OncologyLive® is the flagship publication of OncLive®. Each issue delivers expert insights and clinical oncology news and updates, which impact the day-to-day clinical practice of oncology professionals who work tirelessly to help improve patient outcomes.

Ipatasertib is being investigated in patients with metastatic castration-resistant prostate cancer (mCRPC) as a method of simultaneously blocking a resistance mechanism to hormone therapy and improving responses to abiraterone (Zytiga). The novel small molecule, which targets the AKT node in the PI3K pathway, is being tested in combination with abiraterone and prednisone in the international phase III IPATential150 trial (NCT03072238).

The trial is seeking to recruit approximately 850 adult patients (≥18 years) with asymptomatic or mildly symptomatic previously untreated mCRPC. Tumor samples must be tested for phosphatase and tensin homolog (PTEN) loss on an immunohistochemistry (IHC) assay, as the study patients will be stratified by tumor PTEN status and the testing of the endpoints will be statistically assessed in the unselected and PTEN-loss populations independently (Figure).

Figure. Ipatasertib in Patients With mCRPC

“The proposition is that one of the resistance mechanisms to hormonal therapy is the activation of the PI3-kinase AKT pathway, a survival pathway that can be activated and drive cancer when the androgen receptor is blocked,” said Christopher J. Sweeney, MBBS, a medical oncologist at DanaFarber Cancer Institute and associate professor of medicine at Harvard Medical School, both in Boston. “It is hoped that by blocking one of these resistance mechanisms, it will augment the effectiveness of anticancer therapy and improve cancer control.”

Sweeney, who is an investigator on the trial and contributed to the study design, noted that patients can have various reactions to abiraterone in terms of its effectiveness. Some patients, he said, can have a good response for many months or years, some have a moderate response for a few months and then experience progressive disease, and others have very little benefit. However, Sweeney stressed that abiraterone is a well-tolerated and active drug for treating mCRPC overall, so the goal is to find a complementary agent to allow patients longer and more meaningful control of their cancer with the combination than they would with abiraterone alone.

Ipatasertib inhibits AKT, a key component of the PI3-kinase pathway that is dysregulated by the loss of the tumor-suppressor 

“The cells get activated by various receptors that promote the growth of normal and cancer cells, and that triggers a series of processes that go outside the receptor into the cancer cell,” explained Sweeney. “They activate AKT, which then activates the production of genes and proteins that support cancer growth, and sometimes those pathways are superactivated and preferentially drive [growth of] cancer cells more than normal cells.”

This “superactivation” is predicated by loss of 

, which is one of the most common changes in patients with mCRPC.

 By inhibiting AKT, ipatasertib prevents this chain of signaling at the source, and keeps cancer cells from growing.

This mechanism of action for ipatasertib was demonstrated in the A. MARTIN study, which assessed radiographic progression-free survival (rPFS) and the relationship between PTEN expression by IHC and genomic loss of PTEN

by fluorescence in situ hybridization and next-generation sequencing.

 Investigators randomized 253 patients with mCRPC who were previously treated with docetaxel to 3 arms: ipatasertib at 400 mg, ipatasertib at 200 mg, or placebo, all in combination with abiraterone and prednisone.

At the primary analysis, the investigators observed 173 rPFS events. PTEN status was evaluable by IHC in 165 cases (65%) and PTEN loss was seen in 71 cases (43%). Loss of PTEN was associated with a worse rPFS outcome in the placebo arm, but in both ipatasertib arms, rPFS improved among patients with PTEN loss, with a greater effect seen in the 400-mg dose arm.2 There was high concordance between the 3 testing methods.

Adverse effects related to ipatasertib are relatively mild, according to Sweeney, and include diarrhea and blood sugar elevation, but nothing that resulted in patients not being able to tolerate the drug.

The primary endpoint for IPATential150 is rPFS, since the purpose of the combination is to try to delay the appearance of further metastatic disease on scans. According to Sweeney, these results will be supported by measuring the evidence of benefit and quality of life and preventing the emergence of pain. The investigators will also be assessing overall survival, under the assumption that patients would live longer if they received this combination early in their therapy.

Ipatasertib is also being studied in other tumor types and indications, including as neoadjuvant therapy for triple-negative breast cancer (TNBC) and in locally advanced or metastatic TNBC. The phase II LOTUS trial investigated ipatasertib combined with paclitaxel as first-line treatment in patients with advanced TNBC; results showed that median PFS was longer in patients with PTEN-low tumors who received ipatasertib than in those who received a placebo (6.2 vs 3.7 months, respectively).

“Many investigators around the world are excited about the potential for this study, and that’s why it’s getting such traction and why we’re going to activate it around the world,” Sweeney said.

Ipatasertib (GDC-0068, RG7440). Genentech/Biooncology website. biooncology.com/pipeline-molecules/ipatasertib.html. Accessed August 11, 2017.

De Bono JS, De Giorgi U, Massard C, et al. PTEN loss as a predictive biomarker for the Akt inhibitor ipatasertib combined with abiraterone acetate in patients with metastatic castration-resistant prostate cancer (mCRPC) [ESMO abstract 7180]. 

2016;27(suppl 6): 243-265. doi: 10.1093/annonc/mdw372.

Kim SB, Dent R, Im SA, et al. Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. 

2017; pii: S1470- 2045(17)30450-30453. doi: 10.1016/S1470-2045(17)30450-3.

Articles

Ipatasertib is being investigated in patients with metastatic castration-resistant prostate cancer as a method of simultaneously blocking a resistance mechanism to hormone therapy and improving responses to abiraterone.

AKT Inhibitor May Promote Better Responses to Abiraterone in mCRPC

During the past decade, the treatment of multiple myeloma has significantly changed, enabling more patients to achieve deep and durable responses.

 Several new drug classes with highly effective therapies have emerged, including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, and histone deacetylase inhibitors.

Goals of Therapy for Symptomatic Patients

Greater understanding of tumor biology has also enabled the use of novel treatment combinations and spurred new drug development, particularly as more cytogenetic abnormalities have been discovered.

The heterogeneity of multiple myeloma has led the National Comprehensive Cancer Network to recommend risk-adapted approaches that individualize treatments to improve patient outcomes.

 panel with moderator Keith Stewart, MB, ChB, and other experts in multiple myeloma to discuss the goal of achieving deep and durable responses in more patients, including older adults who are not able to tolerate highly aggressive treatments. During the discussion, the panelists provided personal perspectives and discussed the newest information on the goals of therapy in symptomatic disease, testing for minimal residual disease (MRD), role of transplantation, and the use of maintenance therapy. “We continue to see dramatic shifts in the management of multiple myeloma,” said Stewart.

The panelists agreed that the goal of therapy is to achieve MRD-negative complete remissions, but that the timeline for achieving this goal varies by patient. “For elderly patients, I think you must compromise a little bit on efficacy for the tolerability and safety…achievement of a deep response is important for these patients, but it may take a little longer than in the younger patients,” said Saad Z. Usmani, MD, FACP. This approach was supported by Thomas G. Martin III, MD who concurred that the road to a complete response (CR) can be significantly longer in older populations. “I tell them, ‘You’re going to be on therapy for, potentially, upwards of a year. Hopefully each month [the need for therapy] will go down—slowly, slowly, slowly,’” he said.

In contrast, patients with more severe disease often require a quick response. “I think if there’s a patient who presents in extremis, in acute renal failure, then the rapidity of the reduction of the disease burden is important,” said Ivan M. Borrello, MD, who acknowledged those presentations are rare. “[In most patients], if the trend is going in the right direction, I think [we can] deliver therapy with potentially less intensity and less toxicity over a longer period of time,” he said.

Frontline therapy choices among the panelists varied based on patient factors and institutional practices, but all panelists reported using combination regimens, with most incorporating bortezomib (Velcade) and lenalidomide (Revlimid) into their protocols, preferring 3-drug regimens for younger, more fit patients, and 2-drug regimens for older and more frail patients. “For the transplant-eligible patient, our upfront regimen of choice is bortezomib with lenalidomide and dexamethasone. For the older, truly frail patient, it’s probably lenalidomide and dexamethasone. And now there may be talk about an antibody there,” said Sagar Lonial, MD, FACP. Although 2-drug regimens were generally regarded as safest for less robust patients, Borrello said his institution has used 3-drug regimens in some elderly populations, although at lowerdose intensities.

Most panelists did not routinely use carfilzomib (Kyprolis) combinations upfront, but Martin reported using it with lenalidomide and dexamethasone in younger and more fit patients and in those with high-risk cytogenetics, such as 17p deletion, t[4;14] deletion, or 1q gain. Others noted they might start using it as an upfront therapy based on emerging data. The most unique regimen was reported by Gareth Morgan, MD, FRCP, FRCPath, PhD, whose institution uses combinations with classic chemotherapy agents to enable harvesting stem cells for eventual stem cell transplantation. “We are aiming each point in the process to achieve increasing remissions— aiming for MRD negativity, ultimately,” he said.

Because improved multiple myeloma treatments have led to higher CR rates, there has been a need to redefine response criteria to enable identification of deeper responses than were conventionally possible.

This has led to the emergence of flow cytometry and, more recently, next-generation gene sequencing to identify residual tumor cells in the bone marrow.

The panelists identified numerous pros and cons with each testing method.

Flow cytometry was reported to provide results more quickly, typically within 24 hours, whereas gene sequencing results have been slower, often taking a week or longer to obtain. Reported benefits of next-generation sequencing included not needing a fresh sample and more consistent results. “There’s a lot of variability with flow cytometry that’s operator-dependent, antibody panel—dependent, and many other things,” explained Borrello.

While the panelists varied in their testing methods and preferences, Morgan reminded that both flow cytometry and next-generation gene sequencing have roles to play and might sometimes be beneficial when used in combination. “We have MRD flow cytometry, which is a variable sensitivity—10-4, 10-5 [ie, 1 in 105 nucleated cells or better]&mdash;when you see the patient. If somebody is negative, you can consider sending it off for sequencing,” he said.

A major challenge that remains is standardizing the MRD-negativity threshold across clinical trials, regardless of which testing method is used. Currently, the International Myeloma Working Group criterion is set at 10-5, with sustained MRD negativity requiring 2 such determinations on either flow cytometry or next-generation sequencing taken 1 year apart; however, thresholds in clinical trials have ranged from 10-4 to 10-6. 

The panelists acknowledged that MRD testing is not ready for clinical application outside of clinical trials just yet. The testing mainly serves as a prognostic marker, with MRD-negative patients showing better progression-free survival (PFS) and overall survival (OS) than those who do not achieve MRD negativity, regardless of threshold used. “I don’t think any clinical decisions can be made [based on this testing] at the current time,” said Martin.

While the goal has been to eliminate transplantation, the panelists noted that it remains an important therapeutic option despite the advent of many new highly effective therapies. “If you can tolerate [autologous stem cell transplant], it should be one of the major tools for newly diagnosed patients,” said Morgan.

The panelists proceeded to discuss an important study recently published by Attal and colleagues in the New England Journal of Medicine, which showed transplantation to have some benefit over use of a 3-drug regimen alone.4 The study compared induction therapy with 3 cycles of lenalidomide, bortezomib, and dexamethasone (RVD) followed by consolidation therapy with either 5 more cycles of RVD (n = 350) or high-dose melphalan plus stemcell transplantation followed by 2 additional cycles of RVD (n = 350); both groups received 1 year of lenalidomide maintenance therapy.

Patients who received transplantation had a significantly longer PFS than those who received RVD alone (50 vs 36 months, respectively; adjusted HR for disease progression or death, 0.65; 

 <.001). Additionally, more patients in the transplantation group than in the RVD-only group achieved CR and MRD negativity; however, OS at 4 years was similar between groups (81% and 82%, respectively).

Although no benefit in OS was observed, Usmani noted, “For most transplant trials, you have to wait out 5, 6, or 7 years to see the overall survival curves separate.” Also, several panelists emphasized the importance of the increased MRD negativity observed in the transplant group (ie, 79% vs 65% for the RVD-only group; 

 <.001). “I think that when you [discuss treatment] with the patient, you want to pick the choice that gives your patient the best chance for getting to a deep remission—MRD negativity&mdash;and that’s what you get with early transplant,” said Usmani.

The panelists also discussed the StaMINA trial, which is the largest trial to date assessing transplantation in patients with multiple myeloma.

 The study results were presented at the 2016 American Society of Hematology Annual Meeting, but have not yet been published. “The StaMINA trial compared single transplant with a tandem transplant and a single transplant with consolidation, with the hypothesis that deeper remission would result in longer progression-free survival,” said Stewart. “It didn’t really seem to show that very conclusively,” he noted. The thought has been that the study’s findings might lead to fewer second transplants, supporting a less-is-more approach,

 but follow-up is ongoing and many panelists felt that it is premature to draw such conclusions. “It’s just a little bit early for that trial to have reported—about 5 years too early,” suggested Morgan, who noted that his institution performs tandem transplants and that they are commonly performed in Europe. He also suggested that evidence from other studies has been showing benefit with tandem transplantation; thus, more data are needed before use of second transplants should be ruled out.

The panelists started their discussion of maintenance therapy by examining a trial led by Morgan that assessed the use of lenalidomide in this setting.

In the study, lenalidomide maintenance was associated with a significantly longer median PFS versus observation (HR, 0.47; 95% CI, 0.38-0.60) across all subgroups, including those with high-risk disease. “I think [this trial] was the final piece of evidence that really supports the use of [lenalidomide] maintenance compared with no maintenance…we should have OS data by the end of the year,” said Morgan. Results were improved if maintenance continued past the first year, he noted. While continuation until progression was considered ideal, the panelists acknowledged this is typically not possible because of toxicity.

“At the University of California, San Francisco, we just had a pharmacist look at our data. During the maintenance phase, patients became toxic from fatigue and diarrhea. The average duration of therapy was between 2 and 2.5 years,” said Martin. Several panelists noted that use of medicines that address such toxicities, such as cholestyramine for lenalidomide-induced diarrhea, might enable more patients to remain on lenalidomide maintenance longer, particularly past that first critical year.

Some panelists add bortezomib to lenalidomide during maintenance. “For the translocation t[4;14] patients, we add it,” said Usmani. “The only caveat for bortezomib and lenalidomide in the maintenance setting is considering patients who have not achieved a [very good partial response] before transplant, which tells you that they’re probably not as sensitive to RVD and they’re high-risk,” warned Lonial, noting such patients at his institution receive carfilzomib and pomalidomide maintenance for 3 years. “I think antibodies, though, are going to make the biggest splash in this setting,” he said, indicating that exciting data on such agents are emerging on multiple fronts. “It will be really exciting, over the next 2 to 3 years, to see what we’re going to choose for frontline therapy,” said Martin.

Experts Discuss Strategies for Boosting Frontline Responses in Myeloma

Although drugs that target HER2 have transformed the prognosis for many patients with breast cancer, the development of resistant disease remains a significant clinical challenge. Dual blockade strategies have become a new standard of care for HER2- expressing metastatic breast cancer and have also generated impressive results in earlystage disease.

Now a growing appreciation of the complexities of HER2-positive disease is helping to further carve out a niche for dual blockade in HER2-positive breast cancer, including the possibility of a chemotherapy-free treatment regimen for certain patients. Although increased toxicity is a concern, the looming question for most clinicians and patients is whether insurance providers will cover expensive new combinations. As a result, the most pressing need is to identify patients for whom the benefits justify the cost.

Meanwhile, researchers are also exploring dual HER2 blockade strategies in other malignancies, notably in metastatic colorectal cancer (mCRC), although clinical trial results thus far are limited.

HER2 is a member of a tyrosine kinase receptor family that plays a central role in cell growth, proliferation, survival, and differentiation via multiple signal transduction pathways (Figure). It is overexpressed in many cancers.

An estimated 18% to 20% of breast tumors overexpress the HER2 protein.

 Historically, HER2 overexpression has been associated with an aggressive and metastatic form of breast cancer that has a poor prognosis and a propensity for brain metastases.

 Amplification or overexpression of HER2 is also observed in 10% to 30% of gastric tumors. Additionally, HER2 overexpression is seen in other tumor types, such as ovarian, bladder, lung, and colorectal cancers.

Initial FDA approval for trastuzumab (Herceptin) nearly 2 decades ago marked the beginning of a fruitful foray into targeted therapies for patients with breast cancer. Five drugs employing this approach have now been approved. In addition to trastuzumab, a monoclonal antibody (mAb), the FDA has approved pertuzumab (Perjeta), also a mAb; lapatinib (Tykerb), a small-molecule tyrosine kinase inhibitor (TKI); ado-trastuzumab emtansine (T-DM1; Kadcyla), an antibody—drug conjugate; and neratinib (Nerlynx), a kinase inhibitor.

Thus far, the strategy has had limited success in other tumor types.

 Trastuzumab is also indicated for HER2-positive metastatic gastric and gastroesophageal junction cancer, while afatinib (Gilotrif), an EGFR inhibitor that also targets HER2, is approved for non—small cell lung cancer.

The success of the first-generation drugs in breast cancer has been tempered by the development of resistance in a significant proportion of patients, which limits long-term efficacy. Among possible mechanisms of resistance is the incomplete inhibition of the HER2 pathway, allowing for low levels of signaling to persist. To overcome this type of resistance, numerous studies are now exploring the combination of 2 HER2-targeting drugs with distinct mechanisms of action.

Most ongoing studies of dual HER2 blockade combinations are being conducted in breast cancer settings (Table). Novel combinations include the pairing of T-DM1 with neratinib, the latter of which the FDA approved in July as a single agent for extended adjuvant breast cancer treatment. Additionally, tucatinib, an investigational HER2 inhibitor that may be effective against brain metastases, is being evaluated in combination with T-DM1.

Table. Dual HER2-Targeting Regimens in Clinical Development

Several novel regimens also are under study in CRC, in which HER2 overexpression is typically observed in 3% to 5% of patients. The HERACLES trial combines trastuzumab and lapatinib in patients with heavily pretreated HER2-positive mCRC (NCT03225937). Results presented at the 2017 American Association of Cancer Research Annual Meeting this year showed the combination was well tolerated, with durable responses even among those with as many as 5 previous lines of therapy. The overall response rate was 30% and the clinical benefit rate was 70%.

Among HER2-targeting drugs, pertuzumab has set the pace for dual HER2 blockade strategies. It is approved in combination with trastuzumab and docetaxel for the first-line treatment of patients with HER2-positive metastatic breast cancer and as neoadjuvant therapy for patients with locally advanced or early-stage breast cancer.

Although they are both mAbs, trastuzumab and pertuzumab bind to different parts of the HER2 protein and have distinct effects on HER2 signaling. The portion of the HER2 receptor that protrudes from the cell is made up of 4 subdomains. Pertuzumab binds to domain II, a region that is involved in the dimerization process, and prevents HER2 from being activated by other HER receptors.

Trastuzumab, meanwhile, binds to domain IV, the exact function of which is unknown but which is not involved in receptor dimerization. Trastuzumab has been shown to block ligandindependent HER2 signaling and prevent HER2 cleavage. Both antibodies also induce antibody-dependent cellular cytotoxicity.

Dual targeting of HER2 with these antibodies was evaluated in the phase III CLEOPATRA trial in which 808 patients were randomized to receive trastuzumab and docetaxel with either pertuzumab or placebo. Initial results, which led to the FDA’s approval of pertuzumab in combination with trastuzumab, demonstrated a 6-month improvement in progression-free survival (PFS) in patients treated with dual HER2 blockade compared with the control group (18.5 months vs 12.4 months, respectively; HR, 0.62;

 <.001), with a strong trend toward improved overall survival (OS).

The benefit was confirmed in a final analysis of the trial, in which the level of OS attained was unprecedented in the first-line setting for metastatic breast cancer.

 CLEOPATRA heralded dual HER2 blockade as a new standard of care as firstline therapy for patients with metastatic disease who had not received chemotherapy or prior HER2 therapy in this setting.

Trastuzumab in combination with lapatinib has also been evaluated in phase III clinical trials. While mAbs target the extracellular domain of HER2, TKIs block the intracellular domain and prevent downstream signaling.

Final results of the EGF104900 trial, in which 291 heavily pretreated patients with HER2-positive metastatic breast cancer were randomized to receive lapatinib monotherapy or a combination of lapatinib and trastuzumab, demonstrated significant improvement with the combination in PFS (HR, 0.74; 

 Not all patients benefited, however, including patients with hormone receptor (HR)—positive disease, those with an ECOG performance status of 0 or 1, or those with visceral or brain metastases. Additionally, efficacy came at a cost of greater toxicity, with particular concern over cardiac events.

When T-DM1 became available in 2013, expectations were high that it might replace trastuzumab as the standard of care in the frontline treatment of metastatic HER2-positive breast cancer and allow for a chemotherapy-free treatment regimen. Unfortunately, synergistic activity observed in the preclinical setting did not translate into clinical success. In the phase III MARIANNE trial, 1095 patients were randomized to receive T-DM1 alone, T-DM1 plus pertuzumab, or trastuzumab and a taxane. In both T-DM1 arms, PFS was noninferior, but not superior, to the control arm, although there were fewer discontinuations because of adverse events and health-related quality of life (HRQoL) was maintained for a longer period.

pCR Hints at Improved Survival in the Neoadjuvant Setting

The combination of neratinib with trastuzumab has been evaluated in the phase I FB-8 trial, a single-arm dose-escalation study, and resulted in significant clinical benefit in heavily pretreated patients.

 Similarly, phase Ib trial results for tucatinib in combination with trastuzumab and capecitabine demonstrated encouraging response rates among patients with metastatic breast cancer, including individuals with brain metastases.

 Those results prompted an increase in the projected enrollment in the HER2CLIMB trial testing the same triplet combination (NCT02614794).

In patients with resectable, early-stage disease, the potential of dual blockade has been assessed as both neoadjuvant and adjuvant therapy. As in the metastatic setting, the double antibody combination has proved most effective to date.

The combination of pertuzumab, trastuzumab, and docetaxel was approved by the FDA as a neoadjuvant regimen in 2013 based on the phase II NeoSphere trial. The study enrolled 417 patients who were randomly assigned to 1 of 4 treatment regimens prior to surgery: trastuzumab plus docetaxel, pertuzumab plus trastuzumab with docetaxel, pertuzumab plus trastuzumab, or pertuzumab plus docetaxel.

In the NeoSphere trial, the combination of pertuzumab and trastuzumab with docetaxel was associated with a significant improvement in the pathologic complete response (pCR) rate compared with trastuzumab plus docetaxel, without substantially increased toxicity.

 These results were supported by another phase II trial, TRYPHAENA, which involved 225 patients.

A recently published 5-year analysis of NeoSphere suggested that an improved pCR rate translated into improved PFS and disease-free survival (DFS). Five-year PFS rates were 86% for dual HER2 therapy and 81% for trastuzumab alone, while DFS rates were 84% and 81%, respectively.

The combination of trastuzumab and lapatinib has also been shown to be effective in the neoadjuvant setting, based on the results of the NeoALTTO trial, in which 455 women with operable HER2-positive tumors were randomized to receive either lapatinib or trastuzumab monotherapy or a combination of the 2, followed by paclitaxel, prior to surgery. The pCR was significantly higher with the combination than with trastuzumab alone.

A number of other phase II and phase III studies of this combination in the neoadjuvant setting have been performed. According to a meta-analysis of 767 patients enrolled in 4 neoadjuvant trials, pCR was 55.76% for the combination versus 38.36% for trastuzumab alone (odds ratio [OR]: 1.94; 

 The likelihood of achieving pCR was higher in patients with HR-negative disease. As in the metastatic setting, there was also increased toxicity, including neutropenia and diarrhea.

Meanwhile, the combination of pertuzumab and T-DM1 again was disappointing. In the KRISTINE trial, it failed to improve pCR compared with the standard of care, pertuzumab plus trastuzumab with carboplatin and docetaxel. As in the MARIANNE trial, the T-DM1 regimen was associated with improved toxicity and longer maintenance of HRQoL.

The I-SPY2 trial is using a novel adaptive design to evaluate numerous therapeutic strategies in the neoadjuvant setting in patients with stage II/III breast cancer at 16 sites across the United States and Canada. Two of the treatment arms involve dual HER2 blockade. Interestingly, this trial did demonstrate an improved pCR rate for pertuzumab in combination with T-DM1 of 55% compared with 22% for those who received paclitaxel plus trastuzumab. It should be noted, however, that the trastuzumab-alone arm underperformed and only 30 patients were enrolled in this arm.

The combination of neratinib and trastuzumab is also being evaluated in the neoadjuvant setting. In the phase II FB-7 trial, it resulted in an improved pCR rate compared with the individual drugs.

In the adjuvant setting, enthusiasm for the role of dual blockade has been dampened by the results of the ALTTO trial. An analysis of findings for 8331 patients with operable HER2-positive breast cancer failed to demonstrate that the addition of lapatinib to trastuzumab improved pCR compared with trastuzumab alone. However, 10-year ALTTO follow-up results indicated a benefit of dual HER2 blockade among patients with HR-negative breast cancer.

In the highly anticipated APHINITY trial, 4805 patients with operable, HER2-positive breast cancer were randomized to adjuvant trastuzumab and chemotherapy with either pertuzumab or placebo. In results presented at the 2017 American Society of Clinical Oncology Annual Meeting in June, the trial findings demonstrated a significant reduction in the risk of disease recurrence or death with the dual blockade arm, with no new safety signals. The absolute benefit for the overall study population, however, was relatively small, with an approximately 1% improvement in invasive DFS.

Notably, the effect of dual blockade was most pronounced in patients with HR-negative disease, as in the ALTTO trial, and for participants with node-positive disease, prompting experts to suggest that the regimen be stratified for higher-risk subgroups.

A number of outstanding questions and challenges have arisen as the feasibility of dual HER2 blockade has been explored. As our capacity to understand the genomic underpinnings of cancer has improved, HER2-positive disease has emerged as a heterogeneous group of tumors, with multiple subtypes, in which the efficacy of dual blockade varies.

There are 5 main molecular subtypes of breast cancer, based on the genes they express: luminal A, luminal B, HER2-enriched (HER2-E), triple-negative, and normal-like. About 10% to 15% of breast cancers fall into the HER2-E category and are characterized by high expression of the HER2 gene, as well as low expression of luminal genes, such as the HR genes ESR1 and PGR. However, the HER2-E subtype accounts for only about half of all HER2-positive cases. The other half display high expression of HR genes and are referred to as HER2-positive/HR-positive.

In addition, there is bidirectional cross-talk between the HER2 and estrogen receptor pathways, which can account for resistance to hormonal treatment or HER2-targeted therapies, regardless of the initial HER2 or HR status of the tumor. Thus, dual blockade could be effective in this patient population.

Several studies have demonstrated the benefit of adding HER2-targeted therapy to an aromatase inhibitor (AI) in this type of breast cancer. The phase II PERTAIN study showed that using dual HER2 blockade could improve outcomes even further. Among women with HER2-positive/HR-positive locally advanced or metastatic breast cancer treated with a combination of pertuzumab, trastuzumab, and an AI (anastrozole or letrozole), PFS was extended by more than 3 months compared with trastuzumab and an AI (median PFS, 18.9 months vs 15.8 months; HR, 0.65; 

 = .007). The combination was generally well tolerated, and although adverse events were more common in the triplet arm, the major concern about the potential for increased cardiac toxicity appeared unwarranted.

Historically, the trend in oncology therapeutics has been to add an increasing number of drugs to the standard of care in an attempt to improve efficacy; however, the disadvantages of this approach are skyrocketing costs and increasing toxicity. Several clinical trials of dual HER2 therapy have included arms in which the HER2-targeting drugs were used without chemotherapy; at least a subset of patients appear to benefit from this type of treatment de-escalation.

The greatest promise in this area to date has been in the neoadjuvant setting. In the NeoSphere trial, the pCR rate was 16.8% among patients who were treated with pertuzumab and trastuzumab without chemotherapy. A second trial examining this combination, WGS-ADAPT, included a chemotherapy-free arm and the pCR rate was 33.7%. Patients treated with pertuzumab plus T-DM1 in the KRISTINE trial, meanwhile, achieved a pCR rate of 44%.

The TBCRC006 and TBCRC023 trials specifically examined the use of dual HER2 blockade without chemotherapy in the neoadjuvant setting in patients with HER2-positive breast cancer. The pCR rates in the trials were 27% and 24.2%, respectively.

Although the pCR rate has been higher in the chemotherapy-containing arms in some trials, a deintensification strategy could still prove useful among patients who are not candidates for chemotherapy. The challenge now is to find ways to identify patients who would most benefit. The phase II PAMELA trial is a nonrandomized open-label study designed to evaluate the HER2-enriched subtype as a predictor of response to neoadjuvant dual HER2 blockade.

Patients enrolled in the trial were treated prior to surgery with lapatinib at 1000 mg/day and trastuzumab at 6 mg/kg every 3 weeks for 18 weeks; HR-positive patients also received endocrine therapy according to their menopausal status. The HER2-enriched subtype was a strong predictor of response to dual HER2 blockade without chemotherapy; pCR rates were 40.6% in patients with HER2-enriched tumors compared with just 10% in non—HER2-enriched tumors.

My Cancer Genome. HER2 (ERBB2) overexpression in breast cancer. http://mycancergenome.org/content/disease/breast-cancer/erbb2/238/. Updated October 20, 2014. Accessed July 20, 2017.

Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. 

Gabos Z, Sinha R, Hanson J, et al. Prognostic significance of human epidermal growth factor receptor positivity for the development of brain metastasis after newly diagnosed breast cancer.

2006;24(36):5658-5663. doi: 10.1200/JCO.2006.07.0250.

Iqbal N, Iqbal N. Human epidermal erowth factor receptor 2 (HER2) in cancers: overexpression and therapeutic implications. 

2014;2014:852748. doi: 10.1155/2014/852748.

Siena S, Sartore-Bianchi A, Trusolino L, et al. Final results of the HERACLES trial in HER2-amplified colorectal cancer. Paper presented at: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. http://cancerres.aacrjournals.org/content/77/13_Supplement/CT005.

Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. 

 2012;366(2):109-119. doi: 10.1056/NEJMoa1113216.

Swain SM, Baselga J, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. 

2015;372(8):724-734. doi: 10.1056/NEJMoa1413513.

Blackwell KL, Burstein HJ, Storniolo AM, et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 study. 

 2012;30(21):2585-2592. doi: 10.1200/JCO.2011.35.6725.

Perez EA, Barrios C, Eiermann W, et al. Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: primary results from the phase III MARIANNE study. 

 2017;35(2):141-148. doi: 10.1200/JCO.2016.67.4887.

Jankowitz RC, Abraham J, Tan AR, et al. Safety and efficacy of neratinib in combination with weekly paclitaxel and trastuzumab in women with metastatic HER2-positive breast cancer: an NSABP Foundation Research Program phase I study. 

Hamilton E, Borges VF, Conlin A, et al. Efficacy results of a phase 1b study of tucatinib (ONT-380), an oral HER2-specific inhibitor, in combination with capecitabine and trastuzumab in HER2+ metastatic breast cancer, including patients with brain metastases. Poster presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Poster P4-21-01. http://sabcs16.posterview.com/nosl/i/P4-21-01.

Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial.

2012;13(1):25-32. doi: 10.1016/S1470-2045(11)70336-9.

Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013;24(9):2278-2284. doi: 10.1093/annonc/mdt182.

Gianni L, Pienkowski T, Im YH, et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. 

2016;17(6):791-800. doi: 10.1016/S1470-2045(16)00163-7.

Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. 

2012;379(9816):633-640. doi: 10.1016/S0140-6736(11)61847-3.

Hicks M, Macrae ER, Abdel-Rasoul M, et al. Neoadjuvant dual HER2-targeted therapy with lapatinib and trastuzumab improves pathologic complete response in patients with early stage HER2-positive breast cancer: a meta-analysis of randomized prospective clinical trials. 

 2015;20(4):337-343. doi: 10.1634/theoncologist.2014-0334.

Hurvitz SA, Martin M, Symmans WF, et al. Pathologic complete response (pCR) rates after neoadjuvant trastuzumab emtansine (T-DM1 [K]) + pertuzumab (P) vs docetaxel + carboplatin + trastuzumab + P (TCHP) treatment in patients with HER2-positive (HER2+) early breast cancer (EBC) (KRISTINE). 

 Abstract 500. 2016;34(suppl 15). http://ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.500.

Jacobs S, Robidoux A, Garcia J, et al. NSABP FB-7: A phase II randomized trial evaluating neoadjuvant therapy with weekly paclitaxel (P) plus neratinib (N) or trastuzumab (T) or neratinib and trastuzumab (N+T) followed by doxorubicin and cyclophosphamide (AC) with postoperative T in women with locally advanced HER2-positive breast cancer. 

Abstract PD5-04. 2016;76(suppl 4):PD5-04-PD05-04. doi: 10.1158/1538-7445.SABCS15-PD5-04.

Piccart-Gebhart M, Holmes E, Baselga J, et al. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial. 

 2016;34(10):1034-1042. doi: 10.1200/JCO.2015.62.1797.

von Minckwitz G, Procter MJ, De Azambuja E, et al. APHINITY trial (BIG 4-11): a randomized comparison of chemotherapy (C) plus trastuzumab (T) plus placebo (Pla) versus chemotherapy plus trastuzumab (T) plus pertuzumab (P) as adjuvant therapy in patients (pts) with HER2-positive early breast cancer (EBC). 

 2017;35(suppl; abstr LBA500). doi: ascopubs.org/doi/abs/10.1200/JCO.2017.35.18_suppl.LBA500?af=R.

Arpino G, Ferrero J-M, de la Haba-Rodriguez J, et al. Primary analysis of PERTAIN: A randomized, two-arm, open-label, multicenter phase II trial assessing the efficacy and safety of pertuzumab given in combination with trastuzumab plus an aromatase inhibitor in first-line patients with HER2-positive and hormone receptor-positive metastatic or locally advanced breast cancer. Paper presented at: San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. http://sabcs.org/Portals/SABCS2016/Documents/SABCS-2016-Abstracts.pdf?v=1.

Harbeck N, Gluz O, Christigen M, et al. Final analysis of WGS-ADAPT HER2+/HR+ phase II trial: Efficacy, safety, and predictive markers for 12-weeks of neoadjuvant T-DM1 with or without endocrine therapy versus trastuzumab + endocrine therapy in HER2-positive hormone-receptor positive early breast cancer. Paper presented at: San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX.

Rimawi MF, Mayer IA, Forero A, et al. Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: TBCRC 006. 

 2013;31(14):1726-1731. doi: 10.1200/JCO.2012.44.8027.

Rimawi MF, Niravath PA, Wang T, et al. TBCRC023: A randomized multicenter phase II neoadjuvant trial of lapatinib plus trastuzumab, with endocrine therapy and without chemotherapy, for 12 vs. 24 weeks in patients with HER2 overexpressing breast cancer.

. Abstract S6-02. 2015;75(suppl 9):S6-02-S06-02.

Llombart-Cussac A, Cortes J, Pare L, et al. HER2-enriched subtype as a predictor of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer (PAMELA): an open-label, single-group, multicentre, phase 2 trial. 

2017;18(4):545-554. doi: 10.1016/S1470-2045(17)30021-9.

Although drugs that target HER2 have transformed the prognosis for many patients with breast cancer, the development of resistant disease remains a significant clinical challenge.

Finding the Right Place for Dual HER2 Blockade in Breast Cancer and Beyond

After a decade of little movement in the treatment of advanced hepatocellular carcinoma (HCC), there are promising developments on the horizon, according to recent study findings. These advancements include 1 new drug that was approved earlier this year, 2 agents pending FDA decisions, and later-stage clinical trials for multiple therapies.

The potential for new therapies comes at a time of continuing challenges in the treatment of patients with HCC. It is the second most common cause of cancer deaths across the globe, and the incidence of the disease continues to rise in the United States.

 In 2000, there were 4.4 cases of HCC per 100,000 individuals; this number rose to 6.7 cases per 100,000 in 2012.

 Although treatment for early HCC is often successful, advanced cases usually have a poor prognosis.

“The first systemic therapy with a survival benefit for HCC was introduced literally a decade ago,” said Amit G. Singal, MD, MS, associate professor of medicine, medical director of the Liver Tumor Program, and clinical chief of the Hepatology Division of Digestive and Liver Diseases at University of Texas Southwestern Medical Center in Dallas, in an interview with OncologyLive

. In 2007, the FDA approved sorafenib (Nexavar), a multikinase inhibitor that targets angiogenesis, for the treatment of patients with unresectable HCC.

The drug had previously been approved for patients with renal cell carcinoma and has gained an indication for differentiated thyroid cancer. In HCC, sorafenib provides a median survival and time to radiologic progression that was approximately 3 months longer compared with placebo.

 Unfortunately, this was the last new treatment to be moderately successful for the next 10 years.

“There were many other promising studies, but they all turned out to be negative,” said Tim F. Greten, MD, senior investigator in the Thoracic and Gastrointestinal Oncology Branch and head of the Gastrointestinal Malignancy Section at the National Cancer Institute.

Now, oncologists who treat patients with advanced HCC may have 3 new therapies to administer by the end of this year. In April, the FDA approved regorafenib (Stivarga), a small-molecule multikinase inhibitor, as a second-line treatment for patients with HCC who have previously received sorafenib. The agency is scheduled to decide by September 24 whether to approve a supplemental biologics license application for nivolumab (Opdivo), a PD-1 inhibitor, as second-line therapy for HCC. Additionally, an application is pending for lenvatinib (Lenvima) as a first-line therapy.

Table. Selected Phase III Trials in Hepatocellular Carcinoma

Given the disappointments from earlier trials, most clinicians remain somewhat guarded when considering current phase II studies that appear to have positive results. But there is room for a positive outlook when it comes to several emerging immunotherapy and targeted therapy agents, experts say, and clinical development has rapidly advanced into phase III trials (Table).

The paradigm in HCC treatment started changing last year when the results of the phase III RESORCE trial demonstrated a survival benefit with regorafenib. The drug, which previously was approved for colorectal cancer and gastrointestinal stromal tumors, targets several kinases that promote tumor angiogenesis, such as vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs), along with other kinases. Similarly, sorafenib also targets VEGFRs and PDGFR-beta.

The international, multicenter, randomized, double-blind, placebo-controlled RESORCE study investigated the use of regorafenib among 573 adult patients with advanced HCC who had progressed following treatment on sorafenib.

 The study participants were randomized to receive oral regorafenib at 160 mg once daily during weeks 1 to 3 of each 4-week cycle plus best supportive care (BSC) or placebo plus BSC. The primary endpoint was overall survival (OS), with treatment continuing until disease progression or unacceptable toxicity.

The results showed that patients who received regorafenib had a median OS of 10.6 months compared with 7.8 months for patients who took the placebo (HR, 0.63; 95% CI, 0.50-0.79; 

 <.0001). There was also a statistically significant improvement in progression-free survival (PFS) based on modified RECIST criteria for HCC, with an estimated median PFS of 3.1 months for the regorafenib arm and 1.5 months for the placebo arm (HR, 0.46; 95% CI, 0.37-0.56; 

 <.0001). The overall response rate, also based on modified RECIST criteria, was 11% in the regorafenib arm and 4% in the placebo arm.

Updated findings presented at the 2017 World Gastrointestinal Conference in June revealed that OS was slightly improved over the primary analysis. The median OS with regorafenib was 10.7 months (95% CI, 9.1-12.2) compared with 7.9 months (95% CI, 6.4-9.0) with placebo (HR, 0.61; 95% CI, 0.50-0.75; P <.0001).

Part of the significance of the updated results is that they more clearly show the effects of prolonged treatment with regorafenib, said Jordi Bruix, MD, head of the Barcelona Clinic Liver Cancer (BCLC) group at the University of Barcelona. Using a Swimmer plot to illustrate, he 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.”

Adverse events (AEs) were more prevalent among patients in the regorafenib arm. In the primary analysis, 79.7% of patients in this cohort experienced grade 3 or higher AEs compared with 58.5% percent in the placebo arm, resulting in dose modifications for 68.2% in the regorafenib arm and 31.1% in the placebo arm. However, more deaths occurred in the placebo arm within 30 days of the last treatment (19.7% for placebo vs 13.4% for regorafenib).

The most common grade 3 or higher AEs associated with regorafenib were hypertension, hand-foot skin reaction (HFSR), fatigue, and diarrhea. Other common AEs included pain, decreased appetite, infection, dysphonia, elevated bilirubin, fever, mucositis, weight loss, rash, and nausea.

In the updated analysis, the 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: a median OS of 14.1 months (95% CI, 11.7-16.5) compared with a median OS of 6.6 months (95% CI, 5.0-8.5) for those who did not experience HFSR.7 Overall, the incidence of any-grade HFSR with regorafenib was 53% versus 8% with placebo; grade 3 HFSR incidence was 13% versus 1%, respectively.

There is a strong rationale for pursuing immunotherapeutic strategies in HCC, according to Anthony B. El-Khoueiry, MD, an associate professor of medicine at USC Norris Comprehensive Cancer Center in Los Angeles.

 A growing body of research shows that HCC employs immunosuppressive processes, including the upregulation of inhibitory immune checkpoint molecules and the production of cytokines and myeloid-derived suppressor cells, El-Khoueiry wrote recently in the American Society of Clinical Oncology 2017 Educational Book.

As a result, he said immune checkpoint blockade strategies, notably those targeting the PD-1/ PD-L1 pathway and CTLA-4, have shown promising early results in clinical and preclinical studies. He also noted that cytokine-induced killer cells and other forms of adoptive cell therapies, as well as oncolytic virus therapy, are strategies worth pursuing. Thus far, the PD-1 inhibitor nivolumab is the most advanced immunotherapy in the development process.

“Immuno-oncology seems to have caught the eye of HCC and found an opportunity there that is currently being worked up with several trials, among which nivolumab is one,” said Ghassan K. Abou-Alfa, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, in an interview.

Singal agreed there is reason to be optimistic about upcoming results regarding nivolumab and the field of immunotherapy. “The early data for nivolumab as a second-line agent are very promising, and we are optimistically anticipating final results of the trial.”

The FDA is evaluating nivolumab under its priority review program based on the results of the phase I/II CheckMate 040 trial in which the checkpoint blockade agent provided a durable response with a manageable safety profile as a second-line therapy for patients previously treated with sorafenib.

The trial accrued 262 patients with advanced HCC with or without hepatitis C virus (HCV) or hepatitis B virus (HBV) infection. There were 48 patients in the dose-escalation phase and 214 patients in the dose-expansion phase. Seventy-seven percent of patients in the dose-escalation phase and 68% in the expansion phase had prior sorafenib.

The overall objective response rate (ORR) in the escalation phase was 15% (95% CI, 6%-28%), including 3 complete responses (CRs) and 4 partial responses (PRs). The median duration of response was 17 months (95% CI, 6-24), and the median time to progression was 3.4 months (95% CI, 1.6-6.9). The disease control rate was 58% (95% CI, 43%-72%).

In the expansion group, the ORR was 20% (42/214; 95% CI, 15%-26%), including 3 CRs and 39 PRs. Combining these responses with 96 (45%) patients who had stable disease, the disease control rate was 64% (138/214). The 3 CRs occurred in 2 patients without viral hepatitis and 1 patient with HBV infection. All 3 patients had prior sorafenib.

“This was the first time that any PD-1 inhibitor was tested in an HCC population,” Bruno Sangro, MD, PhD, an investigator on the study, said in an interview. “This is a [difficult] population, because apart from liver cancer, most of these patients have liver cirrhosis.

So, safety was one of the things that we wanted to observe very carefully from the beginning. In this regard, the result that we have observed is that nivolumab has a very similar, or even slightly better, profile in this population compared with what has been observed in other tumor types.”

Sangro, head of the Hepatology Unit in the Internal Medicine Department at Clinica Universidad de Navarra in Spain, said the median OS rate is typically much lower for secondline therapies than the rate observed in the CheckMate 040 trial.

Nivolumab is being evaluated in comparison with sorafenib as a first-line therapy for patients with advanced HCC in the randomized phase III CheckMate 459 study (NCT02576509). Investigators are seeking to recruit 726 patients; global enrollment has been completed but is ongoing for a substudy taking place in China.

While immunotherapy has injected a new modality into the evolving landscape of potential new HCC treatments, researchers are continuing to explore tyrosine kinase inhibitors (TKIs), with some recent successes.

First-line treatment with lenvatinib improved PFS by 3.7 months and was noninferior for OS compared with sorafenib for patients with unresectable HCC, according to results of a phase III trial, involving 954 patients, presented at the 2017 American Society of Clinical Oncology Annual Meeting in June.

In the open-label REFLECT study, or Study 304, the median OS with lenvatinib was 13.6 months compared with 12.3 months for sorafenib (HR, 0.92; 95% CI, 0.79-1.06). The median PFS with lenvatinib was 7.4 versus 3.7 months with sorafenib (HR, 0.66; 95% CI, 0.57-0.77; 

Additionally, the median time to progression was 8.9 months with lenvatinib (95% CI, 7.4-9.2) and 3.7 months with sorafenib (95% CI, 3.6-5.4), representing a 37% reduction in the risk of progression (HR, 0.63; 95% CI, 0.53-0.73; 

 <.00001). The ORR was 24.1% with lenvatinib versus 9.2% with sorafenib (odds ratio, 3.13; 95% CI, 2.15-4.56; 

In July, Eisai Inc announced that it had submitted a supplemental new drug application for lenvatinib as a first-line therapy in HCC, based on the results of the REFLECT trial.

 Lenvatinib also is a multikinase inhibitor that targets angiogenic pathways, including VEGFRs and other processes that promote tumor growth and progression.

Cabozantinib, which inhibits multiple receptor kinases, is another promising agent for HCC that has already been approved by the FDA for the treatment of patients with renal cell carcinoma under the brand name Cabometyx and for medullary thyroid cancer under Cometriq. In preclinical studies, cabozantinib has been shown to suppress MET and VEGFR signaling, and its broad activity has prompted researchers to investigate its potential against multiple tumor types.

Recently published findings of a phase II trial involving 41 patients with advanced HCC showed a median PFS of 5.2 months and OS of 11.5 months, as well as a 78% tumor regression rate, 5% ORR, and reductions in alpha-fetoprotein. More than 70% of the patients had received at least 1 line of prior systemic therapy; 59% had received a prior TKI.

The most common AEs of grade 3 or greater severity included diarrhea (20%), HFSR (15%), thrombocytopenia (15%), hypertension (10%), and transaminase elevation (10%). No dose reductions were reported during the first 12 weeks of the study, although 59% of patients overall reduced their dosage.

After a decade of little movement in the treatment of advanced hepatocellular carcinoma (HCC), there are promising developments on the horizon, according to recent study findings.

Vol. 18/No. 17 | Oncology Live®

AKT Inhibitor May Promote Better Responses to Abiraterone in mCRPC

Experts Discuss Strategies for Boosting Frontline Responses in Myeloma

Finding the Right Place for Dual HER2 Blockade in Breast Cancer and Beyond

HCC Therapies Rapidly Advance After a Decade of Disappointment

Mendelsohn's Antibody Research Reverberates Today

Baylor Team Helps Establish Scalp-Cooling Benefits for Breast Cancer Patients

There's a Growing Need to Look Under the Hood of the Clinical Trial Model