The melanoma field exploded two years ago, with the 2011 and 2012 approvals of Yervoy® (ipilimumab, Bristol-Myers Squibb) and Zelboraf® (vemurafenib, Genentech/Roche/Daiichi Sankyo). The approval of Zelboraf also ushered in the era of personalized medicine in melanoma, effectively segmenting the market in half – those patients with BRAF V600E mutation (approximately 44% of patients), and those without. In May 2013, the field expanded again following the FDA approvals of Tafinlar® (dabrafenib, GlaxoSmithKline) and Mekinist® (trametinib, GlaxoSmithKline), and one month later the European Medicines Agency (EMA) approval of Tafinlar, for treatment of BRAF-mutant unresectable or metastatic melanoma.
According to Kantar Health’s CancerMPact® Treatment Architecture 2013 data, which was surveyed prior to the recent approvals of Tafinlar and Mekinist, 77% of U.S. and 48% of Western European BRAF-mutant metastatic melanoma patients receive Zelboraf as first-line therapy. However despite impressive responses and improved outcomes, resistance to these agents develops and relapse occurs within six months. In these resistant patients, reactivation of the RAF-MEK-ERK pathway and mutations in MEK have been documented. These observations, coupled with preclinical examination of the hypothesis that targeting both BRAF and MEK simultaneously could provide greater efficacy, more durable responses and reduced toxicity, has led to testing of the combination of BRAF and MEK inhibitors in melanoma patients.
At the 2013 American Society of Clinical Oncology (ASCO) annual meeting, we saw data from a Phase I/II trial of the combination of BRAF and MEK inhibitors (Sosman, Abstract 9005), Tafinlar and Mekinist. The combination had impressive objective response rates (63-76% ORR including 8-9% complete responses, CR) in BRAF inhibitor-naïve patients, nearly additive of the ORRs for the monotherapies (50% for Tafinlar and 23% for Mekinist). The PFS ranged from 9.2 to 9.4 months across all dose cohorts (Flaherty et al., NEJM, 2012). Based on this promising data, we expect the combination data to shift market share away from single agents to the combination of Tafinlar and Mekinist. Indeed, this is already occurring, despite lack of approval for the combination therapy. In late June 2012, Kantar Health surveyed 30 U.S. community oncologists about their preferred choice of first line therapy for BRAF-mutant metastatic melanoma patients. The results show nearly one-fifth of patients receiving the Tafinlar-Mekinist combination off-label.
Genentech/Roche is hoping to capitalize on this trend by testing its own BRAF and MEK inhibitor combination. Updated results for the Phase Ib BRIM7 trial were presented on September 28 at the 2013 European Cancer Congress (ECCO-ESMO-EORTC) annual meeting (McArthur, Abstract 3703), examined the combination of Zelboraf (BRAF inhibitor) and cobimetinib (MEK inhibitor) in 63 Zelboraf-naïve and 65 Zelboraf -resistant patients. In the BRAF inhibitor-naïve patients the ORR was an impressive 85%, including a 10% CR rate. The median PFS had not yet been reached despite 10 months of median follow-up. This updated data from the original 2012 publication reflects a slight strengthening of the data, with ORR remaining similar but now observing complete responses in this larger data set. In patients who had progressed on prior Zelboraf there was only a 15% ORR, identical to what was observed in the GSK combination study. This lack of significant efficacy when using the combination therapy after progression on BRAF inhibitor therapy is a strong argument for using the combination therapies upfront.
Generally, there were more adverse events with the combinations than with the monotherapies (with the notable exception of less squamous cell carcinoma with the combination therapy) and differential toxicity profiles between the two combination regimens. The Tafinlar + Mekinist regimen had higher rates of fever than the Zelboraf + cobimetinib combination (71% and 43%, respectively); the Zelboraf + cobimetinib combination had higher rates of diarrhea (all grades: 81% and 36%, respectively; grade 3/4: 8% and 2%, respectively) and rash (all grades: 89% and 27%, respectively; grade 3/4: 13% and 0%, respectively). The incidence of squamous cell carcinoma was similar between the two regimens (5% grade 3/4).
In terms of efficacy it appears that the Genentech/Roche combination has the advantage; however, the GSK combination has a significant first-mover advantage. Not only are both GSK agents already approved in the U.S., but GSK has already received FDA priority review for accelerated approval of its combination based on the randomized Phase II data, with a Prescription Drug User Fee Act (PDUFA) target date of January 8, 2014. In Europe, the pending approval for Mekinist includes a broad label which includes use in combination with Tafinlar. Further, GSK was the first to initiate two phase III trials in mid-2012 – one in comparison with Tafinlar monotherapy (NCT01584648) and one in comparison with Zelboraf (NCT01597908). Genentech/Roche initiated a trial of their combination against Zelboraf (NCT01689519) six months later, in January 2013, putting it two or more years behind GSK. Will the first-to-market advantage favor the GSK combination? Or will physicians, more familiar with Zelboraf, favor the Genentech/Roche combination? It is too early to predict what the phase III data will show, but it will certainly be a showdown.
By: Stephanie Hawthorne, PhD, Director, Clinical and Scientific Assessment, Kantar Health and Mara Jeffress, PhD, Associate Consultant, Clinical and Scientific Assessment, Kantar Health
Two late-breaking abstracts during the colorectal cancer sessions at the 2013 European Cancer Congress were centered on the anti-EGFR therapies Erbitux® (cetuximab, Bristol-Myers Squibb/Eli Lilly/Merck KGaA) and Vectibix® (panitumumab, Amgen/Takeda). Although the data probably won’t immediately change clinical practice, questions continue to arise. If answered favorably, these therapies could conceivably be utilized more strongly in KRAS wild-type patients.
The first presentation was an update of the FIRE-3 data. This trial compared first-line FOLFIRI in combination with low-dose (5 mg/kg every two weeks) Avastin® (bevacizumab, Genentech/Roche/Chugai) or standard dose Erbitux in metastatic colorectal cancer patients with KRAS wild-type tumors. The data presented at the 2013 American Society of Clinical Oncology (ASCO) annual meeting indicated that the primary endpoint of an improvement in the response rate was not met (62% with Erbitux and 58% with Avastin, HR 1.18, p=0.183; Stinitzing, Abstract LBA 3506). There was also no difference in progression-free survival (PFS: 10.0 months versus 10.3 months, HR 1.06, p-0.547) but, surprisingly, there was a significant 3.7 month difference in overall survival in favor of Erbitux (OS: 28.7 months versus 25.0 months, HR 0.77, p=0.017). These data still perplex key opinion leaders – how can there be an improvement in overall survival in the absence of a response or PFS benefit?
This question was not directly addressed at the 2013 European Cancer Congress, but another one was: can these results be improved in patients with no RAS mutation? Although mutations in exon 2 of the KRAS gene are the most prevalent mutation type in colorectal cancer patients (approximately 40%) and constituted the intent-to-treat population in the FIRE-3 analysis, other RAS mutations, in particular NRAS or mutations in exons 3 and 4 of the KRAS gene constitute about 10% of metastatic CRC mutations. In a pre-planned exploratory analysis, neither the response rate (65.5% versus 59.6%, p=0.32) nor PFS (10.4 months versus 10.2 months, HR 0.93, p=0.54) were improved in RAS wild-type patients. However, the overall survival benefit was even stronger, with a 7.5 month survival advantage associated with Erbitux: 33.1 months versus 25.6 months, HR 0.70, p=0.011 (Heinemann, Abstract LBA17, ECCO 2013).
Will these new data matter? The discussant to this presentation, Dr. Tabernero, doesn’t recommend changes to current clinical practice until a biological explanation can be provided for the lack of a response rate or PFS benefit. Plenty of theories have been discussed, but to-date there has been no clear answer as to why this incongruous result was observed. This advice will be followed in the United States, where Avastin is strongly utilized by physicians even in KRAS wild-type patients. However, these new data could strengthen Erbitux’s position in Europe, where it is already preferred slightly over Avastin-based regimens in first-line KRAS wild-type patients (Kantar Health, CancerMPact® Treatment Architecture), even more so than after the release of the ASCO data. Dr. Tabernero predicts that two trials will ultimately decide this competition. The first is CALGB 80405, which is evaluating Avastin versus Erbitux in combination with either FOLFOX or FOLFIRI. The second is the GERCOR STRATEGIC-1 trial, which will evaluate two sequences. In arm A, patients will receive first-line Erbitux plus FOLFIRI followed by Avastin plus oxaliplatin-based chemotherapy. In Arm B, patients will receive Avastin plus oxaliplatin-based chemotherapy followed by second-line Avastin in combination with irinotecan-based chemotherapy, and then an anti-EGFR agent (Erbitux or Vectibix) as third-line therapy. The CALGB study is likely to have the greater impact in the U.S., whereas the GERCOR study may prove to have a more European/regional influence.
The second Late-Breaking Abstract in this colorectal cancer session was presentation of the ASPECCT trial (Price, Abstract LBA18, ECCO 2013). ASPECCT was a non-inferiority study which evaluated third-line Erbitux versus Vectibix in 999 metastatic colorectal cancer patients. The study achieved its primary endpoint of non-inferiority in overall survival (Vectibix, 10.4 months versus 10.0 months, HR 0.97, p=0.0007). Vectibix proved non-inferior to Erbitux in progression-free survival as well (4.1 months versus 4.4 months, HR 1.002). The possible advantage for Vectibix, if there is one, is found in an examination of the toxicity profile. Although there is no general change in the level of all toxicities (for example, grade 3: 36.3% versus 31.6%), the use of Vectibix was associated with a decreased incidence of infusion reactions (any grade, 2.8% versus 12.5%), owing to the humanized nature of this antibody).
This trial is unlikely to change clinical practice. Erbitux is strongly entrenched as the anti-EGFR therapy of choice in the U.S. and Europe, and will remain so based on this data. However, ASPECCT is important for another reason ― this trial will allow the conversion of Vectibix’s conditional approval in Europe to a full approval.
Two sets of data were presented at the European Cancer Congress. Although no changes in treatment practices are expected to arise from these data, enough questions should arise, especially from FIRE-3, to make physicians anticipate the arrival of the next set of data.
By: Stephanie Hawthorne, PhD, Director, Clinical and Scientific Assessment, Kantar Health and Arnold DuBell, PhD, MBA, Associate Consultant, Clinical and Scientific Assessment, Kantar Health
Results of three studies were unveiled at a Presscast in advance of the upcoming 2013 ASCO Breast Cancer Symposium to be held September 7-8, 2013, in San Francisco, CA. Two studies focused on management of ductal carcinoma in situ (DCIS), and a separate study focused on womens’ perception of their personal breast cancer risk.
The main findings of the studies were:
Radiation in DCIS
DCIS is a precancerous lesion that could progress to breast cancer – if untreated – in an unknown percentage of women. Therefore, most women with DCIS undergo surgery, often followed by radiation therapy, to reduce the risk of recurrence. Concern has been raised that radiation to the general region of the heart can increase the risk of cardiovascular disease (CVD), even though modern protocols have been adjusted to reduce exposure of the heart to radiation.
A large population-based study in the Netherlands suggests that radiation does not increase the risk of CVD in women with DCIS compared to the general population and to DCIS patients treated with surgery alone. These results should be reassuring to women and their physicians who include radiotherapy in treatment plans.
The authors state that this is the first large study to evaluate long-term effects of radiotherapy for DCIS on both the incidence of CVD and associated deaths.
Although these results are encouraging, longer follow-up, perhaps 5 to 10 years or more, is needed before definitive statements can be made about the CV safety of radiation in patients with DCIS, said lead author Naomi B. Boekel, MSc, a PhD student at the Netherlands Cancer Institute in Amsterdam, Netherlands.
The retrospective study was based on data from 10,468 women diagnosed with DCIS under the age of 75 years between 1989 and 2004. Surgery alone was performed in about 71% (43% had mastectomy and the remaining women had lumpectomy), and 28% underwent both surgery and radiotherapy. At a median follow-up of 10 years, survivors of DCIS had a similar risk of dying from any cause and a 30% lower risk of dying of CVD compared with the general population in their county. Patients treated with surgery alone had a similar risk of developing CVD as those treated with both surgery and radiotherapy (9% versus 8%, respectively); no difference in risk of CVD was observed between patients who received left-sided radiotherapy (which includes a portion of the heart in the radiation field) or right-sided radiotherapy (which does not include the heart in the radiation field; in these subgroups, the incidence of CVD was 7 % versus 8%, respectively.
DCIS survivors may be more motivated to adopt a healthy lifestyle than the general population, which may explain the slightly lower risk of CVD compared with the general population, noted Dr. Boekel.
MRI in DCIS
A second study featured at the presscast suggests that perioperative MRI may not be necessary in patients undergoing surgery for DCIS. MRI was not associated with reduced risk of locoregional recurrence (LRR) or contralateral breast cancer (CBC) after surgery.
There are no official guidelines for perioperative use of MRI, but some centers order it routinely to detect additional cancers and to confirm or expand on data attained from mammograms or ultrasounds. This study indicates that MRI is not necessary for every patient with DCIS, stated first author Melissa L. Pilewskie, MD, Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City and Commack, NY. These results are important because MRI is expensive and has a high false-positive rate, resulting in additional tests, while it does not appear to improve long-term outcomes for most women with DCIS, she added.
Dr. Pilewskie said that perioperative MRI may be useful in specific patients with DCIS, such as those with a palpable mass and nipple discharge, which are not detected by mammogram screening.
The study analyzed rates of LRR and CBC in 2321 women who underwent a lumpectomy between 1997 and 2010 at MSKCC. Of that group of women, 596 had an MRI before or immediately following lumpectomy, and 1725 did not. Follow-up was a median of 59 months. No significant difference in the 5-year LRR rates was found: 8.5% in those who had an MRI versus 7.2% for those who did not.
In an analysis adjusted for patient characteristics and risk factors associated with recurrence, MRI was not associated with lower rates of LRR. Additionally, no significant differences were seen in the 5-year rates of CBC (3.5 years in both groups).
In a group of patients followed for 8 years, LRR were 14.6% for those who had an MRI versus 10.2% for those who did not. The rate of CBC at 8 years was 3.5% and 5.1%, respectively.
In general, doctors ordered an MRI for women in the study who were at increased risk of developing breast cancer because of age and/or family history, which may explain the higher recurrence rates in that group, said Dr. Pilewskie. She believes that future studies should focus on settings where use of MRI may improves outcomes, such as monitoring response to therapy.
Perceptions of Breast Cancer Risk
In a large survey of almost 10,000 women undergoing mammography screening, more than 90% inaccurately estimated their lifetime risk of developing breast cancer. Results were evenly split between women who over-estimated and those who under-estimated their personal risk. Alarmingly, 40% of survey respondents said they had never discussed their personal risk of breast cancer with a doctor.
“These findings suggest that despite the pink ribbons, marches, and large public health awareness campaigns about breast cancer, educational messages are missing the mark. We should change the way breast cancer awareness is approached,” stated lead author Jonathan Herman, MD, Hofstra North Shore-LIJ Medical School in New Hyde Park, NY. The study is important, because appropriate decision-making rests on an accurate perception of breast cancer risk. Patients can either underutilize available chemoprevention strategies or overuse them depending on perception of personal risk.
The survey included 9873 women aged 35 to 70 years who had a mammogram at 1 of 21 centers on Long Island, NY. Twenty-five survey questions covered demographics, breast cancer risk factors, including personal and family history of breast cancer, and any prior breast cancer risk assessments and discussions. Survey questions were adapted from the NCI Breast Cancer Risk Assessment Tool used to estimate the risk of developing invasive breast cancer.
The actual lifetime risk of developing breast cancer was calculated for each respondent and then compared with that woman’s personal estimate; if the difference from the calculated value was greater than 10%, it was labeled as inaccurate.
Only 707 women (9.4%) correctly estimated their risk; 3359 women (44.7%) underestimated their risk and 3454 (45.9%) overestimated it. In general, Caucasian women were more likely to overestimate their risk, while women in minority groups were more likely to underestimate it.
The level of overall understanding about breast cancer risk was low in this study, and this is especially concerning, since these women were already participating in mammography screening. Dr. Herman said that the level of understanding could be even lower in the general population not concerned enough about breast cancer risk to participate in mammography screening.
by Alice Goodman