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PGx Highlights from the American Society of Clinical Oncology's 2012 Meeting

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The American Society of Clinical Oncology held its annual meeting June 1-5 in Chicago. The following are abstracts presented at the meeting focused on pharmacogenomically guided treatment strategies.


PACE: A pivotal phase II trial of ponatinib in patients with CML and Ph+ALL resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation

An international research team working with Ariad Pharmaceuticals, led by Jorge Cortez of the University of Texas MD Anderson Cancer, presented data from the ongoing PACE trial suggesting that Ariad’s investigational pan-BCR-ABL inhibitor ponatinib has "substantial activity in heavily pretreated patients and those with refractory T315I," according to the group's presentation abstract.

PACE is evaluating ponatinib in chronic myelogenous leukemia patients and Philadelphia-positive acute lymphoblastic leukemia patients resistant or intolerant to dasatinib (Bristol-Myers Squibb's Sprycel) or nilotinib (Novartis' Tasinga), or with the T315I mutation of BCR-ABL. Enrollment in the trial completed last September and the team's presentation represented data collected as of January.

Overall, the study tracked response in 449 patients. Cortez said in his presentation that only 18 patients, or about four percent, died while on ponatinib, and only five of these deaths were possibly related to the study drug.

Of those patients with chronic phase CML, 54 percent achieved a major cytogenetic response overall, and among only those with the T315I mutation, 70 percent had major cytogenic response.

In patients with accelerated phase CML, 58 percent reached a different endpoint of major hematologic response. Among patients with blast phase CML and Ph+AML, about 34 percent had major hematologic response, the group reported.

Overall, response increased over time and was durable, according to the presentation. Cortez said the researchers project that 93 percent of patients will continue to have major cytogenetic response at the one-year mark.

A multivariate analysis suggested that only dosage had statistically significant association with response.

Most adverse events reported were grade one or grade two, according to Cortez's presentation. The group reported that 64 percent of patients remained on therapy and the most frequent reasons for discontinuation were progression — in 12 percent of patients — and adverse events in another 10 percent.


VEGF polymorphism may be associated with overall survival in lapatinib-treated breast cancer patients with brain metastases

A team of GlaxoSmithKline researchers led by Colin Spraggs, senior director of genetics research, shared results of a study evaluating patients with metastatic breast cancer for genetic variants associated with their response to GSK's lapatinib (Tykerb), a dual HER2/EGFR tyrosine kinase inhibitor. The study found that a germline variant in VEGF-A may be associated with survival outcome in MBC patients with brain metastases who are treated with lapatinib, the group reported.

Lapatinib is approved in combination with capecitabine or letrozole for patients with HER2+ metastatic breast cancer. The researchers tested samples from more than 200 patients from two clinical trials for 55 functional SNPs in 24 candidate genes, looking for associations between SNPs and either progression-free survival or overall survival during lapatinib treatment.

The researchers did not find any SNPs significantly associated with progression-free survival, but did identify a C>T SNP in VEGF-A that was significantly associated with overall survival in patients who carried the T allele in one of the two study cohorts. However, the association was not seen in the second cohort, the group reported.

The researchers wrote in their abstract that the finding "may represent activation of VEGF angiogenic pathways to overcome HER2 inhibition in patients carrying the higher expression genotype." The association requires confirmation in an independent dataset, the group concluded.


A neoadjuvant, randomized, open-label phase II trial of afatinib (A) versus trastuzumab (T) versus lapatinib (L) in patients (pts) with locally advanced HER2-positive breast cancer (BC)

Researchers from Boehringer Ingelheim and a number of academic institutions, led by Mothaffar Rimawi of Baylor College of Medicine, presented data from an open-label phase II trial comparing monotherapy using Boehringer's afatinib, Roche's Herceptin (trastuzumab), or GlaxoSmithKline's Tykerb (lapatinib) in patients with HER2-positive breast cancer in a preoperative setting.

Overall, afatinib compared favorably to the approved agents in the small study, "albeit at a slightly higher rate of [adverse events]," the researcher wrote in their abstract.

Afatinib showed a high objective response rate. The group reported that the trial screened 73 patients and randomized and treated 29. The best objective responses during treatment were 80 percent, 75 percent, and 36.4 percent in the patients treated with afatinib, trastuzumab, and lapatinib, respectively.

Seven of the patients given afatinib (70 percent) showed partial response, while six of those on lapatinib (75 percent) and only four of those on trastuzumab (36 percent) reached the same response level, the group reported. Another 20 percent of those on afatinib, 12 percent of those on lapatinib, and 54 percent of those on trastuzumab maintained stable disease. No patients on afatinib progressed, while one in each of the other groups did show progressive disease.

All afatinib-treated patients had some adverse events, while only 75 percent of lapatinib-treated patients, and 45 percent of trastuzumab-treated patients, suffered events.

"Further trials will be needed to identify the potential role of [afatinib] as a single agent or in combination with other agents in HER2-positive [breast cancer]," the researchers wrote.


Impact of PIK3CA mutations and p95HER2 expression on the outcome of HER2-positive metastatic breast cancer patients treated with a trastuzumab-based therapy

Researchers led by Andrea Fontana from the Azienda Ospedaliero-Universitaria in Italy have retrospectively evaluated how well HER2-postive metastatic breast cancer patients harboring PIK3CA gene mutations and p59HER2 expression respond to Herceptin-based therapy.

They presented a study involving 107 HER2-positive metastatic breast cancer patients who had received treatment for their disease in the last decade with a number of agents, including Genentech's HER2-targeted breast cancer drug Herceptin (trastuzumab).

"Currently, no biomarkers of trastuzumab clinical resistance have been validated," Fontana and colleagues wrote in an abstract. "The aim of this pilot study was to evaluate the impact of PIK3CA mutations and p95HER2 (pHER2 truncated form) expression on the efficacy of a trastuzumab-based therapy in HER2-positive metastatic breast cancer patients."

The study authors performed molecular analysis on 70 tumor samples. "The IHC expression of p95HER2 was evaluated by a monoclonal antibody that specifically recognizes only the HER2 external domain; the HER2 integrity was defined by the presence of a homogeneous membrane staining (moderate or intense) in at least 30 percent of the cells, otherwise the HER2 was defined as p95HER2 positive," the researchers described in the abstract. "PIK3CA mutations in exons 9 and 20 were detected by automated sequencing."

The investigators then analyzed the correlation between the molecular profile of the patients' tumors and their time to progression and overall survival after being treated with a trastuzumab-containing regimen.

In the study, 42 percent of the tumor specimens were p95HER2 positive and 22 percent had PIK3CA mutations. Patients with p95HER2 positive tumors had a shorter time to progression and overall survival compared to the overall population, but this wasn't a statistically significant finding. Meanwhile, patients harboring PIK3CA mutations had a worse time to progression and overall survival compared to the overall population.

"These preliminary results suggest a possible role of PIK3CA mutational status in predicting the outcome of metastatic breast cancer patients treated with trastuzumab," the study authors concluded.

Fontana and colleagues disclosed no conflicts of interest with industry.


KIF5B-RET: Discovery of a novel fusion oncogene in lung adenocarcinomas by a systematic screen for tyrosine kinase fusions and identification of patients for a RET targeted therapy trial

Yoshiyuki Suehara of Memorial Sloan-Kettering Cancer Center led a team of researchers who confirmed that KIF5B-RET fusions in lung adenocarcinomas can be used to define a new subset of cancer patients who respond to drugs targeting the RET pathway.

"The mutually exclusive pattern of major targetable driver oncogenes in lung adenocarcinomas suggests that other similar driver oncogenes may exist," the study authors note in an abstract presented at the meeting. "We therefore performed a systematic screen for tyrosine kinase fusions in cases without known driver oncogenes by measuring aberrantly high RNA expression of kinase domain exons relative to more 5’ exons."

Suehara and colleagues enrolled 74 patients whose lung adenocarcinomas did not have ALK fusions or mutations in KRAS, EGFR, BRAF, or HER2. They used an assay developed by NanoString to analyze transcripts of 90 tyrosine kinases at two points: 5’ to the kinase domain and within or 3’ to the kinase domain.

According to the abstract, NanoString's assay was validated on patient samples with known ALK and ROS fusions. Researchers validated their tyrosine kinase fusion events by RT-PCR.

"The NanoString assay identified aberrant 5’ to 3’ ratios in ROS and RET in two cases, respectively, out of 74," the study authors reported. "RACE analysis isolated a novel GOPC-ROS fusion in the former and a novel KIF5B-RET fusion in the latter, both confirmed by RT-PCR." Additional RT-PCR analysis for KIF5B-RET fusions identified one more sample positive for this marker that had not been identified by the NanoString assay.

Of the two patients with KIF5B-RET fusions, one was a 60-year-old female never-smoker and the other was a 73-year-old former smoker.

"The novel KIF5B-RET fusion described [in this study] … defines a new subset of lung adenocarcinomas with a potentially targetable driver oncogene," the study authors concluded.

XL184, an investigational agent being developed by Exelixis, has shown activity in papillary thyroid cancer and in medullary thyroid cancer with RET mutations. Based on this and their genetic findings, Suehara and colleagues have initiated prospective testing for KIF5B-RET as part of their lung adenocarcinoma screening panel. They are further planning a Phase II trial with XL184 in patients with KIF5B-RET or related variant RET fusions.

The researchers reported no affiliation with industry.


Hypersensitivity skin reactions in melanoma patients treated with vemurafenib after ipilimumab therapy

James Harding and other researchers from Memorial Sloan-Kettering Cancer Center conducted a study to investigate why patients treated first with the melanoma drug ipilimumab (Bristol-Myers Squibb's Yervoy) and then treated with the BRAF inhibitor vemurafenib (Roche's Zelboraf) experience adverse skin reactions.

"Ipilimumab and vemurafenib each improve overall survival for patients with metastatic melanoma," Harding and colleagues wrote in an abstract presented at the meeting. Currently, physicians are using both drugs to treat metastatic melanoma patients with BRAF V600E mutations. However, doctors have noted that some patients who are first treated with Yervoy and then receive Zelboraf experience drug-related skin eruptions.

Last year, Bristol-Myers Squibb and Roche announced that they were studying whether combining the two drugs could further improve outcomes in molecularly defined subpopulations of melanoma patients (PGx Reporter 6/8/2011).

In this study, researchers from MSKCC tracked metastatic melanoma patients at the center with BRAF V600E mutated tumors from January 2007 to January 2012 and identified 16 patients who were treated with Zelboraf after receiving Yervoy.

In these patients, the most common drug-related adverse event linked to Zelboraf treatment were rash, seen in 13 out of 16 patients. Four patients experienced a severe form of rash within eight days of starting Zelboraf. Biopsies in two patients showed skin reactions that were symptomatic of drug hypersensitivity reaction.

The researchers noted that these hypersensitivity reactions were not life threatening and they did not need to discontinue Zelboraf dosing in any patients. Those who experienced severe rashes seemed to get them within one month of starting Zelboraf, but such toxicities were not associated with the previous dose or the number of doses of Yervoy, and they were not immune-related adverse events, the researchers reported.

However, they noted that the incidence of severe, Grade 3 rashes were "significantly higher" than seen in patients treated with Zelboraf in a Phase III trial evaluating the safety and efficacy of the drug. However, the objective response rate was similar to the response rates seen in Phase II and Phase III trials of Zelboraf.

"In patients receiving [Zelboraf] who have previously received [Yervoy], dermatologic adverse events appear to be more common," the study authors concluded. "This effect seemed most pronounced if [Zelboraf] was given within one month of completing [Yervoy]."

The reason for this, according to Harding and colleagues, is that the "release of immune checkpoint inhibition by [Yervoy] may predispose patients to hypersensitiviy skin reactions to [Zelboraf]." This finding, however, needs further study, the researchers noted.

Several investigators in this study disclosed having received research funding from Roche's Genentech subsidiary and BMS, as well as from other drug developers.

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