The OBR Blog

May 30, 2020 - 09:05 pm Posted in ASCO and ASH Posted in ASCO Conference Coverage Posted in Breast Posted in Liver (includes HCC, Billiary Tract) comments0 Comments

The live broadcast of the virtual scientific program of the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting kicked off this morning with highlights sessions that captured some of the most important studies.

The gastrointestinal cancer session featured four studies, one of which was a phase 2/3 trial that compared donafenib to sorafenib in liver cancer. HER2CLIMB and MINDACT were both discussed during the breast cancer session. Although not discussed this morning, the results of PHERGAIN dropped at this meeting and offer a de-escalation strategy for patients with early breast cancer.

Another Blow to Sorafenib

Patients with unresectable or metastatic hepatocellular carcinoma who received donafenib in the first-line setting lived a median of nearly two months longer than patients who received standard of care sorafenib (12.1 months vs 10.3 months), results showed in the open-label, randomized phase 2/3 trial (Abstract 4506).

Patients in the donafenib arm (n=334) also had a 17% reduced risk of death compared with the sorafenib arm (n=334; HR=0.831; 95% CI, 0.699 – 0.988; P=0.0363). However, no difference was seen between the donafenib arm and sorafenib arm for progression-free survival (PFS; 3.7 vs 3.6 months; P=0.2824), objective response rate (4.6% vs 2.7%; P=0.2448), and disease control rate (30.8% vs 28.7%; P=0.5532).

Donafenib appeared to have a better safety profile, with a significantly lower rate of drug-related adverse events that led to treatment interruption compared with sorafenib (25.2% vs 36.1%; P=0.0025). The donafenib arm also had a significantly lower rate of drug-related adverse events of grade 3 or higher (37.5% vs 49.7%; P=0.0018).

Marcus Noel, MD, associate professor of medicine, Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, cautioned that this study was conducted in China and is not an international study.

“Not sure if this is going to be able to extrapolate across the globe, but certainly donafenib has a place in first-line therapy, further pushing sorafenib to the side,” he said.

Tucatinib Shows Promise for Brain Mets

Tucatinib in combination with trastuzumab and capecitabine extended overall survival (OS) and delayed disease progression in the central nervous system (CNS) for patients with HER2-positive metastatic breast cancer and brain metastases, results showed from an exploratory efficacy analysis of the phase 2 HER2CLIMB trial (Abstract 1005).

Trial participants were randomly assigned to receive tucatinib in combination with trastuzumab and capecitabine (n=410) or placebo in combination with trastuzumab and capecitabine (n=202). The exploratory analysis included only patients with brain metastases at baseline, of which 291 of 612 (48%) randomized to treatment had.

Patients with brain metastases in the tucatinib arm had a 68% reduced risk of disease progression in the CNS compared with the placebo arm (HR=0.32; 95% CI, 0.22 – 0.48; P<0.0001) and a nearly 6-month gain in median CNS PFS (9.9 vs 4.2 months).

Patients in the tucatinib arm also had a 42% reduced risk of death compared with the placebo arm (HR=0.58; 95% CI, 0.40 – 0.85; P=0.005), and an approximately 6-months gain in overall survival (OS; 18.1 vs 12.0 months). The intracranial response rate more than doubled with tucatinib compared with placebo (47% vs 20%; P=0.03).

“HER2CLIMB serves as a wonderful story for the liberalization of clinical trial entry criteria and inclusion of patients that we need in clinical trials and who need novel therapeutics as well,” said Erika Hamilton, MD, Sarah Cannon.

MINDACT Confirms Clinical Utility of MammaPrint

A long-term analysis of the phase 3 MINDACT trial confirmed that the 70-gene signature MammaPrint assay can identify which breast cancer patients with a high clinical-pathological risk do not need adjuvant chemotherapy (Abstract 506).

Among the intention to treat population with a median follow-up of 8.7 years, patients with high clinical risk but low genomic risk who received adjuvant chemotherapy (n=749) had a small gain in distant metastasis-free survival (DMFS) compared with patients who did not receive chemotherapy (n=748; 92.0%; 95% CI, 89.6 – 93.8% vs 89.4%; 95% CI, 86.8 – 91.5).

A subgroup analysis among hormone-receptor positive and HER2-negative patients revealed no difference in DMFS between treatment groups for patients over the age of 50, yet a 5% difference for patients 50 years or younger, favoring treatment with chemotherapy (93.6%; 95% CI, 89.3% – 96.3% vs 88.6%; 95% CI, 83.5 – 92.3%).

“MINDACT showed us that patients with clinical high, genomic low disease continue to do well without chemotherapy at 8 years of follow-up,” said Angela de Michele, MD, University of Pennsylvania. She cautioned that the DMFS gain seen with chemotherapy for premenopausal patients “may be due to a lack of ovarian function suppressant in the non-chemotherapy arm.”

PHERGAIN Showcases De-escalation Strategy

A PET/CT scan with fluorodeoxyglucose (FDG) tracer helped identify which patients with HER2-positive early breast cancer were most likely to benefit from trastuzumab and pertuzumab with endocrine therapy, according to the results of the PHERGAIN trial (Abstract 503).

Patients with HER2-positive disease were randomized to receive either trastuzumab and pertuzumab with chemotherapy (n=71) or trastuzumab and pertuzumab with endocrine therapy (n=285).

A PET/CT scan was used to guide treatment for patients in the chemotherapy-free arm by having patients undergo imaging after 6 weeks of treatment. If the scan showed a response, patients continued on the chemotherapy-free regimen. If not, patients switched to trastuzumab and pertuzumab with chemotherapy. Patients in the chemotherapy-containing arm also underwent imaging but the results were not used to guide treatment.

For the chemotherapy-free arm, patients who had a PET response achieved a higher pathologic complete response rate compared with patients who did not have a PET response (37.9% vs 25.9% P=0.069).

Study presenter Javier Cortes, MD, PhD, IOB Institute of Oncology, Hospital Quirónsalud, Medica Scientia Innovation Research, and Vall d’Hebron University of Oncology, said the chemotherapy-free strategy did not “jeopardize” breast conserving surgery and was also associated with a “more favorable” toxicity profile.

By Christina Bennett, MS

One of biggest challenges in attending an annual ASCO meeting is time management. With over 2,000 abstracts submitted this year and a wide variety of new drugs and therapeutic targets, ASCO 2019 will be no different.

During a webinar last week sponsored by E-Squared Communications (a Conisus company), OBR and three renowned cancer experts helped identify some of the “high impact studies” that are sure to gain a lot of attention at this year’s ASCO Annual Meeting. For those of you who missed this increasingly popular annual webinar, the experts not only covered the important data but also provided some suggestions on where to go if you happen to play hooky for a day at ASCO. Don Sharpe, President and Founder of OBR, moderated the session, and the primary areas of focus included cervical, prostate, pancreatic, breast, lung, and advanced gastric/gastroesophageal junction cancers as well as multiple myeloma and hepatocellular carcinoma (HCC).

Pending its final outcome, the first trial highlighted in the webinar could well be a practice-changing study. This phase 3 Intergroup trial (E3A06) in patients with asymptomatic intermediate- or high-risk smoldering multiple myeloma is the largest randomized trial in this setting to date. The 182 patients who participated in this study were randomized to either receive lenalidomide alone or observation, with progression-free survival (PFS) being the primary endpoint. At a median of 28 months of follow-up, the 3-year PFS rate in the lenalidomide arm seems to be numerically trending in the right direction (91% vs. 66%). This data will be highlighted in an oral abstract (8001) session on Sunday, June 2nd.

Following an interesting review of a phase 2 study highlighting the use of LN-145 tumor infiltrating lymphocytes in patients with cervical cancer, the next phase 3 study highlighted by the experts was a late-breaking abstract. This Australian and New Zealand Urogenital (ANZUP) Cooperative Group trial (ENZAMET) evaluated enzalutamide as first-line androgen-deprivation therapy for metastatic hormone-sensitive prostate cancer. The abstract LBA2 will be presented at the plenary session on Sunday, June 2nd and is sure to draw comparisons to the earlier LATITUDE study of abiraterone in this setting.

Pancreatic cancer seems to be climbing into the spotlight as well this year, as the OBR experts identified the Adjuvant Treatment in Pancreatic Cancer Study (APACT) as an important one to watch. This study evaluated nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients with surgically resected pancreatic cancer. With 866 patients enrolled, this large clinical trial had a primary endpoint of disease-free survival; however, the authors noted that the overall survival (OS) results seen in this study may better support the rationale of using this combination in the adjuvant setting, especially for patients who are ineligible for FOLFIRINOX.

The PARP inhibitor olaparib was also discussed in the webinar as a potentially new therapeutic option for patients with pancreatic cancer. The phase 3 POLO trial of olaparib versus placebo as maintenance therapy in patients with germline BRCA-mutated metastatic pancreatic cancer whose disease had not progressed following first-line platinum-based chemotherapy will be highlighted during the plenary session on Sunday, June 2nd (LBA4). This study is the first positive phase 3 trial of any PARP inhibitor in germline BRCA-mutated metastatic pancreatic cancer.

Pembrolizumab was highlighted as well in two studies looking at gastric cancer and GEJ adenocarcinoma (KEYNOTE-062) and advanced HCC (KEYNOTE-240). In KEYNOTE-062, pembrolizumab met its primary endpoint by demonstrating OS noninferiority compared to chemotherapy in the intent-to-treat population. In KEYNOTE-240, pembrolizumab showed positive numerical trends but did not meet statistical significance for its co-primary endpoints of OS and PFS; however, it did show an improved response rate versus placebo (ORR 16.9% vs. 2.2%), and it will be interesting to see what impact this might have going forward.

Another important KEYNOTE study is KEYNOTE-189: Updated OS and progression after the next line of therapy (PFS2) with pembrolizumab (pembro) plus chemo with pemetrexed and platinum vs placebo plus chemo for metastatic nonsquamous NSCLC. KEYNOTE-001 is also a late-breaking abstract looking at 5-year long-term OS for patients with advanced non-small cell lung cancer treated with pembrolizumab.

There are certainly other important abstracts at this year’s ASCO Annual Meeting, but at the very least, this review should help narrow down your choices.

By Adrian Barfield, President, Medallion Healthcare

June 04, 2017 - 07:06 pm Posted in ASCO Conference Coverage Posted in Liver (includes HCC, Billiary Tract) comments3 Comments

By Connie Tat, Ph.D. and Arnold DuBell, Ph.D., MBA

Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide, and is responsible for nearly 745,000 deaths per year1.   In 2007, Nexavar, a multi-targeted tyrosine kinase inhibitor (TKI), was established as the first FDA-approved agent for first-line HCC, based on a 2.8-month improvement in overall survival (OS) relative to placebo in the Phase III SHARP trial2. Use of Nexavar came at a high price however, as 80% of the Nexavar-recipient patients in the SHARP trial experienced adverse events including diarrhea, hand-foot skin reaction and others.

Despite the low bar, novel therapeutic contenders have historically struggled to unseat Nexavar as the standard of care in front-line.  For example, four global Phase III trials [evaluating Sutent® (sunitinib, Pfizer), brivanib (Bristol-Myers Squibb), linifanib (AbbVie), and Tarceva® (erlotinib, Genentech / Roche)] failed to meet their primary endpoints. This is due in part to liver dysfunction (cirrhosis) present in many HCC patients as well as other comorbidities resulting from infection with hepatitis B or hepatitis C, and/or occurrence of non-alcoholic fatty liver disease. In practice, systemic therapies such as Nexavar are limited to patients with the least degree of cirrhosis (Child-Pugh A). Those with greatly impaired liver function (Child-Pugh C) are often unable to tolerate current therapeutic options and generally receive best supportive care. Even those with reasonable liver function may struggle to tolerate combination therapies that include Nexavar as a backbone.

As the high unmet needs in hepatocellular carcinoma (HCC) have historically been insurmountable, a novel agent is greatly needed that improves both efficacy and tolerability to encompass more patients in the treatable population.  Eisai entered the competitive landscape in front-line HCC with Lenvima® (lenvatinib) in 2009.  Lenvima is another multitargeted TKI which is approved for use as a monotherapy in differentiated thyroid cancer and in combination with Afinitor® (everolimus, Novartis) for the treatment of advanced RCC following one prior anti-angiogenic therapy.  (Note that for the latter indication, Lenvima is branded in Europe as Kisplyx®). To evaluate Lenvima in HCC patients in the first-line setting, Eisai initiated a global, randomized, open-label Phase III non-inferiority study (“REFLECT”) in 2013.  REFLECT randomized 954 patients with unresectable HCC to Lenvima (12 mg or 8 mg q.d., based on body weight) or Nexavar (400 mg b.i.d.) to support regulatory filings in the U.S., Europe and Japan.  The primary endpoint is non-inferiority in overall survival, and secondary endpoints include PFS, ORR, health-related quality of life, and pharmacokinetics.  Data from this trial were presented at ASCO 20173.  Lenvima met its non-inferiority primary endpoint in OS (13.6 months versus 12.3 months, HR 0.92).  The agent also demonstrated to be statistically superior to Nexavar in terms of PFS (7.4 months versus 3.7 months, HR 0.66, p<0.00001), TTP (8.9 months versus 3.7 months, HR 0.63, p<0.00001) and ORR (24% versus 9%, p<0.00001).

The toxicity profiles for the two agents were roughly similar, with comparable incidence of grade ≥3 treatment-related adverse events (57% versus 49%), dose reductions (37% versus 38%) and drug discontinuations (9% versus 7%). The two grade 3-4 toxicities of note were hypertension (23% versus 14%) and palmar-plantar erythrodysesthsia (3% versus 11%).  Other common grade 3-4 toxicities included decreased weight (8% versus 3%), elevated aspartate aminotransferase (5% versus 8%) and thrombocytopenia (6% versus 3%).  Based on this data, Eisai announced plans to submit for regulatory approval later this year.

Overall, HCC seems to be at a hopefully positive point, as Stivarga® (regorafenib, Bayer) was recently approved for use in Nexavar-refractory HCC patients.   Moreover, Opdivo® (nivolumab, Bristol Myers Squibb / Ono Pharmaceuticals) was recently filed for US accelerated approval in Nexavar-refractory patients based on Phase I/II data, and is currently being evaluated in the Phase III CheckMate 459 trial for use in the first-line setting. REFLECT is one of the few positive trials in the last ten years, and although the results were not groundbreaking, it does suggest that Lenvima may be a potential first-line treatment option in advanced HCC.  Does the REFLECT data suggest that Lenvima will be used over Nexavar in first-line?  The discussant, Katie Kelley, implied that non-inferiority trials are typically used for agents that are less toxic, less costly, or easier to administer.  Kantar Health therefore “seats” Lenvima next to Nexavar, as it only showed non-inferiority with regard to overall survival but did not show a reduced toxicity profile. Further, Nexavar is entrenched in this setting, with 50-60% utilization in first-line based on Child-Pugh status, and 15% utilization in second and third-lines4.

Another concern for Lenvima is drug sequencing.  As noted above, Stivarga is indicated for Nexavar-refractory patients, and Opdivo could soon have a similar label.  This begs the question that if Lenvima is used in the first-line, will physicians need to wait to use Stivarga in the third-line setting after Nexavar is offered in the second-line?  Could physicians’ preference to use first-line Nexavar and second-line Stivarga impact where Lenvima might be offered? We will have to see who else earns their “seat at the table” to determine how this shuffling is to occur.




  1. Ferlay J, Soerjomataram I, Dikshit R et al., “Cancer incidence and mortality worldwide: sources, methods, and major patterns in GLOBOCAN 2012.”  Int J Cancer, 36 (5): 359-386, 2014.
  2. Llovet J, Ricci S, Mazzaferro V, et al.; “Sorafenib in advanced hepatocellular carcinoma;” N Engl J Med, 359 (4): 378-390, 2008.
  3. Cheng A, Finn R, Qin S, et al., “Phase III trial of lenvatinib vs sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma,” Abstract 4001, ASCO 2017.
  4. Kantar Health, CancerMPact® Treatment Architecture.  Accessed June 4, 2017.


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