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Just In... Meeting News
Key news updates from recent oncology and hematology meetings.

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Wednesday, October 29, 2014

 

BY MARK FUERST

 

Increases in breast inflammation may explain why women who are obese and postmenopausal have an increased risk of estrogen receptor (ER)-positive breast cancer, according to a new study.

 

Obesity is a well-established risk factor for the development of breast cancer, particularly for ER-positive, menopausal women. “Regardless of the type of breast cancer, obese patients have inferior outcomes compared with their lean counterparts,” said Neil Iyengar, MD, Assistant Attending Physician in the Breast Cancer Medicine Service at Memorial Sloan Kettering Cancer Center. “We previously demonstrated a link between obesity, inflammation, and the aromatase axis in breast tissue, and now we have established the scientific ground work to develop prevention and treatment strategies that target adipose tissue inflammation, and have mechanistic, not just epidemiologic, data that support the association of obesity and breast cancer.”

 

In an earlier study of 30 women, inflammation of fatty tissue was shown to occur in human breasts, with the majority of inflammation in obese women. “We also found an increase in inflammatory markers of cancer cells, and increased estrogen signaling within the breast,” Iyengar, also Associate Physician at Rockefeller University, said in an interview.

 

The team reported the results at the Breast Cancer Symposium of an expansion study to confirm their initial findings and investigate other factors that contribute to inflammation in the breast (Abstract 40). Specifically, the study examined whether menopause and body mass index (BMI) have an independent impact on breast white adipose tissue (WAT) inflammation.

 

Study Details

The team—which also included Patrick Glyn Morris, Xi Kathy Zhou, Ayca Gucalp, Dilip Giri, Michael Harbus, Domenick Falcone, Linda Vahdat, Mahmoud Awad, Margaret Krasne, Kotha Subbaramaiah, Monica Morrow, Clifford Hudis, and Andrew Dannenbergy--prospectively collected data from 237 breast cancer patients, median age of 48, who had mastectomies; 13 women also had abdominal reconstructions. Also examined was fatty tissue from the breast that was not in a cancerous area.

 

The researchers detected WAT inflammation by immunohistochemistry, using the presence of dead or dying adipocytes surrounded by an envelope of macrophages known as crown-like structures of the breast (CLS-B), considered to be a reliable histologic marker of inflammation already used in diabetes to detect adipose tissue inflammation; this was also the inflammatory marker previously detected in the breasts, Iyengar explained in an interview.

 

The inflammatory marker was seen more frequently among overweight/obese patients (those with a BMI of 25 or higher) and postmenopausal patients compared with those with a lean BMI (less than 25) and premenopausal patients.

 

In multivariable analyses, BMI and postmenopausal state were independently associated with the presence of CLS-B. “Some 90 percent of the obese patients and about two-thirds of the postmenopausal patients had fatty inflammation in the breast,” he said. “They have a pro-estrogenic environment that can promote breast cancer. This provides a mechanistic explanation of how obesity is associated with breast cancer.”

 

The most striking finding, he said, was the association of inflammation with postmenopausal status. 


“Independent of BMI, postmenopausal women are more likely to have breast inflammation as opposed to premenopausal women. This suggests that being obese or postmenopausal puts a woman at risk of inflammation of the breast tissue. Those at greatest risk are postmenopausal, obese women, which fits in with epidemiologic data that consistently show that being obese is a risk for postmenopausal breast cancer.”

 

This data suggests that clinicians should tell patients on chemotherapy to maintain their weight without the fear of cancer cachexia, he said.

 

“As we embark on newer treatments for breast cancer, and as cachexia is no longer as prominent for most patients, evolving data supports that we should not tell patients who are overweight to gain weight. More data supports the recommendation to maintain a healthy weight to prevent breast cancer, and that losing weight may also be important if a patient is overweight.”

 

In addition, the study found that inflammation in abdominal fat corresponded with the inflammatory status of the breast. In patients with bilateral breast WAT and abdominal WAT, concordant CLS-B status was found in about three-quarters of the patients. Iyengar said that it would be less burdensome for women in future clinical trials to test prevention techniques if researchers biopsied abdominal fat rather than the breasts.

 

Perplexing Finding

In a perplexing finding, one-third of normal weight women had breast inflammation. “We don’t know why normal weight, lean patients had fatty inflammation of the breast. This is the most vulnerable group of patients. They appear to be healthy, but may be harboring inflammation,” he said, speculating that diet and other environmental factors may play a role.

 

The researchers hope to be able to predict which patients may be most at risk of breast cancer and also to develop clinical trials of prevention and treatment. “Behavioral approaches of tailored exercise prescriptions and weight loss strategies in the obese may reduce inflammation in the breast,” Iyengar said. Anti-inflammatory pharmaceuticals, such as fish oils, may also be therapeutic.

 

Phase II Study

The team has also begun a randomized Phase II study supported by the NCI as part of the MD Anderson Early Phase Chemoprevention Consortium. The goal is to enroll 50 patients and perform biomarker analysis at Weill Cornell. Overweight and obese patients who are six months out from breast cancer treatment and who are now free of cancer will be randomized to receive the omega-3 fatty acid DHA or placebo for three months.

 

“We will assess changes in circulating and tissue markers of inflammation,” Iyengar said.

  

In the near future, the researchers plan to develop a blood test to detect inflammation in the breast. “If we can detect breast inflammation from changes in the abdomen, this may be a systemic process,” he said. He and his colleagues have already identified blood markers of inflammation using a combination of common inflammatory markers and specific metabolites.

 

“Our goal is to provide targets for rational therapies,” Iyengar said.

 

Asked her opinion for this article, Jennifer Ligibel, MD, Senior Physician at Dana-Farber Cancer Institute and Assistant Professor of Medicine at Harvard Medical School, said, “For a long time we have known there is a connection between obesity and an increased risk of developing breast cancer in postmenopausal women. Premenopausal women have a lower rate of breast cancer, but no one knows why. Hypotheses have been estrogen-based. Obese women may have polycystic ovarian disease, which has led to the postulation that there is a difference in estrogen concentration.

 

“This paper provides tantalizing information on the microenvironment where the breast tumor forms and how obesity may affect premenopausal and postmenopausal women.” A high level of estradiol has been related to premalignant changes in animal studies, she added.

 

The structures identified by the researchers are present in both visceral and fatty tissue, and are markers of inflammation, Ligibel continued. “These structures have been correlated with aromatase expression and local estradiol levels. We can’t say how the mechanism works in humans, but it may be part of the chain. We are now learning about the differences in obese versus non-obese women. And for the first time, we see differences in premenopausal and postmenopausal women. If additional pieces fall into place, this mechanism could be the answer to the difference. ”

 

Upcoming Studies on DHA

Upcoming studies on DHA to decrease inflammation may show if there is an impact on these structures and inflammatory markers. “What we don’t know for sure is whether the structures lead to breast cancer. We know they are present and present a higher risk, but we don’t know the cause of the risk,” she said.

 

“We are starting to unravel how obesity affects premenopausal and postmenopausal women in terms of breast cancer risk. This exciting development in breast inflammation adds a piece to the puzzle. We may be able to manage lifestyle in those who already have had cancer. If a woman has had cancer once, she has a high risk of getting cancer again. Lifestyle interventions suggest another mechanism at higher risk of breast cancer. We may be able to intervene and lower that risk.”

 

The next step, she said, is to show a more causal relationship between the structures and breast cancer itself--“If something arose in a more direct response to the structures, that would have significant clinical meaning,” she said.


Tuesday, October 28, 2014

 

BY MARK FUERST

 

A novel immunotherapy peptide vaccine decreases recurrence in HER2-positive (HER+) breast cancer patients among women who received trastuzumab as part of standard treatment, according to a new study.

“Peptide vaccines have been around since the mid-1990s to treat metastatic melanoma and ovarian cancer, but with little success. Our group is one of the first to put forward the hypothesis that peptide vaccines may be more effective in the adjuvant setting after the patient is disease-free to prevent recurrence,” said Elizabeth Mittendorf, MD, Associate Professor in the Department of Surgical Oncology at the University of Texas MD Anderson Cancer Center.

Despite improvements in breast cancer care, up to 20 percent of patients eventually have recurrences. “This suggests that novel therapeutic strategies are necessary, including an immunotherapy approach to mobilize the patient’s own immune system against the cancer,” she said.

She and colleagues at MD Anderson have been examining CD8+ T-cell eliciting vaccines given in the adjuvant setting after surgery, chemotherapy, and chemo-radiation with the goal of preventing disease recurrence. Peptides derived from tumor-associated antigens are combined with an immunoadjuvant, such as granulocyte macrophage colony stimulating factor (GM-CSF), to form a vaccine.

“Peptide vaccines have the benefit of being easy to construct and manufacture on a large scale, they are inexpensive, and are ‘off the shelf’ therapy exportable to the community,” she said. The vaccine is administered as a simple intradermal inoculation. The vaccine is not designed to replace therapy but rather as “an add-on with hopes of preventing recurrence,” she emphasized.

E75

The most studied of the HER2-derived peptide vaccines is E75 (nelipepimut-S), or NeuVax. In Phase I and II trials, the vaccine was shown to be safe and capable of stimulating an antigen-specific immune response, with evidence of clinical benefit. The five-year analysis of the Phase I optimal dose of the vaccine showed increased disease-free survival compared with controls.

Mittendorf noted that a Phase III international registration trial is now ongoing, with accrual almost complete.

She explained that the GP2 vaccine is a 9 amino acid peptide from the transmembrane domain. It stimulates the CD8+ T-cell response and is a subdominant epitope -- that is, it is not naturally processed by the immune system, which make it less likely the patient has developed tolerance. A Phase I trial has demonstrated that the vaccine is safe and capable of stimulating a HER2-specific immune response.

At the most recent Breast Cancer Symposium, Mittendorf presented the results of a Phase II trial that included 190 women, median age of 51, with histologically confirmed breast cancer, either node positive or high-risk node negative disease of any level of HER2 expression (Abstract 134).

The women received a simple intradermal injection of the vaccine plus GM-CSF (89 patients) or GM-CSF alone (91 patients) once a month for six months, and then injections every six months as a booster out to three years. The patient characteristics were well-matched between the two groups.

The MD Anderson researchers predicted that the vaccine would decrease recurrence rates when administered in an adjuvant setting after completion of standard-of-care therapy. Patients who received the vaccine had a significant increase in in-vivo antigen-specific immune response.

After a median follow-up of 34 months, the disease-free survival rate was 88 percent in the vaccine group and 81 percent in the control group, a 37 percent risk reduction. Eight patients had early recurrence or developed a second malignancy and did not complete the vaccine trial.

After excluding these patients, the disease-free survival per treatment showed an even more significant difference: 94 percent in the vaccine group and 85 percent in the control group, a 57 percent risk reduction.

The majority of patients experienced mild side effects, including erythema and pruritus at the injection site, fatigue, and bone pain that was relieved by acetaminophen, she said. “The toxicity of vaccinated patients is comparable to that of controls, suggesting that toxicity is due to the GM-CSF adjuvant. The vaccine is very well-accepted by clinicians and patients because it is well-tolerated. We can’t ask patients to take something that is toxic.”

Combination Immunotherapy

Combination immunotherapy in the current trial investigated sequential use of trastuzumab plus vaccine. There were two early recurrences, and one second malignancy in less than six months, she reported. Women with HER2 +3 who were administered trastuzumab as part of the standard of care prior to receiving the vaccine experienced no cases of cancer recurrence. “Concurrent use of the vaccine with trastuzumab may address these early recurrences,” Mittendorf said, noting that a Phase I trial of concurrent-use NeuVax also showed the vaccine combination to be safe with no increase in either local or systemic toxicity.

She speculated that trastuzumab may act as a primer for the vaccine by stimulating CD4+ T cells to initiate an antigen-specific antibody response. Other potentially immune-mediated mechanisms of action in play include antibody-dependent cellular cytotoxicity and HER2-specific humoral (antibody) response.

The researchers are now set to begin enrolling patients into a Phase II trial in high-risk HER2+ breast cancer patients, who will receive a combination of trastuzumab plus the GP2 vaccine. The plan is to enroll 100 patients who did not achieve a complete response after neoadjuvant chemotherapy plus HER2 targeted therapy -- “These patients tend to have a three-year disease-free survival rate of about 80 to 85 percent.

“We think we can improve that by administering the vaccine,” she said. The goal is to confirm the efficacy signal and then design a larger Phase III trial.

In conclusion, Mittendorf said. “The GP2 vaccine is safe and capable of stimulating an immune response. In HER2+ patients who complete the primary vaccination series after standard-of-care trastuzumab, there have been no recurrences. Combination immunotherapy with trastuzumab and CD8+ T-cell-eliciting vaccine warrants further investigation.”

She noted that practicing oncologists are aware of the enthusiasm of immune therapy in general: “Melanoma is not the only tumor that can be positively impacted by immunotherapy. Breast cancer can be targeted in this way as well. We hope the vaccine strategy will be effective in the adjuvant setting. This is critical for breast cancer clinicians to help them identify the appropriate strategy based on subtype and disease stage.

In the adjuvant setting, we can’t submit breast cancer patients to toxic immunotherapy, such as CAR T-cells. In the metastatic setting, a more aggressive strategy may be more tolerated. We believe many more patients will benefit in some way from immunotherapy. The challenge will be identifying the right immunotherapeutic approach for each individual patient. When doctors are able to do that, cancer therapy, and immunotherapy specifically, will follow a more personalized approach.”


Monday, October 27, 2014

BY AXEL GROTHEY, MD

Professor of Oncology

Division of Medical Oncology

Mayo Clinic Rochester

 

The 2014 ESMO Congress in Madrid saw several interesting presentations on colorectal cancer which will influence clinical practice. This included several trials on maintenance therapy after induction treatment, head-to-head comparisons between bevacizumab and cetuximab in first-line therapy, and data on new agents in this disease.

 

Maintenance Therapy

Over the last years several studies have investigated the role of maintenance therapy after an oxaliplatin-based induction phase as component of first-line therapy for metastatic colorectal cancer (mCRC). Investigating maintenance therapy in mCRC emerged as a question of high clinical relevance due to the cumulative toxicity of oxaliplatin which limits its duration of therapy and the realization that prolonged duration of bevacizumab therapy is associated with improved outcomes.

 

Since 2013, data from various clinical trials have been published or presented, most prominently the Dutch CAIRO-3, the German AIO KRK0207, and the French DREAM trials. The Dutch and German trials both utilized a fixed number of oxaliplatin-based induction therapy cycles before patients who had at least stable disease after induction therapy were randomized to maintenance treatment versus observation. Both trials used the time to progression after reintroduction of therapy after maintenance as the primary endpoint, but differed in other key characteristics.

 

While the CAIRO-3 trial used only 18 weeks of induction therapy and randomized patients to maintenance with low-dose continuous capecitabine plus bevacizumab, AIO 0207 subjected patients to a planned 24 weeks of induction (equivalent of 12 cycles of FOLFOX) and then proceeded with a three-arm randomization: fluoropyrimidine plus bevacizumab, bevacizumab alone, or observation.

 

The consensus of the studies was that maintenance therapy -- in particular, a combination of fluoropyrimidine plus bevacizumab -- is able to significantly delay tumor progression, with a hazard ratio (HR) of around 0.45, thereby doubling the time to progression compared with no therapy. While no significant effect on overall survival has yet been documented – likely due to the design of the trials and the availability of several subsequent lines of therapy – maintenance therapy with a fluoropyrimidine plus bevacizumab can be considered as one of the standards of care for clinical practice.

 

A somewhat surprising result was presented by the DREAM study which randomized patients after any investigator-defined bevacizumab-containing induction therapy to bevacizumab alone or a combination of bevacizumab and erlotinib, an oral EGFR inhibitor. In this trial of about 450 patients, the combination arm was superior to the bevacizumab single-agent treatment in terms of progression-free (PFS) and overall survival (PFS: HR 0.77, OS: HR 0.79, respectively).

 

The absence of a “standard” control arm (e.g., fluoropyrimidine plus bevacizumab), the heterogeneity of the induction treatments, and the observed toxicities (skin, diarrhea) will not allow us to embrace a combination of bevacizumab and erlotinib in clinical practice at this point without the data of confirmatory studies.

 

Key Message: After induction chemotherapy with an oxaliplatin-based first-line treatment in metastatic colorectal cancer, maintenance therapy with a fluoropyrimidine plus bevacizumab can be considered as one of the standards of care for clinical practice.

 

Head-to-Head Comparison between Cetuximab and Bevacizumab in First-Line Metastatic Colorectal Cancer with expanded RAS Mutation Testing

The most hotly debated topic in mCRC over the last year has been the results of trials comparing EGFR antibodies and bevacizumab added to a chemotherapy backbone head-to-head. The first phase III trial to present outcomes results was the German/Austrian FIRE-3 study, which compared FOLFIRI + bevacizumab with FOLFIRI + cetuximab as first-line therapy in 582 patients with KRAS exon 2 wild-type mCRC.

 

The rather unusual primary endpoint of this phase III study was investigator-assessed response rate (RR), which showed no difference between cetuximab and bevacizumab in the intent-to-treat analysis. Thus, the study was negative for its primary endpoint and it also did not show a difference in PFS. Surprisingly, though, the overall survival curves split after about two years -- meaning more than a year after progression on first-line therapy -- and the difference in OS eventually reached statistical significance in favor of the cetuximab arm (median OS of 25.0 vs.  28.7 months, HR 0.77, p=0.017).

 

When patients with any RAS mutation beyond KRAS exon 2 were further excluded (15% of the KRAS exon 2 wild-type population), the results for RR and PFS were rather unchanged, but the difference in OS widened in favor of cetuximab (25.6 vs. 33.1 months, HR 0.70, p=0.011). These unexpected results warranted validation by a separate, adequately powered trial to determine if the OS difference observed in FIRE-3 in spite of identical PFS for the treatment arms could be confirmed.

 

The US Intergroup trial CALGB/SWOG 80405 had a very similar trial design as FIRE-3. Cetuximab or bevacizumab was added to an investigator-chosen chemotherapy backbone (70% FOLFOX, 30% FOLFIRI) as first-line therapy in 1137 patients KRAS exon 2 wild-type mCRC. Preliminary data presented at ASCO 2014 had already shown that for this patient population no statistical outcomes difference was observed for PFS and OS, independent of the underlying chemotherapy regimen.

 

At ESMO 2014, this analysis was greatly extended and now also included an “all-RAS” mutational analysis, which further refined the patient population and which could potentially derive benefit from EGFR monoclonal antibodies. Again, no difference in time-related endpoints, PFS and OS was observed, independent of the chemotherapy backbone. Median OS for the bevacizumab arm was 31.2 months compared with 32.0 months in the cetuximab arm (HR 0.9, p=0.40). CALGB/SWOG 80405 did demonstrate a higher RR associated with cetuximab, mirroring the updated results of FIRE-3 presented at ESMO in form of an independent review of response.

 

Overall, the outcome results of FIRE-3 and 80405 were remarkably similar in almost all criteria, with the notable exception of the performance of the bevacizumab arm in FIRE-3. A pooled analysis of both trials including data on subsequent lines of therapy after first-line progression is planned to determine factors influencing the optimal treatment strategy for patients with mCRC.

 

At this point in time, the use of bevacizumab or cetuximab added to either FOLFOX or FOLFIRI can be considered as practice standard of care in patients with RAS wild-type mCRC. The results also highlight the importance of implementing comprehensive RAS mutation testing for mutations in exons 2, 3, and 4 of KRAS and NRAS before patients get exposed to EGFR monoclonal antibodies. This mandate has recently been integrated into NCCN guidelines (2015 v2).

 

Key message: The use of bevacizumab or cetuximab added to either FOLFOX or FOLFIRI can be considered as practice standard of care in patients with RAS wild-type mCRC.

 

New Agents in Colorectal Cancer

In 2012, regorafenib, an oral multikinase inhibitor, was approved as salvage therapy for patients with mCRC who had received prior therapy with a fluoropyrimidine, oxaliplatin, irinotecan, a VEGF-inhibitor, and – if KRAS wild-type, an EGFR antibody. The pivotal CORRECT phase III study demonstrated a benefit of regorafenib versus placebo with HRs of 0.77 for OS and 0.49 for PFS. Questions have been raised about whether the moderate gain in median OS for the overall study group of 1.4 months justified the use of this agent given its side-effect profile with a high rate of hand-foot skin reaction and fatigue. It had been speculated whether less heavily pretreated patients might derive a greater benefit from regorafenib.

 

At ESMO 2014, a confirmatory phase III study of single-agent regorafenib in a later-line setting was presented. The CONCUR study randomized 214 patients in Asia 2:1 to regorafenib or placebo. Only 60 percent of these patients had received prior therapy, including biologic agents, compared with 100% of patients in CORRECT.

 

In CONCUR, outcomes data favored regorafenib more strongly than in CORRECT with a difference in median OS of 2.5 months (median OS 8.8 vs 6.3, HR 0.55) and a PFS HR of 0.31 -- both results being highly statistically significant. While regional differences could play a role in these results, it can be speculated that patients who are exposed to regorafenib earlier in their lines of therapy might derive a larger benefit, which could make the side-effect profile more worthwhile. Further studies are warranted to validate this hypothesis.

 

A lot of emphasis has been placed in the last decade on developing novel targeted agents in oncology overall and in colorectal cancer in particular. In contrast, very little focus has been placed on conventional cytotoxic agents. This trajectory changed to some extent with the presentation of convincingly positive phase III data of a new oral cytotoxic agent, TAS-102, a fluorinated thymidine, which inhibits DNA replication.

 

The RECOURSE trial mirrored the CORRECT trial on regorafenib in many aspects with regard to statistical assumptions, 2:1 randomization against placebo, and the treatment-refractory patient population it targeted. This worldwide trial included 800 patients and demonstrated a significant differences in OS, the primary endpoint, for the use of TAS-102 (median OS 7.1 vs 5.3 months, HR 0.68, p<0.0001) as well as improvement in PFS (HR 0.48).

 

Interestingly, the shape of the PFS curve was almost superimposable on the PFS curve associated with regorafenib in the same clinical setting. Again, similar to regorafenib no relevant tumor shrinkage by RECIST criteria was observed. The toxicity profile of TAS-102, however, differed greatly from that of regorafenib since no skin toxicity and only a little fatigue was noted. The most prominent side-effect was neutropenia with, however, only a few patients experiencing neutropenic fever.

 

TAS-102 is currently being evaluated by regulatory agencies. It is expected to obtain FDA approval in 2015 and will enrich our armamentarium of active agents against advanced colorectal cancer. Its relatively benign side-effect profile could conceivably lead to efforts to integrate TAS-102 as fluoropyrimidine in combination regimens with oxaliplatin and irinotecan.

 

Key messages: Regorafenib might provide more benefit in less heavily pretreated patients with colorectal cancer. TAS-102 will likely soon obtain approval as salvage therapy option in patients with metastatic colorectal cancer.


Friday, October 24, 2014

BY REBECCA SUK HEIST, MD, MPH

Assistant Professor

Department of Medicine

Harvard Medical School;

Assistant Professor in Medicine

Massachusetts General Hospital Cancer Center

 

A common theme among the presented abstracts in the Development Therapeutics section at the European Society for Medical Oncology Congress was the importance of biomarker selection and target validation, and the complexity of targets across different diseases.

 

Updated results of the Phase 1 study of AD9291 in patients with EGFR TKI resistant NSCLC were presented.  AZD9291 is an oral irreversible inhibitor of both sensitizing EGFR mutations and the T790M resistance mutation. No dose-limiting toxicities were reported in any of the dose-escalation cohorts. The most common adverse events (AEs) were diarrhea and rash, most of which were grade 1-2 events. 

 

The confirmed overall response rate (RR) in patients with T790M-positive tumors was 61 percent, with a disease-control rate of 95 percent. The preliminary median duration of response was 8.2 months, and preliminary median progression-free survival was 9.6 months.

 

In discussing the abstract, Dr. Emiliano Calvo noted that sparing the wildtype EGFR improves the toxicity profile of the third-generation EGFR inhibitors, with less rash and diarrhea than seen with erlotinib. While CO-1686 also has the AEs of hyperglycemia and some QT prolongation, the response rates reported for both these third-generation compounds are similar and seem to point a way towards registration in a molecularly defined cohort of patients.

 

The development of these third-generation EGFR inhibitors has marked an important advance in EGFR-directed therapy, as the hurdle of effective therapy for resistant disease mediated by T790M, the most common resistance mechanism, is finally starting to be cleared. Unanswered questions in this field include whether starting EGFR-directed therapy with a third-generation inhibitor, versus sequencing after first-line EGFR inhibition, will yield better overall survival results.

 

In addition, emergence of resistance after third-generation inhibitors and the mechanism of that resistance will be important to assess.

 

RDX-101 is an oral ATP competitive inhibitor of TrkA, B, C, ROS1, and ALK. Trk rearrangements are seen in one to three percent of patients with NSCLC, 10 percent of patients with papillary thyroid cancer, and one percent of patients with colorectal cancer.  A dose-escalation study enrolled patients with advanced solid tumors with alterations in Trk, ROS, or ALK. Thus far 25 patients have been treated; the most common AEs that were possibly drug related were paresthesia, nausea, diarrhea, asthenia, myalgia and dysgeusia. There were no dose-limiting toxicities reported thus far.  There was a signal of antitumor activity seen with responses in ALK and ROS1 translocated cancers.

 

One patient with colorectal cancer and TrkA translocation had a partial response, the first report of a response to a TRK inhibitor in a patient with Trk alteration. It remains to be seen whether the Trk alterations will be an indication of a truly oncogene addicted pathway similar to ALK and ROS1. 

 

While targeting an oncogene-addicted pathway can yield great success, clearly many oncogenic pathways are complex and further refinement is needed. Data from the Phase 1b trial of BYL719, thePI3K-alpha selective oral inhibitor, and the phase 1b trial of MSC2156119J, a c-met inhibitor, were presented. 

 

In the phase 1b trial of BYL719, the PI3K-alpha selective oral inhibitor, the maximum-tolerated dose (MTD) was established at 150 mg bid, with the most common drug related AEs being hyperglycemia, nausea, diarrhea, decreased appetite, fatigue, and stomatitis. Fifteen of 131 evaluable patients had PR, including two out of 24 patients with PIK3CA-altered ER-positive breast cancer. 

 

In the phase 1b trial of MSC2156119J, an MTD was not reached; the recommended Phase 2 dose (RP2D) of MSC2156119J was established at 500 mg qd based on pharmacokinetic and pharmacodynamic data.

 

Most common AEs included lipase and amylase elevations, LFT elevations, and nausea/vomiting. While the overall response rate was low, there was correlation of response with met overexpression and amplification.

 

In discussing these abstracts, Dr. Manuel Hidalgo made the point that the waterfall plots for these agents as single agents do not look similar to waterfall plots seen in clearly oncogene-addicted targets, such as vemurafenib activity in BRAF-mutated melanoma as a counterpoint. The development path forward might include refining target selection and better understanding of co-mutations and their effects on target inhibition and response, as well as exploring combination strategies with other agents that might yield synergy.

 

One interesting example of a combination that yielded synergy was presented by Dr. Steven Isakoff, who reported results of the phase 1b trial of the AKT inhibitor ipatasertib in combination with paclitaxel in advanced solid tumors. The study established the MTD of ipatasertib at 400 mg qd (21/7) with paclitaxel 90 mg/m2 d1, 8, 15 of a 21-day cycle, well tolerated with manageable and expected AEs of fatigue, diarrhea, and hyperglycemia. 

 

Intriguingly, PRs were seen in a variety of solid tumors, predominantly breast but also bladder and salivary cancers. Mutations in PI3K or AKT seemed to be associated with higher response. Responses were seen even among several patients who had had prior PI3K-inhibitor therapy or paclitaxel therapy, suggesting that the combination of ipatasertib with paclitaxel is able to overcome resistance in this setting. 

 

Biomarker Selection

As we focus on biomarker selection, it is also important to note that biomarkers should be informative and non-redundant.  Dr. Yuqiu Jiang presented biomarker analysis of the PALOMA1/TRIO18 trial. In Part 1 of this phase 2 study, 66 patients with ER+/Her2- breast cancer were randomized to treatment with palbociclib and letrozole versus letrozole alone; in Part 2, 99 patients with ER+/Her2- breast cancer with CCND1 amplification and/or loss of p16 were randomized to treatment with palbociclib and letrozole versus letrozole alone. PFS was significantly improved in the combination arm in both Part 1 and Part 2.

 

Analysis of the patients in Part 1 was performed to assess for CCND1 amplification and p16 loss. Both biomarker-positive and -negative patients benefited from the combination therapy. Jiang noted that these biomarkers are highly correlated with ER status. Further refinement beyond ER status may not actually be necessary in this scenario.

 

Overall the abstracts yielded interesting insights into the changing landscape of early-stage development trials.  There is clearly much progress being made, especially when a validated biomarker for response can be identified. 

 

Identification of these biomarkers remains a key element of drug development, but there is a great deal of complexity and heterogeneity across different molecular pathways and disease types.

 

///////////////////////////////////////////////////////////// 

 

Abstracts Discussed

·    Yang J, Kim D, Planchard D et al. Updated safety and efficacy from a phase 1 study of AZD9291 in patients with EGFR TKI resistant non-small cell lung cancer.

·    De Braud F, Pilla L, Niger M, et al. RXDX-101, an oral pan-trk, ROS1, and ALK inhibitor, in patients with advanced solid tumors with relevant molecular alterations.

·    Juric D, Burris H, Schuler M, et al. Phase 1 study of the PI3Ka inhibitor BYL719, as a single agent in patients with advanced solid tumors.

·    Falchook G, Hong D, Amin H, et al. First in human phase 1 trial assessing the highly selective c-met inhibitor MSC2156119J in patients with advanced solid tumors.

·    Isakoff S, Infante J, Juric D, et al.  Phase 1b dose escalation study of the akt inhibitor ipatasertib with paclitaxel in patients with advanced solid tumors.

·    Jiang Y, Randolph S, English P, et al. Cell cycle biomarker analysis from the PALOMA-1/TRIO18 palbociclib plus letrozole phase 2 study in ER positive HER2 negative advanced breast cancer.


Friday, October 24, 2014

 

BY SARAH DIGIULIO

 

New randomized controlled clinical trial data have found that post-vascular phase contrast-enhanced ultrasonography was superior to B-mode ultrasonography for detecting smaller hepatocellular carcinomas (HCCs) for patients with liver cirrhosis, according to a plenary paper presented at the International Liver Cancer Association Annual Conference. In addition, the contrast-enhanced ultrasonography method was found to be able to confirm the presence of tumor cells, which eliminates the need for the more expensive follow-up CT and MRI testing currently used to confirm B-mode ultrasound findings.

           

“Using conventional B-mode ultrasound, it is very difficult to pick up small lesions because of background coarse liver parenchyma due to cirrhosis,” the study’s lead author, Masatoshi Kudo, MD, PhD, Professor and Chairman at the Department of Gastroenterology and Hepatology of Kinki University School of Medicine and President of Kinki University Medical School, said via email.

 

“On the other hand, using a contrast agent makes it very easy to find very small defects in the Kupffer cells—the examiner only needs to pick up the black lesions in the background white liver.”

           

Study Details

The trial randomized 622 patients with liver cirrhosis associated with hepatitis B virus or hepatitis C virus to receive B-mode ultrasound or contrast-enhanced ultrasound. Patients in the latter group had contrast-enhanced ultrasound performed 30 to 40 minutes after intravenously receiving Sonazoid, a contrast agent that enables dual-phase imaging during both the vascular and post-vascular phases. For both groups, ultrasound was performed every three to four months.

           

The efficacy of Sonazoid had been established in a pilot study that was previously published by Kudo and his colleagues in The American Journal of Gastroenterology (2011:106;368-370).

           

Over the 46-month follow-up period (median 974 days), HCC was found in 95 patients, with the tumor size at first detection being 16.7 millimeters for the patients who had been screened with B-mode ultrasound and 13 millimeters for patients who had been screened with contrast-enhanced ultrasound. The median period of initial detection of HCC was 297.5 days for the group screened with B-mode ultrasound and 346.5 days for the contrast-enhanced ultrasound group--not a significant difference, Kudo noted. 

           

The data also found that the presence of HCC was confirmed for 65.4 percent of the patients whose tumors had been detected with B-mode ultrasound versus 100 percent of the patients who had been screened with contrast-enhanced ultrasound.

 

Barriers to Implementation

Kudo called the study findings conclusive and noted that they are well-accepted in Japan already. “The problem is that the contrast agent Sonazoid is approved only in Japan, Korea, Taiwan, China, and Norway—but not in all European countries or in the U.S,” he said.

           

Asked to comment for this article, Donald N. Di Salvo, MD, Director for Ultrasound Imaging at Dana-Farber Cancer Center and Associate Professor of Radiology at Harvard Medical School, said that currently there is no consensus for which screening method should be considered standard of care: “If you look at the international hepatology societies, they are all over the map.”  

           

Di Salvo spent six months practicing in Italy where contrast-enhanced ultrasound is approved and widely used—and said he considers the screening method to be far superior to B-mode ultrasound. But in the U.S., he noted, it is currently thought of as a “secondary modality” because there is widespread availability of other modalities for screening, including B-mode ultrasound and CT and MRI screening. He was also involved in industry trials in the U.S. that have supported the method’s efficacy. But, he said: “We’re still waiting for FDA approval.”

           

One challenge for wider adoption of contrast-enhanced ultrasound is that the screening requires the physician be in the room with the patient while the test is being done to read the results, rather than the situation for B-mode ultrasound or other CT or MRI testing—for which technologists perform the test and send the physician the results to read, Di Salvo explained—“I think that’s part of the reason it’s been delayed.”

           

But, the test takes only five to 10 minutes, he added. “So that’s a minor potential drawback. I’m convinced by the studies I’ve seen that have come out of the countries that use it that it is definitely a very valuable tool, and I think it will ultimately become approved.”