In epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NCSLC), tyrosine kinase inhibitors (TKIs) such as Tarceva® (erlotinib, Genentech/Roche/Astellas) are the standard of care for first-line metastatic patients in the United States and Europe/Japan, respectively. However, patients receiving TKIs eventually progress, and in approximately 50%-60% of cases, progression is due to development of an additional EGFR mutation called T790M. T790M is termed the “gatekeeper” mutation because none of the approved TKIs for NSCLC patients inhibit the mutation. This represents an unmet need for patients with metastatic NSCLC and is a commercial market opportunity.
Enter third generation EGFR-TKIs, which are all oral, irreversible inhibitors of EGFR that selectively target the mutant protein (including T790M) while leaving the wild-type mostly unmolested. Several such agents, including, AstraZeneca’s AZD9291 (Abstract 8009), Clovis’ CO-1686 (Abstract 8010), and Hanmi’s HM61713 (Abstract 8011), are in early development giving hope to patients with NSCLC who fail first-line EGFR inhibitors. Data from all three of these drugs were presented at this morning’s meeting at the American Society for Clinical Oncology (ASCO).
AZD9291 and CO-1686 both recently received FDA breakthrough status and trials were performed in global populations, with AZD9291 being the largest. HM61713 was studied in a Korean population. All three Phase I trials were performed in well-defined populations with mandatory T790M testing for all patients in the expansion cohorts. The timing of patients’ last TKI was similar across all three trials; however the HM61713 trial had a larger proportion of third-line patients.
In general, all three agents demonstrated impressive efficacy results in the T790M-positive population. The data for AZD9291 and CO-1686 put them ahead of the competition (see table below). In particular, the estimated median progression-free survival (mPFS) of >12 months for CO-1686, if it holds up, as well as the early evidence that it is active against brain metastasis, gives the Clovis compound an edge. However, the PFS data for both agents are still immature.
|Efficacy Data for Third-Generation TKIs in EGFR mutant NSCLC|
|Sample Size||ORR in T790M+||ORR in T790M–||mPFS|
|CO-1686||72||58%||NR||NR (est >12 mos)|
ORR=overall response rate; NR=not reported
Adverse events were generally mild (mostly Grade 1-2) for all three agents, especially in comparison to the high rates of diarrhea (57%) and rash (80%) seen with the first-generation TKI Tarceva. Both AZD9291 and HM61713 treatment resulted in rash characteristic of EGFR wild-type inhibition, while CO-1686 rash levels were nearly absent. Treatment with AZD9291 and HM61713 also resulted in some interstitial lung disease (ILD) or dyspnea. In contrast, CO-1686 had higher rates of hyperglycemia and prolongation of QTc. Dr. Sequist, who presented the data, was quick to point out that 10% of patients enrolled in the CO-1686 study were diabetic; the discussant, Dr. Lynch, suggested that hyperglycemia management with metformin is well-established and easy to administer but warned that it may have an anticancer effect, which could possibly confound the results in that subgroup. It would be interesting to see the efficacy and safety results in only the non-diabetic patients.
|Toxicities||AZD9291 (at RP2D of 80mg)||CO-1686||HM61713|
|QTc prolongation||1%||15% (7%)||3%|
It is too early to tell which agent, AZD9291 or CO-1686, will win the race to be first to market in the second-line setting, post-EGFR TKI, EGFR T790M+ space, however, both AstraZeneca and Clovis are charging ahead with additional Phase II and Phase III trials. AstraZeneca’s global Phase II AURA2 trial (NCT02094261) will further test the 80 mg QD dose in patients and the planned confirmatory Phase III AURA3 trial will randomize EGFR TKI-pretreated second-line T790M+ patients against a platinum doublet.
Clovis’ TIGER program includes three trials: TIGER1, a Phase II/III trial in first-line patients (EGFR mutant, not screened for T790M, randomized to receive CO-1686 or Tarceva); TIGER2 (NCT02147990), a Phase II trial that will further test CO-1686 in second-line T790M+ patients; and TIGER3, a Phase III trial that will randomize EGFR TKI-pretreated second-line T790M+ patients against chemotherapy.
The second-line EGFR mutant population is a minor segment of the NSCLC population. In Caucasian NSCLC patients, approximately 15% have an EGFR mutation; thus the T790M acquired resistance population is less than 10% of all NSCLC patients; in Asian patients, this may be up to 20% of the population. Successful penetration of the second-line market will hinge on a change in biomarker testing practices, since it will require (or assume) that physicians confirm a T790M mutation in a post-progression patient. This may not be an easy task to accomplish in practice, since it may require obtaining new biopsy samples or development of less intrusive testing methods (such as circulating DNA).
Both Clovis and AstraZeneca are guiding for submissions in second-line T790M+ patients in 2015, based on their respective Phase I/II trials combined with data from recently initiated AURA2 and TIGER2 trials. And both companies have confirmatory randomized Phase III trials about to initiate. The race is on!
By Stephanie Hawthorne, Ph.D., Senior Director, and Mara Jeffress, Ph.D., Associate Consultant, Kantar Health
More than 30,000 attendees from all over the world are expected to attend the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO) on May 30-June 3, 2014, in Chicago. In the pre-meeting presscast, five studies were selected and highlights ranged from resource utilization and low-dose computed tomography screening for lung cancer to novel therapies targeted to specific abnormalities.
Low-dose Computed Tomography Screening in NSCLC
A study based on mathematical modeling projected the 5-year outcomes of implementing the United States Preventive Services Task Force (USPSTF) recommendation to screen patients at high-risk of lung cancer with low-dose computed tomography (LDCT) in the Medicare population. Looking at an expected-use scenario (50% of patients offered screening undergo screening), the study showed that LDCT as recommended would detect 54,900 more cases of lung cancer over 5 years compared with screening, and the majority of these cancers would be stage I.
In fact, this program would increase the proportion of early-stage diagnosis from 15% to 33%. This effort would entail use of 11.2 million more scans, and cost $9.3 billion more in expenditures (primarily on LDCT scans). This boils down to a $3 per month premium increase per Medicare member, explained lead author Joshua A. Roth, PhD, MHA, a postdoctoral research fellow at Fred Hutchinson Cancer Research Center in Seattle, WA.
Dr. Roth said that this study was not designed to look at QALY or value of LDCT, but as a projection of what to expect in terms of resource utilization so that Medicare and other healthcare systems can plan accordingly if the USPSTF recommendation is implemented.
Obesity and Breast Cancer
A study showed that obesity (i.e., body mass index [BMI] ≥30 kg/m2) increases breast cancer mortality only in women with pre-menopausal ER+ disease, but not in post-menopausal ER+ disease or ER-negative breast cancer. The study included more than 80,000 patients enrolled in 70 trials. Data were collected on BMI, ER status, menopausal status, breast cancer recurrence, and death. Obese women with early breast cancer were compared with women of normal weight. Obesity was an independent factor predicting breast cancer mortality in 20,000 premenopausal women with ER+ breast cancer (relative risk ratio of 1.34), while obesity had little effect on breast cancer mortality in 40,000 post-menopausal women with ER+ breast cancer or in the 20,000 women with ER-negative breast cancer. The rate of breast cancer mortality was 21.5% in obese women with premenopausal ER+ breast cancer versus 16.6% in women of normal weight, amounting to a 10-year difference of about 5%, said lead author Hongchao Pan, PhD, a researcher at the University of Oxford, U.K.
“This is yet another study showing the detrimental effects of obesity in cancer. Overall, obesity is a negative prognostic feature and we need to attend to this,” said Clifford A. Hudis, MD, ASCO president.
PSA Relapse in Prostate Cancer
A large observational study included 14,300 men diagnosed with biopsy-proven prostate cancer who completed curative surgery or radiation; of these, 2012 men developed PSA relapse (rising PSA but asymptomatic) and were treated with immediate androgen deprivation therapy (ADT, within 3 months of rising PSA) or delayed ADT (at least 2 years after PSA relapse or when they presented with metastasis, symptoms, or short doubling of PSA time). In the study, PSA relapse was defined as ≥.02 ng/ml or 3 rising PSA measurements in asymptomatic patients with no evidence of metastatic disease.
Median time from primary treatment to PSA relapse was 27 months. After relapse, patients were followed for 41 months. The estimated 5-year overall survival was 85.1% for the immediate ADT group and 87.2% in the delayed ADT group. Ten-year OS was identical in both groups: 71.6%.
“Survival was similar for prostate cancer mortality and all-cause mortality,” stated lead author Xabier Garcia-Albeniz, MD, a research associate at Harvard University School of Public Health in Boston, MA.
This study provides some fodder for discussions with patients, some of whom may not want to go on ADT because of the side effects. Dr. Garcia-Albeniz said results will not change clinical practice. For that to happen, results of an ongoing randomized Phase III trial comparing the two strategies will be needed.
Mutation Resistance in NSCLC
A phase I study found that a novel selective EGFR tyrosine kinase inhibitor (TKI) known as AZD9191 appears to overcome the mutation T790M responsible for resistance to previous TKI therapy in patients with non-small cell lung cancer (NSCLC) who harbor that mutation. The study did not identify a dose-limiting toxicity or a maximal tolerated dose for AZD9191.
This preliminary study included 199 patients with advanced NSCLC and EGFR mutations who progressed on 1 or more standard EGFR therapies. Overall 51% of patients experienced tumor shrinkage; response was more robust in those with the T790M mutation (64% versus 23% in those who were T790M-negative).
“Currently there is no appropriate therapy for these patients. This drug warrants further study,” said lead author Pasi A. Jänne, MD, PhD, Dana-Farber Cancer Institute and Harvard Medical School in Boston.
Pigmented Villonodular Synovitis
A small phase I study showed that a novel oral therapy PLX3397 targeted to the colony-stimulating factor 1 (CSF1) receptor and other molecular targets appears to improve the symptoms and functionality of patients with a rare neoplastic joint disorder called pigmented villonodular synovitis (PVNS). About 600 patients are diagnosed with PVNS each year in the U.S. and the disease is characterized by collagen scarring, bone destruction, and repeat joint bleeds. It is associated with functional impairment and disability. Some patients may even need limb amputation. The study enrolled 23 patients with PVNS, and 11 of 14 evaluable patients showed rapid, dramatic, sustained responses to PLX3397. PLX3397 was well tolerated and patients achieved marked clinical improvement.
“These results are a shining example of how patients can experience a meaningful clinical benefit when we are able to match the right treatment with the right target,” said lead author William D. Tap, MD, Memorial Sloan-Kettering Cancer Center in New York City. A Phase III trial of this compound is planned.
by Alice Goodman
The annual meeting of the American Society of Clinical Oncology (ASCO) is nearing and Kantar Health has identified several pivotal abstracts that will be presented. The 2014 ASCO annual meeting promises to be packed with the latest data and trends from the world of oncology, and the meeting has the potential to alter treatment practices in several tumor types. The following is a brief discussion of the three abstracts that are likely to generate the most discussion and have the highest impact. For a full discussion of all 10 of our top abstracts, please see the associated article in the May issue of OBR Green.
Both Avastin® (bevacizumab, Genentech/Roche/Chugai) and Erbitux® (cetuximab, Bristol-Myers Squibb/Eli Lilly/Merck KGaA) are approved for the treatment of first-line metastatic colorectal cancer (mCRC) and have demonstrated progression-free survival (PFS) and overall survival (OS) benefits when added to standard chemotherapy in these patients; however, Erbitux is approved for use only in the subgroup of patients with wildtype KRAS. As with all new therapies that enter the same indication, physicians are left wondering how best to incorporate these agents into their practices. As multiple Phase III trials showed combining the agents are not effective, two trials set about to understand in which order these agents should be offered to patients.
At the 2013 ASCO annual meeting, the data from one of these trials, FIRE-3, was presented. FIRE-3 was designed to evaluate FOLFIRI plus either Erbitux or Avastin as first-line therapy, but was amended in 2008 to include only KRAS wildtype patients. The data suggested a non-significant benefit compared to Avastin in the primary endpoint (overall response rate; 62% versus 58%, p=0.183). A PFS benefit was not observed (HR 1.06, p=1.06), however, Erbitux was associated with a significant 3.7-month OS benefit compared to Avastin (HR 0.77, p=0.017).
The conflicting data found in FIRE-3 beg for a repeat, and thankfully we have one: CALGB 80403, for which the data will be presented in the ASCO 2014 plenary session. CALGB 80403 is a three-armed trial comparing Avastin plus physician’s choice of first-line chemotherapy (FOLFOX or FOLFIRI) versus Erbitux plus chemotherapy versus Avastin plus Erbitux plus chemotherapy in approximately 2,900 mCRC patients. The trial, which was initiated in November 2005, was later amended to include only KRAS wildtype patients. The primary endpoint is OS. Given past data, the combination arm may prove to be ineffective; however, the more important comparison will be the direct comparison of Avastin-based chemotherapy versus Erbitux-based chemotherapy.
Currently, U.S. physicians strongly favor Avastin-based regimens in first-line over Erbitux-based regimens in patients with KRAS wildtype mCRC, according to Kantar Health’s CancerMPact® Treatment Architecture data. This is largely based on order of entry, with Avastin receiving a first-line FDA approval eight years before Erbitux. Western European physicians slightly favor Erbitux-based regimens in first-line over Avastin-based regimens in patients with KRAS wildtype mCRC. This may be based on a preference for biomarker-driven treatment selection, which Erbitux affords. Both are also influenced by a lack of data to understand whether one of these agents is superior to the other. Since questions remain after the results of FIRE-3, the results of CALGB 80405 will ultimately be cited in comparisons between the two agents. Should the results of CALGB 80405 favor Avastin or show no significant difference between the two regimens, Kantar Health anticipates little impact on the current market.
The past several years have seen an explosion of new agents for the treatment of advanced melanoma: Yervoy® (ipilimumab, Bristol-Myers Squibb), Zelboraf® (vemurafenib, Genentech/Roche/Daiichi Sankyo), Tafinlar® (dabrafenib, GlaxoSmithKline) and Mekinist® (trametinib, GlaxoSmithKline). Moreover, other agents are waiting in the wings, as past ASCO meetings have highlighted the promise of Bristol-Myers Squibb’s anti-PD-1 monoclonal antibody nivolumab. However, at ASCO 2014 another anti-PD-1 monoclonal antibody, lambrolizumab (MK3475, Merck), will take center stage.
As Bristol-Myers Squibb initiated Phase III trials for nivolumab in December 2012 (for relapsed melanoma) and January 2013 (for first-line melanoma), it appeared that this agent would be the first to market. However, Merck announced in January that they started to file a rolling submission for lambrolizumab based on the results of a Phase II trial, which will be presented at this ASCO meeting, and they expect to complete this application in the first half of 2014. This Phase II trial compares lambrolizumab to standard cytotoxic chemotherapy in approximately 500 patients who have progressed after prior therapy, although it appears that data from only 411 patients will be presented at the ASCO 2014 presentation.
Given the high level of competition as mentioned above, it will be important to compare the efficacies and toxicity profiles. The co-primary endpoints for the lambrolizumab Phase II trial are PFS and OS, and given past Phase I data, Kantar Health feels that lambrolizumab will show a benefit compared to the control arm and therefore should be strong enough to support Merck’s rolling submission. The toxicity profile of lambrolizumab is expected to be manageable, based on data from the Phase I trial, with lambrolizumab having about 4% grade 1-2 pneumonitis.
Although Merck’s submission might allow lambrolizumab to beat nivolumab – one of lambrolizumab’s more direct competitors given their similar mechanisms of action – to market in relapsed or refractory patients, nivolumab still might ultimately prevail, as it is being examined in two Phase III trials in newly diagnosed melanoma patients. If one or both of these trials are successful, nivolumab could enjoy strong utilization in this setting – and as a consequence, keep lambrolizumab confined to later lines of therapy.
The primary question for lambrolizumab in this phase II trial, therefore, will be efficacy as this will be a guide in assessing lambrolizumab’s further prospects in other melanoma settings. Will it be strong enough to offer hope against front-line Yervoy and, in the future, nivolumab?
Both Imbruvica® (ibrutinib, Pharmacyclics/Johnson & Johnson) and idelalisib (Gilead) are generating a lot of excitement as potential treatment options in non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Arzerra® (ofatumumab, Genmab/GlaxoSmithKline) is currently approved for use in refractory CLL patients in both the United States and Europe. Although Arzerra was the second-most utilized agent in the United States in CLL patients after their second relapse, it was still only used in 14% of U.S. CLL patients, according to Kantar Health’s CancerMPact® Treatment Architecture data. This utilization rate highlights the unmet need for more therapies and helps partly explain the level of excitement for new therapies such as Imbruvica and idelalisib.
Imbruvica, an inhibitor of the Bruton’s Tyrosine Kinase (BTK), has already garnered accelerated approvals as a monotherapy for both mantle cell lymphoma and CLL based on Phase II data. While work on these two applications were ongoing with the FDA, Pharmacyclics initiated a Phase III trial (RESONATE) that compares Imbruvica versus Arzerra in 391 patients with relapsed/refractory CLL or small lymphocytic lymphoma. In January 2014, the companies announced that the trial met its primary endpoint of PFS as well as a secondary OS endpoint.
The data from this trial, to be presented at this ASCO conference, will be closely monitored. How much difference will there be in these two efficacy endpoints for Imbruvica and Arzerra? In the Phase Ib/II trial from which the application for accelerated approval for Imbruvica was made, the overall response rate (ORR) was 71%, and the 12-month PFS rate was 86%. These data compare favorably against current treatment options, including Arzerra, which showed a 58% ORR in CLL patients previously treated with fludarabine and Campath® (alemtuzumab, Genzyme), warranting the accelerated approval. However, these data come after release of Phase III data for the PI3Kδ inhibitor idelalisib, in which the added efficacy of idelalisib to Rituxan® (MabThera® in Europe, rituximab, Biogen Idec/Roche) was evaluated in 220 relapsed or refractory CLL patients. Idelalisib significantly improved PFS (HR 0.15, p<0.0001) and OS (HR 0.28, p-0.018). Although physicians have been equally excited about both idelalisib and Imbruvica, they will look closely at the efficacy data from RESONATE to help guide them as they select which agent to use or in which patient subtype to offer a particular agent.
If doctors cannot choose which regimen to use strictly on comparisons of efficacy, then the adverse event profile will be monitored. In the Phase Ib/II trial, Imbruvica was relatively well tolerated with less than 10% incidence of grade 4 neutropenia, anemia and thrombocytopenia. It is expected that no untoward signals will be reported.
If these efficacy and tolerability data trends continue to be seen in RESONATE, Imbruvica will continue to justify the strong level of excitement directed toward it.
 Ribas, Abstract 9009, ASCO 2013
 O’Brien, Lancet Oncol, 15: 48-58, 2014.
 O’Brien, Abstract 983, ASH 2011.
 Wierda, J Clin Oncol, 28:1749-1755, 2010.
 Furman, Abstract LBA6, ASH 2013