an additional 54 patients enrolled to stage 2. At the time of presentation 6 patients (15%) from stage 1 and 14 patients (26%) from stage 2 remained on treatment. For the 75 patients who discontinued therapy, the cited reasons included progressive disease (64%), adverse effects (AEs; 21%), investigator decision (8%), and other (7%).

Patients with treatment-naïve mCRC and a confirmed 

 V600E mutation were treated with oral encorafenib (300 mg daily), oral binimetinib (45 mg orally twice daily), and intravenous cetuximab (400 mg/m2 loading dose, followed by 250 mg/m2 weekly for the first 28 weeks, followed by 500 mg/m2 once every 2 weeks).

At baseline evaluation, the median age was 65 years (range, 30-84) with median time since initial diagnosis of 66 days. Most patients (60%) had right-side or transverse primary tumors and the remaining (40%) had either left-side tumors or tumors located in the rectum. In terms of metastases, most patients (75.8%) had greater than 2 organs involved including the liver (54.7%), lymph node (51.6%), peritoneum/omentum (48.4%), and lung (36.8%).

Secondary end points of the study were progression-free survival (PFS), overall survival (OS), safety, quality of life, and pharmacokinetics.

At median follow-up of 4.8 months the median PFS was 5.8 months (95% CI, 2.6-6.4) for patients treated with the triplet. At a median follow-up of 14.4 months, the median OS was 17.2 months (95% CI, 14.1-21.1). For 95 patients included in the OS analysis the OS rates at 12, 18, and 24 months were 65%, 49%, and 29%, respectively.

Investigators noted that most patients were able to receive active subsequent therapies. The median time to subsequent therapy was 6.9 months (range, 5.9-8.4). Specifically, 43.2% of patients went on to receive antineoplastic therapy of either oxaliplatin-based doublet with or without bevacizumab (Avastin), FOLFOXIRI with or without bevacizumab, or immunotherapy.

In terms of safety, the results reported for the triplet combination were similar with those reported for recommended chemotherapy-based regimens. The most common all-grade AEs were diarrhea (67.4%), nausea (45.3%). dermatitis acneiform (40%), rash (40%), and vomiting (37.9%). The most common grade 3 or higher AEs were anemia (10.5%), increased lipase levels (10.5%), diarrhea (9.5%), and nausea (8.4%).

Further, the most frequent serious AEs of grade 3 or higher were intestinal obstruction (14.7%), renal failure (7.4%), nausea (5.3%), and abdominal pain (4.2%). Investigators also noted that no meaningful changes in patient reported outcomes.

Eric Van Cutsem, MD, who reported the data at the conference noted that these results were “encouraging” and “support exploring the combination of encorafetinib plus cetuximab with chemotherapy in the first line setting.” Van Cutsem is the division head of clinical digestive oncology at University of Leuven and University Hospitals Gasthuisberg, Leuven, Belgium.

Investigators of the ongoing BREAKWATER study (NCT04607421) will evaluate the efficacy of encorafetinib plus cetuximab with or without FOLFOX or FOLFIRI vs the control of physician’s choice of either FOLFOX, FOLFIRI, FOLFOXFIRI, or CAPEOX with or without anti-VEGF therapy. Patients who received prior systemic therapy in the metastatic setting are not eligible for enrollment. The primary end points of the study are PFS for arm A vs control and arm B vs control by blinded independent central review. Key secondary end points are OS for arm A vs control and arm B vs control. Other end points include incidence of dose-limited toxicities, AEs, dose modifications and drug-drug interactions.

In April 2020, the combination of encorfenib and cetuximab was approved for the treatment of patients with metastatic CRC with a confirmed 

 V600E mutation who experienced disease progression after 1 or 2 prior lines of therapy based on results of the BEACON CRC trial (NCT02928224).4 Investigators of the trial examined outcomes of the doublet regimen as well as the triplet regimen of encorafenib, binimetinib, and cetuximab against the control of investigators’ choice of either cetuximab and irinotecan or cetuximab and FOLFIRI.

Although the triplet combination group outperformed the doublet therapy group against the control arm, respectively, the trial was not powered to compare the 2 experimental arms.

Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, binimetinib, and cetuximab in 

. 2019;381(17):1632-1643. doi:10.1056/NEJMoa1908075

Van Cutsem E, Tabernero J, Taieb J, et al. ANCHOR CRC: results from a single-arm, phase 2 study of encorafenib, binimetinib plus cetuximab in previously untreated BRAF V600E–mutant metastatic colorectal cancer. 

. 2021;32(suppl 3):S222. doi:10.1016/j.annonc.2021.05.014

BRAF V600E-mutant colorectal cancer study of encorafenib taken with cetuximab plus or minus chemotherapy (BREAKWATER). ClinicalTrials.gov. Updated July 12, 2021. Accessed July 28, 2021. 

https://clinicaltrials.gov/ct2/show/NCT04607421

Braftovi. Prescribing information. Array BioPharma Inc; 2020. Accessed July 28, 2021. 

https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/210496s006lbl.pdf

This article was originally published on OncLive as 

“Triplet Combination Demonstrates Promise for Frontline Treatment of BRAF V600E–mutant CRC”

A combination of encorafenib (Braftovi), binimetinib (Mektovi), and cetuximab (Erbitux) in the first-line setting was tested for efficacy in patients with BRAF V600E–mutant CRC.

Triplet Chemotherapy Combination a Viable Option for Colorectal Cancer Mutation

Journal of the National Comprehensive Cancer Network

 demonstrated that brain imaging should become routine for patients with advanced or metastatic renal cell carcinoma (mRCC) with high metastatic burden and who have progressed following first-line therapy treatment.

Results from a large multi-institutional cohort study found that 4.3% (95% CI, 3.3%-5.3%; n = 72) of 1689 patients with mRCC had incidental brain metastases without documented neurological symptoms. The median overall survival (OS) in these patients was 10.3 months (range, 7.0-17.9) and the 1-year OS rate was 48% (95% CI, 37%-62%).

When stratified by International Metastatic RCC Database Consortium (IMDC) risk status, survival outcomes were not found to significantly differ between those with favorable-, intermediate-, or poor-risk patients vs the use of log-rank testing (

= .3). The median OS in the favorable-risk, intermediate-risk, and poor-risk subgroups was 12.7 months (range, 4.8–not evaluable [NE]), 12.4 months (range, 7.4-19.7), and 4.5 months (range, 3.8–NE), respectively. The 1-year OS probability of favorable-, intermediate-, and poor-risk disease was 53% (95% CI, 33%-86%), 52% (95% CI, 38%-71%), and 29% (95% CI, 9%-92%), respectively.

“With 4% overall incidence in this cohort, one might conclude that baseline brain imaging should be considered in all patients with metastatic kidney cancer, particularly those with multiorgan involvement and/or pulmonary metastases” lead study author Ritesh R. Kotecha, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, stated in a press release.

Although brain metastases occur in approximately 5% to 20% of patients with mRCC, no standard guidelines exist for brain imaging in the absence of symptoms. As such, asymptomatic patients may not be included in historical rates, making this population difficult to define. Earlier detection of brain metastases through standardized screening guidelines could help to solidify the rates among patients with mRCC, as well as improve survival outcomes.

To characterize those with mRCC who were diagnosed with asymptomatic brain metastases, investigators performed a retrospective review of data from patients who were screened prior to entering clinical trials. Data from 68 clinical trials performed at Memorial Sloan Kettering Cancer Center and Gustave Roussy between 2001 and 2019 were reviewed and utilized to evaluate baseline characteristics, as well as reported symptoms. Any clinical trials that did not require brain imaging for participation were not reviewed.

“Brain imaging is routinely obtained for [patients with] kidney cancer with symptoms that suggest central nervous system [CNS] metastases, but none of the patients with brain metastases included here were symptomatic,” senior researcher Martin H. Voss, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, stated in the release. “In current practice, the chest, abdomen, and pelvis are routinely imaged from the time that metastatic disease is first detected, yet many oncologists do not image the brain.”

Of the 72 patients found to have incidental brain metastases without neurologic symptoms, the median age at the time of cancer diagnosis was 56 years (range, 37-77) and 75% of patients were male. Additionally, 88% (n = 63) of patients had undergone prior nephrectomy, and 68% had received at least 1 prior line of treatment. All patients had a clear cell histologic subtype, and 60% (n = 43) presented with stage IV disease at initial diagnosis. In terms of brain metastases characteristics, 63% (n = 45) of patients had a solitary lesion, and CNS involvement was multifocal in 38.5% of patients.

Among the 72 patients reviewed, 61 had additional follow-up data that indicated they received brain metastases site-directed therapy. Of those patients, 83% (n = 52) received a corticosteroid, and 93% (n = 57) underwent site-specific therapy, such as stereotactic radiotherapy (72%), whole-brain radiotherapy (14%), surgical resection (11%), or both radiotherapy and resection (4%). Moreover, the median time between brain imaging and site-directed therapy was 30 days (range, 4-262).

Additional data indicated that OS was not found to differ significantly in patients with solitary disease vs those with multifocal disease. The median OS for patients with solitary disease was 14.2 months (range, 9.5-21.6) vs 5.8 months (range, 4.1-18 months) for those with multifocal disease; the 1-year OS probability rates were 57% (95% CI, 44%-74%) and 33% (95% CI, 19%-58%), respectively. Difference across other subgroups, including lesion size, also did not show statistical differences.

“The findings in this study are important for 2 reasons. First, they show that the overall prognosis of patients with brain metastases is consistently worse than the broader population of patients with metastatic renal cell carcinoma. We need to develop a deeper scientific understanding of why this patient population has a worse outcome, and we need to include them in future clinical trials,” Eric Jonasch, MD, a professor of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center, stated in the release. “Second, they underscore the utility for MRI imaging of all patients with metastatic renal cell carcinoma both at initial diagnosis, and at regular intervals, to detect occult brain metastases, since specific treatment strategies are required for this patient population.”

Kotecha RR, Flippot R, Nortman T, et al. Prognosis of incidental brain metastases in patients with advanced renal cell carcinoma. 

2021;19(4):432-438. doi:10.6004/jnccn.2020.7634

JNCCN study: important potential role for routine brain imaging in advanced kidney cancer. News release. The National Comprehensive Cancer Network. April 13, 2021. Accessed April 22, 2021. 

This article was originally published on OncLive as “

Brain Metastases Occur in Significant Percentage of Advanced RCC, Underscoring Potential Role for Routine Brain Imaging”

New data emphasizes need for routine brain imaging in patients with advanced or metastatic renal cell carcinoma with prior treatment and high metastatic burden. 

Brain Imaging Guidelines Needed for Patients with Metastatic Kidney Cancer

A post-hoc analysis of the phase 3 REFLECT trial (NCT01781266) indicated that patients with unresectable hepatocellular carcinoma (uHCC) with Child-Pugh class B (CP-B) liver function fared similarly to their Child-Pugh class A (CP-A) counterparts who received lenvatinib (Lenvima). The tumor size reduction was similar between the 2 groups, according to an analysis presentated at the 2021 European Society for Medical Oncology World Congress on Gastrointestinal Cancer.

“The results of this post hoc analysis suggest that patients with uHCC whose liver function deteriorates to CP-B after initiation of therapy may continue to receive lenvatinib,” the researchers wrote.

Results from the randomized, multicenter phase 3 REFLECT study– which led to the FDA’s approval of the agent for the first-line treatment of patients with uHCC – showed a benefit from lenvatinib, compared with sorafenib (Nexavar), irrespective of baseline liver function, including albumin-bilirubin (ALBI) grade 1 or 2 and CP score of 5 or 6.

However, of note, the trial enrolled patients with CP-A liver function per the study inclusion criteria, but not CP-B specifically.

“In the absence of any initial enrollment of patients with CP-B liver function, we conducted a post hoc exploratory analysis of key efficacy and safety outcomes in patients from REFLECT whose liver function had deteriorated to CP-B versus those whose liver function remained CP-A within 8 weeks post-randomization.”

The post hoc analysis assessed overall response rate (ORR), and landmark analyses that began after week 8, including progression-free (PFS) and overall survival (OS), both in patients whose liver function had deteriorated to CP-B and in patients whose liver function remained CP-A within 8 weeks post-randomization. In addition, safety was evaluated from baseline and adjusted by treatment duration.

Among patients treated with lenvatinib in the CP-B (n = 60) and CP-A (n = 413) subgroups, the median percent changes in tumor size from baseline to week 8 were –16.2% (range, –100 to 25) and –15.9% (range, –100 to 187), respectively, compared with 1.7% (range, –36 to 64) and 0% (range, –100 to 106) in patients treated with sorafenib in the CP-B (n = 47) and CP-A (n = 427) subgroups.

In the lenvatinib group, the CP-B and CP-A subgroups demonstrated ORRs of 28.3% (95% CI, 16.9-39.7) and 42.9% (95% CI, 38.1-47.6), respectively. In particular, for the CP-B subgroup of the lenvatinib arm, there were 0 complete responses (CRs), 17 (28.3%) partial responses (PRs), 17 (28.3%) patients with stable disease (SD), 12 (20.0%) with progressive disease (PD), and 14 (23.3%) were not evaluable (NE), compared with 10 (2.4%) CRs, 167 (40.4%) PRs, 142 (34.4%) with SD, 67 (16.2%) with SD, and 27 (6.5%) NE for the CP-A subgroup.

In the sorafenib group, the CP-B and CP-A subgroups demonstrated ORRs of 8.5% (95% CI, 0.5-16.5) and 12.9% (95% CI, 9.7-16.1), respectively. In particular, for the CP-B subgroup of the sorafenib arm, there were 0 CRs, 4 (8.5%) PRs, 12 (25.5%) with SD, 23 (48.9%) with PD, and 8 (17.0%) NE, compared with 4 (0.9%) CRs, 51 (11.9%) PRs, 207 (48.5%) with SD, 129 (30.2%) with PD, and 36 (8.4%) NE.

After week 8, median OS was 6.8 months (95% CI, 2.6-10.3) and median PFS was 3.7 months (95% CI, 1.8-7.4) in lenvatinib-treated patients within the CP-B subgroup, compared with 13.3 months (95% CI, 11.6–16.1) and 6.5 months (95% CI, 5.6–7.4), respectively, in the CP-A subgroup. In the sorafenib-treated CP-B subgroup, median OS and PFS were 4.5 months (95% CI, 2.9–6.1) and 0.5 months (95% CI, 0.1–3.6), respectively, compared with 12.0 months (95% CI, 10.2–14.0) and 3.6 months (95% CI, 0.1–3.6) in the CP-A subgroup.

In the CP-B and CP-A subgroups treated with lenvatinib, the median duration of treatment was 3.2 months (range, 0.3-31.5) and 6.9 months (range, 0.0-35.0), respectively, compared with 1.9 months (range, 1.9 months (range, 0.2-22.4) and 3.7 months (range, 0.1—38.7) in the sorafenib-treated CP-B and CP-A subgroups.

The mean dose intensity of lenvatinib was 8.4 mg/day/patient (standard deviation [SD], 3.07) and 9.5 mg/day/patient (SD, 6.01) in the CP-B and CP-A subgroups, respectively, whereas the mean dose intensity of sorafenib was 653.2 mg/day/patient (SD, 165.75) and 664.8 mg/day/patient (SD, 174.23) in the CP-B and CP-A subgroups, respectively.

Among the CP-B and CP-A patients, rates for grade 3 or higher treatment-related adverse events (TRAEs) in the lenvatinib arm were 3.65% (n = 95) and 1.41% (n = 419), respectively, and 3.38% (n = 42) and 1.71% (n = 388), respectively, in the sorafenib arm.

In their conclusion, the researchers noted, “As this post hoc analysis is limited by its descriptive nature, the efficacy results cannot be compared between CP–B and CP–A subgroups,” adding that further investigation is warranted.

“Although the treatment landscape for patients with unresectable hepatocellular carcinoma (uHCC) has recently expanded, there remains an unmet need for effective treatment options in patients with Child–Pugh class B (CP-B) liver function. Such patients are rarely included in clinical trials,” the researchers wrote in their poster.

In the trial, patients with uHCC were randomly assigned 1:1 to receive lenvatinib – for which dosage was based bodyweight: 12 mg/day for those weighing ≥ 60 kg; 8 mg/day for those weighing < 60 kg) – or sorafenib 400 mg twice daily in 28-day cycles.

At baseline, patients whose liver function deteriorated to CP-B within 8 weeks in the lenvatinib and sorafenib arms, 73.3% and 61.7%, respectively, had an ALBI score of 2, and 60.0% and 44.7% had a CP score of 6. Similarly, among those whose liver function remained CP-A within 8 weeks in both arms, 73.1% and 75.4%, respectively, had an ALBI score of 1, and 83.5% and 78.5% had a CP score of 5.

In the prior analysis, treatment with lenvatinib demonstrated higher ORR, compared with sorafenib, in patients with a CP score of 5 (OR, 4.88; 95% CI, 3.37-7.08) and in those with a CP score of 6 (OR, 5.25; 95% CI, 2.32-11.85), as well as in patients classified as either ALBI grade 1 (OR, 5.48; 95% CI, 3.70-8.10) or ALBI grade 2 (OR, 5.37; 95% CI, 2.61-11.06).

Huynh J, Thet Cho M, Jae-Hoon Kim E, Ren M, Amaya-Chanaga C, Vogel A. Post hoc analysis in patients with unresectable hepatocellular carcinoma who progressed to Child–Pugh B liver function in the phase 3 REFLECT study of lenvatinib vs sorafenib. 

. 2021;32(suppl 3) doi:10.1016/j.annonc.2021.05.133

“Lenvatinib Treatment Can Continue in Unresectable HCC With Child–Pugh Class-B Liver Function”

Researchers observed a similar tumor size reduction between 2 arms of patients with hepatocellular carcinoma who were stratified by their liver function class and treated with lenvatinib.  

Patients with Unresectable Hepatocellular Carcinoma with Moderately Impaired Liver Function May Continue Lenvatinib Therapy  

The data to determine the optimal sequence of therapies in the second- or later-lines of treatment for patients with hepatocellular carcinoma are lacking.

There are, however, 2 ongoing trials which were presented at the 2021 European Society for Medical Oncology World Congress on Gastrointestinal Cancer that may provide those much-needed answers.

While the first-line standard of atezolizumab (Tecentriq) and bevacizumab (Avastin) has been available since 2020 after demonstrating a 6.9-month progression-free survival (PFS), 19.2-month overall survival (OS), and 30% overall response rate (ORR). However, it is unclear how this combination can be used as subsequent therapy.

Additionally, there is a need for predictive markers to help guide the selection and sequencing of therapy, and for innovative options to overcome primary and secondary resistance to treatment.

“Tislelizumab is an active and safe investigational PD-1 antibody, in second and third line, comparable to other PD-1 agents,” Chris Verslype, MD, PhD, a digestive oncologist at the University Hospitals Leuven, Belgium, said in his presentation. The global, single-arm, phase 2 RATIONALE 208 study (NCT03419897) of the investigational agent tislelizumab at 200 mg intravenously every 3 weeks was evaluated in 249 patients with previously treated advanced HCC.

This trial had a 13.3% ORR, a PFS of 2.7, and an OS of 13.2 months. Patients number of prior lines of therapy did not affect the results. The treatment-related adverse events of grade 3 or more occurred in 14.5% of patients, and 4.8% discontinued treatment.

In this group of patients, 80% had metastatic disease, 36% had non-viral etiology, and 90% had Barcelona-Clinic Liver Cancer (BCLC) stage C. They could not have prior PD-1 or PD-L1 inhibitors.

Verslype compared these data with the phase 3 KEYNOTE-240 trial (NCT02702401) of pembrolizumab (Keytruda) versus placebo in 413 patients with pretreated advanced HCC, randomized 2:1. Seventy percent had metastatic disease, 80% had BCLC stage C, 58.6% had non-viral etiology, and 87% had progressive disease after receiving sorafenib. The results of this trial showed an 18.3% ORR, 3-month PFS, and 13.9-month OS. Grade 3 or more events of interest occurred in 7.2%.

The results from RATIONALE-208 and KEYNOTE-240 are comparable. Currently, there is a phase 3 trial of tislelizumab versus sorafenib in the first line setting for patients with unresectable HCC, though they are unlikely to yield clinically relevant results, according to Verslype’s discussion.

Subsequently, Verslype went over the phase 2 HEPANOVA trial (NCT03606590) of TTFields at 150 kHz for 18 or more hours a day plus daily sorafenib at 400 mg twice daily. The 27 patients on this trial were diagnosed with advanced HCC by biopsy or imaging plus alpha-fetoprotein, had BCLC stage 0-C, 5 to 8 Child-Pugh score, and could not receive surgery or local therapy.

In this trial, the ORR was 9.5%, the PFS was 5.8 months, and the OS rate at 1 year was 30%. There were 67% of patients with grade 1 or 2 TTFields-related skin toxicity, and 1 patient had grade 3 toxicity.

“For TTFields, there are no new safety concerns. [These are the] first good data in HCC, but more data are needed to appreciate the efficacy of TTFields in advanced HCC,” Verslype said.

Treatment for this trial started 7 days or less after enrollment, and TTFields start more or less than 7 days from starting sorafenib. Follow-ups occurred every 4 weeks and CT/MRI scans were scheduled for every 12 weeks. TTFields and follow-ups continued until progressive disease per RECIST. Follow-up visits after patients experienced progressive disease were 30 days after discontinuation. Survival follow-ups were every 8 weeks until death. Verslype also noted that there were 78% of patients with BCLC stage C, 51% with Child-Pugh B, and 22% with an ECOG performance status of 2 recently.

“Updated results from the IMbrave150 [NCT03434379] study evaluating atezolizumab/bevacizumab versus sorafenib [showed] that you can have with sorafenib…11% ORR and even a very high overall survival at 1 year,” Verslype explained during his presentation. “So in my opinion, recent studies with sorafenib as the control have shown better results than historical controls used in [HEPANOVA]. Is this really showing more efficacy than sorafenib? I doubt it.”

Verslype C. Discussant: LBA-2, O-1. Presented at: 2021 European Society for Medical Oncology World Congress on Gastrointestinal Cancer; June 30-July 3, 2021; virtual.

“Tislelizumab, TTF Studies Poised to Address HCC Questions”

The aim of the two ongoing studies is to determine the optimal sequence of therapies in the second-or later-line treatment settings for patients with hepatocellular carcinoma. 

2 Novel Studies Set to Address Unanswered Questions in Liver Cancer

The phase 3 COSMIC-312 trial (NCT03755791) treated patients with advanced hepatocellular carcinoma (HCC) through a combination of cabozantinib (Cabometyx) and atezolizumab (Tecentriq) which resulted in superior progression-free survival (PFS) compared to sorafenib (Nexavar), meeting a primary end point of the trial.1

The combination of cabozantinib (Cabometyx) and atezolizumab (Tecentriq) was found to significantly improve progression-free survival (PFS) compared with sorafenib (Nexavar) when used in the first-line treatment of patients with advanced hepatocellular carcinoma (HCC), meeting a primary end point of the phase 3 COSMIC-312 trial (NCT03755791)

In the planned primary analysis for PFS in the intent-to-treat patient population, cabozantinib plus atezolizumab resulted in a significant 37% reduction in the risk of disease progression or death vs sorafenib (HR, 0.63; 95% CI, 0.44-0.91; 

Additional data from a prespecified interim analysis for the second primary end point of overall survival (OS), which was done at the same time as the primary analysis for PFS, demonstrated a trend toward the doublet over sorafenib but was not found to reach statistical significance.

Based on the preliminary findings for OS, Exelixis Inc., shared that the probability of reaching statistical significance at the time of the final analysis is low. However, the trial will continue as planned to the final analysis of OS, and data are anticipated in early 2022.

The safety of the doublet appears to be consistent with the known profiles of both agents. No new safety signals were observed with the combination in this trial.

“While we are encouraged by the data supporting the potential for the combination of cabozantinib and atezolizumab to reduce the risk of disease progression or death, we are disappointed by the interim result of lack of significant improvement on OS vs the comparator arm,” Michael M. Morrissey, PhD, president and chief executive officer of Exelixis, Inc. stated in a press release. “As these data continue to mature, we are working to understand the potential impact of various contributing factors on the results, including patient demographics, subsequent anticancer therapy and the impact of COVID-19 on the trial. We anticipate presenting the results at a future medical conference.”

In the global, multicenter, randomized, phase 3 trial, investigators set out to examine the safety and efficacy of cabozantinib plus atezolizumab vs standard-of-care sorafenib in adult patients with advanced HCC who have not previously received systemic anticancer therapy.

The trial is aimed to enroll approximately 840 patients. To be eligible for enrollment, patients needed to have histological or cytological diagnosis of HCC, disease that is not amenable to a curative approach, measurable disease per RECIST v1.1 criteria, Barcelona Clinic Liver Cancer stage category B or C disease, and an ECOG performance status of 0 to 1.

If patients had fibrolamellar carcinoma, sarcomatoid HCC or mixed hepatocellular cholangiocarcinoma, received previous systemic anticancer therapy for advanced disease, or underwent radiation therapy for bone metastasis within 2 weeks of treatment or any other radiation therapy within 8 weeks before randomization, they were excluded. Moreover, if patients had known brain metastases or cranial epidural disease and if they were receiving concomitant anticoagulation with oral anticoagulants, they were not included on the study.

Study participants was randomized 2:1:1 into 1 of 3 arms: cabozantinib at a daily dose of 40 mg plus atezolizumab at 1200 mg every 3 weeks; sorafenib alone at a twice-daily dose of 400 mg; or cabozantinib monotherapy at a daily dose of 60 mg.

The co-primary end points of the trial were PFS and OS in the experimental arm vs the control arm. The secondary end point focused on PFS in the single-agent arm vs the control arm.

Exelixis, Inc. plan to discuss the data from COSMIC-312 and next steps for potential regulatory filing with the FDA.

Exelixis and Ipsen announce cabozantinib in combination with an immune checkpoint inhibitor significantly improved progression-free survival in phase 3 COSMIC-312 pivotal trail in patients with previously untreated advanced liver cancer. News release. Exelixis, Inc. June 28, 2021. Accessed June 28, 2021. 

Study of cabozantinib in combination with atezolizumab versus sorafenib in subjects with advanced HCC who have not received previous anticancer therapy (COSMIC-312). ClinicalTrials.gov. Updated June 4, 2021. Accessed June 28, 2021. 

https://clinicaltrials.gov/ct2/show/NCT03755791

This article was originally posted on OncLive as 

“Frontline Cabozantinib Plus Atezolizumab Significantly Improves PFS in Advanced HCC”

A combination of cabozantinib and atezolizumab improved the PFS in patients with Advanced HCC

Cabozantinib/Atezolizumab Shows Promise in Treating Advanced HCC 

Patients with renal cell carcinoma (RCC) who underwent a nephrectomy or underwent a nephrectomy with resection of metastatic lesions demonstrated superior disease-free survival (DFS) when using adjuvant single agent pembrolizumab (Keytruda) as an adjuvant treatment.

Additionally, the toxicity profile of pembrolizumab proved to be consistent with what had previously been reported with the agent.

The trial will continue to examine the overall survival (OS) benefit achieved with the immunotherapy, as an important secondary end point. Data from the trial will be shared at an upcoming medical conference, according to Merck; the findings will also be presented to regulatory authorities.

“Since its first approval in RCC nearly 2 years ago, [pembrolizumab] has become an important first-line treatment option in combination with axitinib [Inlyta] for patients with advanced RCC,” Roy Baynes, MD, PhD, senior vice president, head of global clinical development, and chief medical officer at Merck Research Laboratories, stated in a press release. “These new data are the result of our research to evaluate the role of [pembrolizumab] in helping patients with earlier stages of disease and are the first positive results for an anti–PD-1 therapy in the adjuvant treatment of patients with RCC.”

In the double-blind phase 3 trial, investigators examined single-agent pembrolizumab in the adjuvant treatment of patients with RCC who had intermediate-high risk, high-risk, or M1 no evidence of disease with a clear cell component who had undergone nephrectomy.

To be eligible for enrollment, patients had to have an ECOG performance status of 0 to 1 and acceptable organ function.

Patients could not have previously received systemic therapy for advanced disease. If they had undergone major surgery other than nephrectomy within 12 weeks before randomization, received previous radiotherapy, had pre-existing brain or bone metastatic lesions, or had residual thrombus following nephrectomy in the vena renalis or vena cava, they were excluded.

A total of 950 patients were enrolled to the trial. Participants were randomized to receive either intravenous pembrolizumab at 200 mg on day 1 of each 3-week cycle for up to 17 treatment cycles or placebo on day 1 of each 3-week cycle for up to 17 cycles.

The primary end point of the trial was DFS, with key secondary end points of OS and safety.

In the United States, Europe, and Japan, the 

PD-1 inhibitor has been approved for use in combination with axitinib

 in the frontline treatment of patients with advanced RCC based on data from the phase 3 KEYNOTE-426 trial (NCT02853331). Here, the combination was found to result in a significantly better overall response rate, PFS, and OS vs sunitinib (Sutent) in patients with advanced disease.

 Specifically, the doublet reduced the risk of death by 47% vs sunitinib (HR, 0.53; 95% CI, 0.38-0.74; 

<.0001); the regimen also reduced the risk of progression of disease or death by 31% vs sunitinib (HR, 0.69; 95% CI, 0.57-0.84; 

Merck’s KEYTRUDA (pembrolizumab) demonstrated superior disease-free survival (DFS) compared with placebo as adjuvant therapy in patients with renal cell carcinoma (RCC) following surgery. News release. Merck. April 8, 2021. Accessed April 8, 2021. 

Safety and efficacy study of pembrolizumab (MK-3475) as monotherapy in the adjuvant treatment of renal cell carcinoma post nephrectomy (MK-3475-564/KEYNOTE-564). ClinicalTrials.gov. Updated May 28, 2020. Accessed April 8, 2021. 

https://clinicaltrials.gov/ct2/show/NCT03142334

FDA approves Merck’s KEYTRUDA (pembrolizumab) in combination with Inlyta (axitinib) as first-line treatment for patients with advanced renal cell carcinoma (RCC). News release. Merck. April 22, 2019. Accessed April 8, 2021. 

Adjuvant Pembrolizumab Demonstrates Superior DFS Over Placebo in Post-Nephrectomy RCC.”

Phase 3 KEYNOTE-564 trials demonstrated that single-agent pembrolizumab resulted in improved DFS in comparison to placebo group. 

Post-Nephrectomy Patients with RCC Show Improved DFS with Adjuvant Pembrolizumab 

 mutational status and geographical region were associated with time on treatment (TOT), and body mass index (BMI) and age were linked with overall survival (OS) in patients with metastatic colorectal cancer mCRC) being treated with second-line cetuximab (Erbitux) after irinotecan or oxaliplatin-based regimens, according to data from a real-world retrospective analysis presented at the 2021 ASCO Annual Meeting.

Results, indicated that the median TOT in patients who received second-line cetuximab was 3.94 months (median interquartile range [mIQR], 3.51-4.40), while the median OS was 14.36 months (mIQR, 13.01-15.70).

Moreover, receiving second-line treatment with cetuximab plus FOLFIRI (median TOT = 4.43 months; mIQR, 3.71-5.36), having 

 wild-type status, and receiving second-line cetuximab following frontline capecitabine plus oxaliplatin (CAPOX), were all associated with a longer median TOT. Moreover, residing in the South region vs the Midwest of the United States was linked with a shorter median TOT.

Having a higher BMI was associated with a longer median OS (obese vs underweight HR, 0.46; 95% CI, 0.32-0.66), while receiving treatment with second-line cetuximab plus 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) was linked with a shorter median OS (10.97 months; mIQR, 5.55-14.06). Additionally, being older than 65 years was also linked with a shorter median OS (≥65 years vs <65 years; HR, 1.24; 95% CI 1.05-1.46).

Anti-epidermal growth factor receptor drugs are being increasingly utilized in later lines of therapy in patients with mCRC, but the real-world TOT and OS of patients who receive cetuximab in second-line setting has not been examined. As such, investigators set out to examine characteristics linked with TOT and OS using retrospective observational data.

Between January 2013 and August 2020, 1011 patients were selected from the nationwide Flatiron electronic health record database. Patients were included in the analysis if they had a mCRC diagnosis, received second-line treatment with a cetuximab-based regimen, and had progressed on oxaliplatin/irinotecan-based regimens in the frontline.

Investigators defined TOT as the time from start of cetuximab in the second line to the last date of evidence of administration. Moreover, end of treatment was defined if patients progressed to a third line of therapy or if they had a death record. Additionally, OS was calculated from index date to the date of death or censored to the last visit date available.

Among the 1011 patients included in the analysis, more than half were younger than 65 years (58%) and male (60%). Additionally, most patients had a median BMI of 26.6 kg/m², had previously received FOLFOX regimens in the first-line setting (61%), and received treatment in the community setting (96%). The most frequently used second-line treatment regimens were cetuximab plus FOLFIRI (46%) and cetuximab plus irinotecan (29%).

Gathirua-Mwangi W, Yang T, Khan T, et al. Real-world time on treatment and overall survival in patients with metastatic colorectal cancer receiving cetuximab in second line after failing irinotecan or oxaliplatin-based regimens. 

. 2021;39(suppl 15):e15568. doi:10.1200/JCO.2021.39.15_suppl.e15568

KRAS mutational status and geographical region were associated with time on treatment (TOT), and body mass index (BMI) and age were linked with overall survival (OS) in patients with metastatic colorectal cancer mCRC) being treated with second-line cetuximab (Erbitux) after irinotecan or oxaliplatin-based regimens.

Patient Characteristics Linked to Time on Treatment and Survival in Patients With mCRC Receiving Cetuximab

Screenings for breast cancer, colorectal cancer (CRC), and prostate cancer declined sharply from March to May 2020 vs the same time span in 2019, suggesting that public health efforts, such as increased use of screening modalities that do not require a procedure, are needed to address the deficit caused by the COVID-19 pandemic, according to findings from a study that were published in 

Within the 3-month period in 2020, the sharpest decline in screening for breast cancer, CRC, and prostate cancer was observed in April 2020 compared with the same month in 2019; screenings declined by 90.8%, 79.3%, and 63.4% in breast cancer, CRC, and prostate cancer, respectively.

Compared with April 2019, the incidence of breast cancer screenings in April 2020 declined from 4287 per 100,000 individuals (95% CI, 4258-4316) to 394 per 100,000 individuals (95% CI, 385-403). The incidence of CRC screenings declined from 2073 per 100,000 individuals (95% CI, 2058-2087) to 430 per 100,000 individuals (95% CI, 423-436). The incidence of prostate cancer screenings declined from 4025 per 100,000 individuals (95% CI, 3993-4057) to 1474 per 100,000 individuals (95% CI, 1454-1493).

Notably, near complete recovery in monthly screening rates were observed by July 2020 for patients with breast cancer and prostate cancer.

"Unfortunately, by causing cancellations of appointments and cancer screenings, COVID will indirectly cause an increase in cancer deaths—another negative consequence of COVID that has not yet received much public attention," said lead study author Ronald C. Chen, MD, MPH, the Joe and Jean Brandmeyer Endowed Chair in the Department of Radiation Oncology at the University of Kansas Medical Center.

The COVID-19 pandemic significantly affected all elements of health care, including cancer treatment and screening, across the United States in 2020, Chen and co-authors wrote.1 Stay-at-home orders and safety guidelines issued by the CDC to minimize COVID-19 transmission resulted in a significant decline in non-emergency clinical visits, particularly among older, high-risk patients, explained Chen and co-authors.

The study evaluated 3 distinct cohorts of patients from the HealthCore Integrated Research Database, which comprises single-payer administrative claims data and enrollment information from about 60 million patients in Medicare Advantage and commercial insurance plans across the United States. The cohorts included women with breast cancer, men and women with CRC, and men with prostate cancer.

Cancer screenings were evaluated from 2018 to 2020. Evaluable individuals for breast cancer screening or CRC screening were aged 50 to 79 years, and evaluable individuals for prostate cancer screening were aged 50 to 69 years. Individuals had to have at least 2 years of continuous enrollment before the first day of the index month. Restrictions based on medical claims and personal history codes for cancers of interest further refined the evaluable population.

“Excluding individuals with a history of the cancer of interest allowed us to more accurately assess cancer screening,” wrote Chen and co-authors.

Additional results from the study revealed that despite the rebound in monthly cancer screening rates, a deficit in total cancer screenings from January to July 2020 remained compared with January to July 2019. This translated to a United States–population deficit in breast cancer, CRC, and prostate cancer screenings of approximately 3.9 million women, 3.8 million men and women, and 1.6 million men, respectively. Moreover, the total deficit in cancer screenings was estimated at 9.4 million individuals in 2020 compared with 2019.

By geographic region, the Northeastern United States reported the sharpest decline in cancer screenings in March, April, and May for all 3 cancer types. The Western region had a slower recovery in screening during June and July compared with the Midwest and South regions.

Regarding socioeconomic status, prior to the pandemic, screening rates were higher for all 3 cancer types in the highest 2 socioeconomic index quartiles compared with the lower 2 socioeconomic index quartiles. However, the highest socioeconomic index quartile reported the largest decline in screening for all 3 cancer types from January to July 2020 compared with the same period in 2019. Moreover, the decline narrowed the gap in screening rates across the quartiles in 2020 vs 2019.

Other key findings from the study showed that increasing age was associated with less screening in all 3 cancer types. Individuals in the higher quartiles were screened less for breast cancer and CRC in April 2020 compared with individuals in the lower quartiles.

Notably, individuals who utilized telemedicine services had higher rates of cancer screening across the 3 cancer types evaluated.

“Telehealth has a measurable positive effect on whether patients get their cancer screenings,” Chen said.2 “This study also justifies a continued use of telehealth even after the pandemic.”

Chen and co-authors reported that analyzing only insured individuals, the lack of racial/ethnic diversity in the study population, the use of nonspecific codes for screening, and the inclusion of individuals without a history of cancer were limitations of the study.

“As a physician, I wasn’t surprised to see that screenings had declined, but this study measures by how much. There needs to be a concerted public health educational campaign across the country to reinforce the importance of cancer screening. Hospitals across the country also need to devote effort to contact patients to reschedule canceled screening tests, in order to minimize the delay in screening and cancer diagnoses from the missed tests,” concluded Chen.2

Chen RC, Haynes K, Du S, et al. Association of cancer screening deficit in the United States with the COVID-19 pandemic. 

. Published online April 29, 2021. Accessed May 13, 2021. doi:10.1001/jamaoncol.2021.0884

Massive negative impact of COVID-19 on cancer screenings quantified in KU Medical Center faculty study published in JAMA Oncology. News release. April 29, 2021. Accessed May 13, 2021. https://bit.ly/3ojB2fJ.

This article was originally published on OncLive as, "

Routine Screening Rates for Breast, Colorectal, and Prostate Cancers Decline During COVID-19 Pandemic

Public health efforts must address new methods of cancer screening, an expert says.

Routine Cancer Screening Declined During the COVID-19 Pandemic

The FDA approved adjuvant nivolumab (Opdivo) for the treatment of completely resected esophageal or gastroesophageal (GEJ) cancer with residual pathologic disease in patients who have previously had neoadjuvant chemoradiation treatment, according to Bristol Myers Squibb, the manufacturer of the immunotherapy agent.

"Esophageal and GEJ cancer patients with residual pathologic disease following neoadjuvant CRT and complete resection face a high risk of disease recurrence; however, the predominant option for these patients has been surveillance,” said Adam Lenkowsky, senior vice president and general manager, U.S. Cardiovascular, Immunology and Oncology, Bristol Myers Squibb in a statement. “Today’s news marks an important step for patients as well as meaningful progress toward our commitment to pioneering immunotherapy treatment options in earlier stages of disease where there is the potential to reduce the risk of recurrence.”

The approval is based on findings from the phase 3 CheckMate-577 trial (NCT02743494), which involved 794 patients with stage II esophageal or GEJ cancer, adenocarcinoma or squamous cell carcinoma. To be eligible, patients had to have undergone neoadjuvant chemoradiation and surgical resection and have residual pathologic disease and an ECOG performance score of 0 to 1.

Study participants were randomized 2:1 to receive either 240 mg of nivolumab once every 2 weeks for 16 weeks then 480 mg once every 4 weeks; or placebo once every 2 weeks for 16 weeks and then once every 4 weeks. Treatment continued for up to 1 year.

Trial results proved that nivolumab led to a clinically meaningful improvement in disease-free survival (DFS) compared with placebo, 22.4 months versus 11.0 months, respectively in patients with resected esophageal or GEJ cancer after neoadjuvant chemoradiation.

There was also a 31% reduced risk of disease recurrence or death with nivolumab compared to placebo.

While patients were stratified based on histology (squamous or adenocarcinoma) pathologic lymph node status, and PD-L1 expression, benefit with nivolumab treatment was seen across all subgroups, also including age, sex, race, ECOG performance status, disease stage at initial diagnosis, and tumor location.

“Locally advanced esophageal and gastroesophageal junction cancers are aggressive tumor types that often require multiple approaches to address the disease, including chemotherapy, radiation and surgery,” said Ronan J. Kelly MD, MBA, director, Baylor Scott & White Charles A. Sammons Cancer Center, and W.W. Caruth Jr. Endowed Chair of Immunology at Baylor University Medical Center.

While the majority of patients on nivolumab experienced an adverse event (AE) of any grade, far fewer 33% had a severe (grade 3 or 4) AE. Two percent of more of patients receiving nivolumab experience pneumonitis. One patient died of myocardial infarction while taking nivolumab.

Common AEs that were reported in 20% or more of patients were fatigue (34%), diarrhea (29%), nausea (23%), rash (21%), musculoskeletal pain (21%), and cough (20%).

“Even after neoadjuvant CRT followed by surgery, there may be a high risk of recurrence for patients who do not achieve a pathologic complete response.2,3,7 In the CheckMate -577 trial, we saw a doubling in median disease-free survival compared to placebo, which suggests that 

 could become a new standard of care for these patients.1,9 This is exciting news, providing renewed hope,” Kelly said.

Bristol Myers Squibb. U.S. Food and Drug Administration Approves Opdivo® (nivolumab) as Adjuvant Treatment of Completely Resected Esophageal or Gastroesophageal Junction Cancer in Patients who have Received Neoadjuvant Chemoradiotherapy. May 20, 2021. 

https://news.bms.com/news/details/2021/U.S.-Food-and-Drug-Administration-Approves-Opdivo-nivolumab-as-Adjuvant-Treatment-of-Completely-Resected-Esophageal-or-Gastroesophageal-Junction-Cancer-in-Patients-who-have-Received-Neoadjuvant-Chemoradiotherapy/default.aspx

The FDA approved adjuvant nivolumab for the treatment of patients with resected esophageal or gastroesophageal (GEJ) cancer who have previously had neoadjuvant chemoradiation treatment. 

Gastrointestinal Cancer