On Target Molecular Medicine Update Three Trends from the 2012 Annual ASCO Meeting

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1 On Target Molecular Medicine Update Three Trends from the 2012 Annual ASCO Meeting Conference Trends Shifting Toward a Molecular Anatomy of Cancer Crossing Over One Drug, Many Cancers A Rising Call for Multiplexed Molecular Diagnostic Testing Highlights Target and Combine The Evolution of Targeted Drugs

2 It has been 14 years since the concept of personalized medicine made its official debut with the US Food and Drug Administration s approval of trastuzumab for the treatment of breast tumors with a specific molecular profile. Since then, there has been a rising level of activity in molecular medicine that is completely changing the landscape of cancer research and treatment. Staying on top of that flurry of activity is a challenge. Every year, thousands of physicians, healthcare administrators, and business executives converge on the American Society of Clinical Oncologist (ASCO) meeting to do just that learn about and discuss the latest studies and treatments that will help cancer patients live longer or overcome their disease. This year s event in Chicago (June 1-5, 2012) marked several key developments in the rapid evolution of oncology and its move towards more widespread incorporation of the molecular understanding of disease and approach to the diagnosis and treatment of cancer. This report summarizes overarching trends in targeted therapies, along with the specific developments that will likely have an impact on your clinical practice in the near future. This year s meeting will continue to highlight advances in precision medicine that identify and exploit cancer s genetic weak spots to halt tumor growth and in some cases eradicate disease. Precision medicine is another term for a treatment plan that is carefully individualized for each patient, based on the patient s genetics and the unique genetics of their tumor. -Dr. Michael Link, President of the American Society for Clinical Oncology (ASCO), 48th Annual ASCO Meeting press briefing, May 2012 Commercial/ Pre-commercial Phase 3 Phase 2 Phase 1 Preclinical (Publically Disclosed) Figure 1a. (above) A robust pipeline of targeted treatments. There are about 30 targeted therapies currently FDA approved, with at least 500 in clinical trials or early development. Figure 1b. (right) The time from discovery of a potential driver mutation to clinical proof-of-concept and the approval of a new drug is getting shorter as compounds become more targeted. Recently approved targeted therapies, such as crizotinib for late-stage, non-small cell lung cancers (NSCLC) that express the abnormal ALK gene have been approved under the FDA s accelerated approval program, potentially shortening development timelines for indications where there are limited treatment options. Source: Chin L, Andersen J & Futreal PA. Cancer genomics: from discovery science to personalized medicine. Nature Medicine (2011) 17, 3:297 1

3 Trend 1: Shifting Toward a Molecular Anatomy of Cancer Perhaps most evident at the meeting was the prevalence of a new lexicon of cancer, where tumors are defined not simply by their tissue of origin or pathologic characteristics, but also by the genomic alterations that drive or modify their progression, and their response to treatment. HER2, EGFR, ALK, ROS1, BRAF, KRAS, etc. are genes that, when altered, effect an oncogenic pathway, and many of these genes are found to be altered in a range of different cancers. The approach toward a molecular anatomy of cancer has taken hold, first in breast cancer, but then in other areas such as colorectal and lung cancer. Over the last several years we ve learned a lot about the genomic heterogeneity of lung cancer, says Dr. Pasi Jänne, Harvard Medical School and the Dana-Farber Cancer Institute. 2 Adenocarcinoma Squamous Cell Carcinoma Molecualr Histological Unknown EGFR Unknown FGFR Amplification FGFR Mutation DDR2 BRAF ERBB2 MEK1 PIK3CA MET amplification ALK ROS RET KRAS Fusion Oncogene PIKC3A Figure 2: From a histological to a molecular anatomy of lung cancer. Next-generation sequencing informs a genomic profile for each tumor, providing a more in depth understanding of the drivers of cancer: Pasi Jänne Treatment and Clinical Trial Design in the Era of Personalized Medicine ASCO 2012 Validated and approved therapies target tumors with EGFR (erlotinib) mutations and ALK (crizotinib) rearrangements, he reports, and clinical trials are in the works for drugs targeting many of the other mutations. In fact, Jänne points out that a Lung Cancer Mutation Consortium genotyping study of over 500 patients found (reported at the 2011 ASCO Annual Meeting) that 54% of them had mutations in their tumors that are targeted by approved drugs or new treatments in clinical trials. It s a signal that the strategies for treating advanced lung cancer are set to change. Promising results from several clinical trials focusing on molecularly defined subsets of patients were reported at this year s ASCO meeting. Patients with EGFR mutated tumors have several options for treatment with targeted drugs, including gefitinib and erlotinib for lung cancer, and cetuximab for colon cancer. Another drug, afatinib, represents a new class of irreversible inhibitors of EGFR kinases. Results from the LUX-Lung 3 Phase III study using afatinib as a first-line treatment showed that lung cancer patients lived on average for almost a full year (11.1 months) before their tumor started growing again compared to just over half a year (progression free survival, or PFS, of 6.9 months) for those on standard chemotherapy. A variety of different EGFR mutations are linked to cancer, and data show that some mutations lead to better outcomes with certain targeted treatments. For the most common mutations (del19 and L858R), patients treated with afatinib experienced a median PFS of 13.6 months. 4 Part of the excitement over afatinib is that it is also active against EGFR mutated tumors that do not respond to first generation kinase inhibitors erlotinib and gefitinib. In addition, since it is active against HER2, which belongs to the same family of receptor kinases as EGFR, it is also being investigated for breast cancer and other HER2 driven cancers. 2

4 MET amplification is another genomic alteration found in multiple cancers. An oral MET inhibitor, tivantinib, demonstrated robust efficacy in a Phase 2 trial conducted in patients with unresectable hepatocellular carcinoma (HCC) 5 leading to a near doubling of overall survival (OS) from 3.8 to 7.2 months. The benefits were observed in the subgroup of patients whose tumors showed a high level of MET expression a factor usually associated with poor prognosis. The findings represent the first identification of a biologic subgroup of [HCC] patients responding to a targeted therapy, said Dr. Lorenza Rimassa of the Humanitas Cancer Center, Italy, who presented the findings at the Gastrointestinal (Noncolorectal) Cancer session. This year s meeting also marked the first validation of ROS1 as a therapeutic target. At the clinical science session Emerging New Targets and New Drugs in Non Small Cell Lung Cancer, Dr. Alice Tsang Shaw of Massachusetts General Hospital Cancer Center described studies examining whether crizotinib, already approved for treatment of the 6% of lung cancer patients with ALK rearrangements in their tumors, would also work for patients with tumors harboring ROS1 gene rearrangements. 6 To date, the overall response rate to crizotinib for the ROS1 subset is 57.1% (8 of 14 patients). This Phase 1 study is continuing enrollment, while crizotinib treatment will be evaluated in other cancers with ROS1 rearrangements, including glioblastoma multiforme and cholangiocarcinoma. Dr. Gregory Riely, of Memorial Sloan-Kettering Cancer Center, observed that studies like these signal a new approach to treatment discovery: find the target (in this case ROS1), find the drug, then find the patients. We are not just looking for a treatment for lung cancer, Dr. Riely noted, we are looking for a treatment for driver mutations that may be found in many cancers, where patients are identified through genomic screening. We ve already seen how certain targeted drugs, approved or studied in one cancer, are often studied for their effectiveness in other cancers that share the targeted mutation. Afatinib, for example, could be effective in both lung cancer and breast cancer. One of the most compelling examples of such crossover treatments was reported by Dr. Yael Mosse of Children s Hospital of Philadelphia. CONFERENCE HIGHLIGHT: TARGET AND COMBINE In metastatic disease, where we are going for one major target because there is one major driver mutation such as with basal cell cancers, ALK-mutated lung cancer, or BRAF-mutated melanoma, for example the majority of these patients will eventually go on to progress despite continued therapy. Based on this evidence, combination targeted therapies are the way to go forward. -Dr. Patrica LoRusso, Barbara Ann Karmanos Cancer Institute Phase 3 study results were reported for the targeted drugs vemurafenib, dabrafenib (BREAK 3 study) 13 and trametinib (METRIC study), 14 providing some hopeful news for patients with metastatic melanoma. All three drugs yielded substantial improvements in outcomes compared to chemotherapy. Patients treated with dabrafenib, a BRAF inhibitor, experienced a median PFS of 5.1 months. Vemurafenib, another BRAF inhibitor, extended that result to 6.9 months. And finally, trametinib, which targets a different part of the disease pathway involving the MEK protein, had a median PFS of 4.8 months. Compare these numbers to 1.6 to 2.7 months for standard chemotherapy measured in the trials, and it s clear we are going in the right direction. What is hidden in these numbers is that although the drugs may be an improvement over chemotherapy, with significantly fewer side effects and an improved quality of life for patients, at some point they lose effectiveness. Tumors mutate and become resistant to the targeted drug. Taking a more aggressive approach, clinical investigators are excited about the prospect of using a combination of targeted drugs to treat melanoma. By inhibiting multiple points of a disease pathway simultaneously, it might be possible to stop a tumor before it has a chance to develop resistance to treatment. Following up on this hypothesis, Dr. Jeffrey Weber presented an elegant Phase 1/2 combination study looking at the BRAF inhibitor dabrafenib combined with the MEK inhibitor trametinib. The response rate was an unprecedented 74%, and remarkably, progression free survival was extended to 10.8 months. Not only was the combination far superior, almost doubling time patients keep their cancer under control relative to either monotherapy vemurafenib or dabrafenib, but the combination evidently reduced the occurrence of common skin toxicities when either drug is used alone. About 38% of the patients were still undergoing treatment at the trial cutoff date, so follow-up reports will refine and may improve the numbers. Combination strategies came up several times during the meeting. Dr. Patrica LoRusso, who offered commentary at the end of the session, 16 said In metastatic disease, where we are going for one major target because there is one major driver mutation such as with basal cell cancers, ALK-mutated lung cancer, or BRAF-mutated melanoma, for example the majority of these patients will eventually go on to progress despite continued therapy. Based on this evidence, combination targeted therapies are the way to go forward. 3

5 Trend 2: Crossing Over One Drug, Many Cancers According to Mosse, a Phase 1 clinical trial of crizotinib for the treatment of ALK-driven tumors (the Childrens Oncology Group Study), suggests the drug to be safe and potentially effective for children with neuroblastoma, anaplastic large cell lymphoma (ALCL), or inflammatory myofibroblastic tumors (IMT). These are tumors that have no other targeted therapeutic option, so the results suggest a potential future when more easily tolerated and potentially more effective options are available to conventional chemotherapy. Interestingly, the fact that ALCL can be driven by an ALK gene rearrangement had been known for 25 years. There had been little effort by companies to develop a treatment for this type of cancer because it is so rare, affecting a few hundred children a year in the US. Eventually, it was discovered that ALK drives about 6% of lung cancers a substantial market leading ultimately to the approval of ALK targeted crizotinib in Now the circle has closed, enabling Mosse and colleagues to demonstrate that the same drug can be used to treat ALK-driven ALCL, IMT and neuroblastoma. The results were remarkable, with 7 of 8 ALCL patients having a complete response to the drug (the tumors disappeared,) and even demonstrating complete response or prolonged stable disease in familial neuroblastoma. Phase 2 trials are in the planning stages. It s a story that is likely to be repeated drug treatments will crossover to cancers that had been considered unique or even rare, but ultimately found to share a common driver mutation with another cancer. Crizotinib and mechanistically similar drugs may indeed be applied in the future to other cancers with an ALK-driven subset, including renal cell carcinoma, anaplastic thyroid carcinoma, and rhabdomyosarcoma. While there may be cases where the same genomic alteration does not connote the same sensitivity to the same kinase inhibitor in a different tumor type, an emerging consensus is that this will be the exception rather than the rule. Figure 3. Cancer complexity defies single marker characterization. While most known driver alterations were discovered in a specific tumor type, many are found across a broad number of disease states. Source: Levi A. Garraway, Dana-Farber / Harvard Cancer Center. 4

6 Trend 3: A Rising Call for Multiplexed Molecular Diagnostic Testing There are simply too many molecular and genomic categories with unique treatment protocols to characterize them serially, one gene or protein at a time. Dr. Pasi Jänne, Harvard Medical School and the Dana-Farber Cancer Institute. With cancer treatments guided increasingly by a tumor s molecular and genomic alterations versus its histology or tissue of origin, there was quite a bit of discussion around how genomic screening needs to adapt. Jänne noted that there was an explosion in understanding about the genomic complexity in lung cancer, and that except for certain very common alterations, it makes more sense to take a broader molecular profile of a tumor to guide treatment. There are simply too many molecular and genomic categories with unique treatment protocols to characterize them serially, one gene or protein at a time. He also pointed out that the cost of doing separate tests for different mutations can become prohibitively expensive up to ~$300,000/QALY for low frequency mutations in lung cancer, according to Dr. Natasha Leighl. Multiplex genomic testing using next-generation sequencing enables several hundred genes to be examined and can significantly change the logistics of the target and treat paradigm. This technology can discover single base pair substitutions, small insertions and deletions, copy number alterations and select rearrangement. Analyzing scores of genes for potentially actionable molecular targets, multiplex tests can both guide patients and physicians to the right treatment and also direct them to relevant clinical trials for promising drugs still in development. Jänne pointed out that in a genomic profiling initiative at the Dana Farber Cancer Institute, over 50% of lung cancer patients could be directed to appropriate treatment or ongoing clinical trials. Dr. Martine Piccart-Gebhart also advocated a more comprehensive approach to genomic profiling of tumors. 10 She described cancer genomics as a Darwinian evolutionary system with driver mutations whose effects are modified by somatic and epigenetic changes ( passenger mutations ) taking the tumor off to branching trajectories that can inhibit or enhance its survival. Successful treatment will need tracking of the clonal architecture of the disease. That may mean not only taking a broad genomic profile of the primary tumor, but two or more metastasized sites as well. CONFERENCE HIGHLIGHT: THE EVOLUTION OF TARGETED DRUGS Drug resistance, even to targeted therapies, is a persistent challenge, but if tumors have evolved to evade treatment, the technology of treatment is evolving to respond. One such technology, antibody drug conjugates, made a big splash at this year s ASCO event. One antibody drug conjugate, T-DM1, is a well-crafted weapon against metastatic breast cancer a smart bomb of sorts that links an antibody ( T for trastuzumab) already proven to home in on tumor cells harboring the HER2 receptor to a highly potent chemotherapy drug ( DM for derivative of maytansine). The conjugate is delivered right to the tumor, with little systemic toxicity, while the linker releases the microtubule-busting toxin as soon as the conjugate is internalized into the cell. A Phase 3 trial (EMILIA) comparing T-DM1 to capecitabine plus lapatinib for the treatment of HER2 positive breast cancer, was presented by Dr. Kimberly Blackwell of Duke Cancer Institute. 17 Speaking for her co-investigators, they were happy to report that patients treated with T-DM1 had improved responses (44% vs 31%), kept their disease under control for a longer period of time (9.6 months vs 6.4 months), experienced fewer side effects, and lived longer. Almost two-thirds of the patients taking T-DM1 were alive after two years, compared to less than half receiving caecitabine/lapatinib. Building on another trend the combination of targeted treatments a study coupling T-DM1 and pertuzumab is in the works. Pertuzumab is the first of a new class of therapeutic agents called HER dimerization inhibitors. By preventing HER2 dimerization at the cell surface, pertuzumab inhibits downstream signals that would otherwise stimulate tumor growth. Hitting the tumor with a one-two punch of T-DM1 and pertuzumab, it is hoped, may be more effective than either agent used alone. Dr. George Fisher from Stanford, commenting on next-generation sequencing, 11 the technology that will drive the future of multiplex gene analysis, said: The technology is incredibly enticing, the cost is decreasing, and patient demand is increasing. And Dr. George Sledge former president of ASCO, at the 2011 ASCO meeting predicted that the shift will create ripples that impact the way we do clinical trials: 12 We have next-generation sequencing. We need a next-generation clinical trials system, based on personal genomics. [ ] If we are to attack multiple targets simultaneously, we need investigators at many centers testing multiple combinations derived from genomic analysis of the primary or metastatic tumors of individual patients. 5

7 Conclusion We are entering a new era of understanding in the molecular anatomy and taxonomy of cancer, where the relevant designation may be something like BRAFdriven or ROS1-driven, cutting across multiple tissue types such as breast, lung or colon cancer. Treatment will be tailored to a tumor s genomic profile, with drugs that may be combined to hit several key targets at once. Pharmaceutical cocktails could have a similar impact in cancer to the way the same strategy had an impact on HIV treatment turning the tide on an intractable disease by hitting it hard before it has the chance to mutate, evolve, and thus evade treatment. Results presented at the 2012 ASCO meeting made it clear that there are potentially dozens of driver mutations in cancer. The only way to adequately characterize these tumors is to test for all of the potential genomic alterations at once, rather than one at a time, in the same way that a physician looks at multiple factors when taking a routine blood test. In fact, many predict that genomic profiling will become as routine at simple blood testing for every cancer patient. 1 Definitions: Targeted Therapies therapies designed to target molecular mechanisms of disease, based on knowledge of relevant variations between individuals with that disease, and by relevant molecular variations in the expression of that disease. ALK: Anaplastic lymphoma kinase gene which codes for a protein important to neurological development becomes oncogenic when fused with the nucleophosmin gene in anaplastic large cell lymphoma, or with the M+EML4 gene in non-small cell lung cancer BRAF: Codes for a serine/threonine-protein kinase that helps direct cell growth. This mutation has been linked to papillary thyroid carcinoma, colorectal cancer, melanoma and non-small-cell lung cancer HER2: Human Epidermal Growth Factor Receptor 2 is a protein encoded by the ERBB2 gene. It is a member of the epidermal growth factor receptor family. Over-expression of ERBB2 is known to contribute to progression of certain forms of breast cancer, and has recently been linked to other cancers KRAS: Kirsten rat sarcoma viral oncogene homolog. KRAS mutations are found in leukemias, colon cancer, pancreatic cancer, and lung cancer. MEK: A tyrosine/threonine kinase that is part of the MAPK/ERK pathway. Defects in the pathway can lead to uncontrolled cell growth. Several drug candidates target MEK to modify this pathway. MET: A gene that encodes hepatocyte growth factor receptor (HGFR), which has a role in embryonic development and wound healing. Overexpression is linked to poor prognosis in a variety of cancers. ROS1: The C-ros oncogene 1 codes for a receptor tyrosine kinase that plays a role in epithelial cell differentiation. Gene rearrangements involving ROS1 have been linked to lung cancer, breast cancer and glioblastoma among others References 2 Source: Jänne, Pasi. Treatment and Clinical Trial Design in the Era of Personalized Medicine ASCO Chih-Hsin Yang, James. LUX-Lung 3: A randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFRactivating mutations. (Abstract #LBA7500) ASCO Abstract no: LBA7500, LUX-lung 3: A randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFRactivating mutations. Oral Presentation at 48th Annual Meeting of the American Society of Clinical Oncology (ASCO) Rimassa, Lorenza. Tivantinib (ARQ 197) versus placebo in patients (Pts) with hepatocellular carcinoma (HCC) who failed one systemic therapy: Results of a randomized controlled phase II trial (RCT). (Abstract #4006) ASCO Tsang Shaw, Alice. Clinical activity of crizotinib in advanced non-small cell lung cancer (NSCLC) harboring ROS1 gene rearrangement. (Abstract #7508). ASCO Riely, Gregory. Discussion: Crizotinib Treatment for ROS1 Rearranged Lung Cancers ASCO Mosse, Yael. Efficacy of crizotinib in children with relapsed/refractory ALK-driven tumors including anaplastic large cell lymphoma and neuroblastoma: A Children s Oncology Group phase I consortium study. (Abstract #9500) ASCO Leighl, Natasha. Moving toward Personalized Medicine in Non-small Cell Lung Cancer: The Cost of Targeting Therapy, Including Diagnostics, Patient Selection, and Targeted Therapies ASCO Piccart-Gebhart. Martine. Discussion of Whole Genome Sequencing to Characterize luminal-type B.C ASCO Fisher, George. Poster Discussion Session: Gastrointestinal (Colorectal) Cancer Track. ASCO Sledge,George. The Challenge and Promise of the Genomic Era-- Presidential Address ASCO Hauschild, Axel. Phase III, randomized, open-label, multicenter trial (BREAK-3) comparing the BRAF kinase inhibitor dabrafenib (GSK ) with dacarbazine (DTIC) in patients with BRAFV600E-mutated melanoma. (Abstract #LBA8500) ASCO Robert, Caroline. METRIC phase III study: Efficacy of trametinib (T), a potent and selective MEK inhibitor (MEKi), in progression-free survival (PFS) and overall survival (OS), compared with chemotherapy (C) in patients (pts) with BRAFV600E/K mutant advanced or metastatic melanoma (MM). (Abstract #LBA8509) ASCO Weber, Jeffrey. Updated safety and efficacy results from a phase I/II study of the oral BRAF inhibitor dabrafenib (GSK ) combined with the oral MEK 1/2 inhibitor trametinib (GSK ) in patients with BRAFinaive metastatic melanoma. (Abstract #8510) ASCO LoRusso, Patricia. Clinical Development: MEK 2012 ASCO Blackwell, Kimberly. Primary results from EMILIA, a phase III study of trastuzumab emtansine (T-DM1) versus capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC) previously treated with trastuzumab (T) and a taxane. (Abstract #LBA1) ASCO 2012 Foundation Medicine gratefully acknowledges Mike Silver, Ph.D., for the research and writing of this document. 6

8 We welcome your feedback on this report, please get in touch! WWW To learn more about Foundation Medicine s fully informative genomic profile, visit foundation medicine, inc / one kendall square, b3501 / cambridge, ma / tel / / fax / info@foundationmedicine.com / FMI-O