Lisa Hutchinson

High drug attrition rates—where are we going wrong?

Drug attrition rates for cancer are much higher than in other therapeutic areas. Only 5% of agents that have anticancer activity in pre clinical develop ment are licensed after demonstrating sufficient efficacy in phase III testing, which is much lower than, for example, 20% for cardiovascular disease. To compound this issue, many new cancer agents are being withdrawn, suspended or discontinued. Figure 1 illustrates that this trend is extremely prevalent for VEGF inhibitors although less so for drugs targeting Aurora B kinase and some targeted therapies. The reasons for this high attrition rate are complex; however, several articles in this issue provide insights into why this is occurring. In essence, the pre clinical strategies to evaluate novel agents are sub optimal, and identifying the correct target using appropriate preclinical models will be critical to prevent further drug failures. Ian Tannock and coauthors discuss the limitations of preclinical models for drug assessment. A key drawback of animal models is that they do not represent the primary tumors from which they are derived in terms of tumor heterogeneity and the mechanisms of drug resistance. Xenograft models lack the broad molecular transformation events that occur in human tumors. Furthermore, since the stromal component of the tumor is not human the effects of the microenvironment on drug response are often not reflective of the primary tumor. Importantly, the growth rates of human-derived xenografts are considerably more rapid than primary tumors and, as a result, are much more likely to respond to anti proliferative agents. Testing of antiproliferative drugs in animal models might provide a false indication of the potential efficacy of a drug. Also, the immune system in such animal models is compromised, hindering the testing of immunomodulatory agents. Genetically-engineered mouse models circumvent some of these limitations as they are immune competent but they still suffer from having rodent-derived stroma. Getting the target right is a crucial aspect of drug development. Komlodi-Pasztor and coauthors discuss why mitosis-specific agents—including those that target aurora kinases and polo-like kinases—have limited success in the clinic, especially compared with micro tubule-targeting agents (MTAs) that have proved success ful despite both classes of agent having the same putative target. A closer examination of the mechanisms of action of MTAs reveals that they exert their effects not on mitosis but predominantly via interphase cellular mechanisms and microtubules, which are present in both mitotic and non-mitotic cells. Most human tumors divide slowly, and so mitosis is rare or absent; therefore, it is an unlikely target for MTAs. The doubling times in humans means that cancer cells multiply at similar rates to bone-marrow cells, explaining why agents that target mitosis also cause neutropenia and myelosuppression. Komlodi-Pasztor et al. state that although mitotic kinases produced disappointing results in the clinic, the drugs were well designed and had a valid target—that is mitosis —but unfortunately their efficacy was at the expense of high toxic effects and the fact that not many of the tumor cells were ‘druggable’ because the target was transient. However, agents that target mitotic kinases have a lower attrition rate compared with other (non-targeted) cancer drugs (Figure 1), which might be because the trial data are not mature but this is promising nevertheless. These findings emphasize the importance of identifying and validating the target and understanding resistance mechanisms. Interestingly, regarding correct target identification, the HER2-targeting agent trastuzumab may have limited benefit in patients with very high levels of HER2, as indicated by an inferior recurrence-free survival compared with patients who express more moderate levels of the target (Joensuu, H. et al. Ann. Oncol. doi:10.1093/annonc/ mdq710). This might explain why some patients with HER2-positive tumors do not respond to trastuzumab, as this agent might affect other HER family members or compromise downstream signaling effects if HER2 levels are extremely high. Ebos and Kerbel postulate why the success of antiangiogenic agents in the metastatic setting has not been mirrored in the adjuvant setting. They suggest the nature of disease progression following antiangiogenic therapy might be distinct to that seen with cytotoxics. Evidence from preclinical studies indicates that in certain situ ations antiangiogenics may increase invasiveness and metastatic potential. In orthotopically implanted mouse tumors, an increase in metastasis and shortened survival was seen when mice were treated with an anti-VEGF therapy before metastasis was induced—thus short-term treatment with antiangiogenic drugs may influence micrometastatic disease, which has critical implications for the preclinical models used in drug development. It is possible that if VEGF suppression is not sustained this could lead to a ‘rebound’ effect in terms of tumor growth. This may explain the results from the recent AVANT trial, in which a positive effect on progression-free High drug attrition rates—where are we going wrong?

Lung cancer: Squiring immunotherapy to CheckMate

In patients with advanced-stage squamous non-small-cell lung cancer (NSCLC) there remains a high unmet need to improve outcomes: over the past two decades, no new standard-of-care therapy has been approved. Now, two phase III studies of two different targeted agents for NSCLC show great promise in turning this trend around. Necitumumab, a second-generation anti-EGFR monoclonal antibody, was shown to be well tolerated in a phase I study. This finding prompted Nicholas Thatcher and coauthors to conduct the open-label, randomized phase III SQUIRE trial comparing necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone in patients with previously untreated stage IV squamous NSCLC. Patients with extensive metastatic disease who were assigned to the necitumumab combination had an improved overall survival (11.5 months versus 9.9 months) and corresponding significant improvement in progression-free survival (PFS). Thatcher puts these impressive results in context “SQUIRE was the first randomized phase III trial to show that the addition of a targeted agent to a platinum-based doublet improves survival in the first-line treatment of advanced-stage squamous NSCLC. These results confirm the benefit of the addition of an anti-EGFR antibody to standard chemotherapy in this setting, and represent clinically meaningful progress in the treatment of squamous NSCLC.” In the second study, CheckMate 017, 272 patients with stage IIIB or IV squamous NSCLC were randomly assigned to secondline therapy with docetaxel or the anti-PD-1 antibody nivolumab. Impressively, overall survival was significantly improved with nivolumab (9.2 months versus 6.0 months); moreover, the overall survival rate at 1 year was almost twice as high for nivolumab compared with docetaxel (42% versus 24%). The median PFS was also improved with nivolumab. Importantly, significantly fewer grade 3 adverse events were observed with nivolumab compared with docetaxel (7% versus 55%). Collectively, these results point to new standards of care in this patient population.

Targeted therapies: PARP inhibitor olaparib is safe and effective in patients with BRCA1 and BRCA2 mutations.

parp inhibitor olaparib is safe and effective in patients with BRCA1 and BRCA2 mutations Women who harbor BRCA1 or BRCA2 mutations have a high risk of developing breast and ovarian cancer. the BRCA1 and BRCA2 gene products are involved in a specialized form of Dna repair, known as homologous recombination. if the wild type BRCA allele in a tumor cell is lost, the repair mechanism is compromised and the resulting genetic instability can cause tumor development. Poly (aDP ribose) polymerase (ParP) is involved in repairing single-strand Dna breaks, and inhibition of ParP results in single-strand breaks that accumulate to form doublestrand breaks. these errors are repaired by components of the homologous recombination repair pathway, which includes BrCa1 and BrCa2. However, tumors that cannot repair their Dna owing to compromised BrCa function are highly sensitive to ParP inhibition. this finding provides the concept of synthetic lethality, whereby a lethal synergy occurs between two non-lethal events—in this case inhibition of ParP induces a genetic lesion that is lethal in patients who lack a functional Dna repair pathway owing to loss of BrCa function. Previous research by alan ashworth’s group in cell line models showed that when Dna repair is defective owing to loss of BrCa function, this defect was lethal when combined with induced loss of ParP, but only when cells lacked functional BrCa. thus, treatment with ParP inhibitors could be particularly beneficial in women with BRCA-mutated breast and ovarian cancers. andrew tutt, from alan ashworth’s group together with other international investigators, set out to show whether ParP was selectively lethal for tumors with loss of function of BRCA1 and BRCA2. olaparib is a novel, orally active ParP inhibitor that induces synthetic lethality in homozygous BRCA-mutated cells. a phase i study revealed that olaparib was safe and well tolerated as a single agent in BRCA mutation carriers. therefore, two proof-of-concept phase ii studies—one lead by andrew tutt and the other by william audeh—were carried out to test olaparib safety and efficacy in patients with advanced or recurrent breast or ovarian cancer who had BRCA1 or BRCA2 mutations. “targeting loss of BrCa1 or BrCa2 function with a ParP inhibitor can lead to a meaningful anticancer activity in patients who have had or become resistant to other forms of standard chemotherapy” explains tutt. in the first phase ii trial by tutt and coauthors, women with advanced breast cancer and BRCA1 or BRCA2 mutations who had received at least one chemotherapy regimen were enrolled in two sequential cohorts from 16 centers. in the first cohort, patients received 400 mg olaparib twice daily, and in the second cohort they received 100 mg olaparib twice daily. the primary end point was objective response rate (orr) and safety and tolerability were also assessed. the orr was higher in the first cohort than the second (41% versus 22%) and toxic effects—fatigue, nausea and vomiting— were mainly low grade and manageable. the median progression-free survival was 5.7 months for the high-dose cohort and 3.8 months for the low-dose cohort. in the second phase ii trial led by william audeh, the efficacy and safety of olaparib was tested at the 100 mg and 400 mg doses in women with recurrent ovarian cancer. in both phase ii studies, as the frequency of early progression was higher in the low-dose group the studies were amended to allow patients to receive the higher dose if disease progression occurred. the orr (primary end point of the trial) was 33% for the high-dose cohort and 13% for the low-dose cohort. median progression-free survival was 5.8 months for the high-dose group and 1.9 months for the low-dose group. the clinical benefit rate was higher in women receiving the 400 mg dose. the most frequent adverse effects were nausea and fatigue, but in general these were mild in intensity. as audeh observes “these patients were heavily pre-treated and some have had prolonged partial and complete responses”. the results from both studies show that the underlying pathways that are aberrant may be more important than the organ of origin when selecting therapy. “Currently, the presence of mutations in BRCA1 or BRCA2 does not inform systemic therapy recommendations for women with breast cancer, but the results of this and subsequent studies might change established practice” concludes tutt. audeh also notes “the implications of our trial suggest that a broader group of patients may benefit from ParP inhibitor therapy”. andrew tutt and his colleagues are now developing ParP inhibitors to test in clinical trials as single agents and in combination with standard therapies in a wider range of sporadic and BRCA1 BRCA2 associated breast, ovarian and other solid tumors.

Conflict of interest disclosures.

Aarabi, Bizhan Abbed, Khalid Abdel-Wanis, Mohamed Abdollah Zadegan, Shayan Abduljabbar, Fahad Abedi, Aidin Abiola, Godwin Abolfotouh, Sameh Abu-Bonsrah, Nancy Acharya, Shankar Achilles, Felix Adamski, Stanisław Adjei, Joshua Afaunov, Asker Agrahari, Yogendra Aguiar, Carlos Aguilar, Tania Aguiló, Daniela Ahangar, Pouyan Aharma, Pankaj Ahmad, Alaaeldin Ahmadje, Uzair Ahmed, A. Karim Ahmed, Ashfaq Ahmed, Naeem Ahn, Christine Ahn, Hyo Sae Ahuja, Christopher Ailon, Tamir Aiyer, Siddharth Ajello, Marco Ajit Kumar, N Akbar, Muhammad Akbulut, Deniz Aker, Loai Akgul, Turgut Akinjolire, Akinwande Akiyama, Shoshi Akoury, Elie Akula, Maheswara Akula, Yeswanth Alam, Waqar Alant, Jacob Albayrak, Akif Albayrak, Kutalmış Alberto Espitia, Carlos Alentado, Vincent Aleynik, Alexander Alfayez, Saud Alican, Mannuel Feliciano Alini, Mauro Alkadhaib, Bdulrahman Alkhalid, Yasmine Alkot, Amer Almairac, Fabien Almajed, Husam Al-Mutair, Abdulaziz Alonso, Fernando Alotaibi, Naif AlSaran, Yazeed Alshafai, Nabeel Alsultan, Omar Altafulla, Juan Altschul, David Amato, Mary Kate Amato-Watkins, Anthony Amirjamshidi, Abbas Ammar, Adam Amri, Khalil Anand, Manikant Anandan, Kavitha Ancheschi, Bruno Andersen, Mikkel Oesterheden Anderson, Melanie Andrade Neto, Jader Andresen, Andreas Kiilerich Angerler, Gerlinde Annamalai, Devadoss Annis, Prokopis Aoude, Ahmed Aranovich, Anna Araújo Ferreira da Silva, Igor Arce, Marysol Arnold, Joshua Arnold, Paul Arnone, Gregory Arora, Shobha Arreola Rodrı́guez, Erick Jeancarlo Arun, Mike Asano, Satoshi Assietti, Roberto Atesok, Kivanc Athanassacopoulos, Michael Attiah, Mark Auerswald, Marc Autore, Giovanni Ávila, Luiz Avilés, Carolina Awwad, Waleed Ayhan, Selim Azadmanjir, Zahra Aziz, Amer Aziz, Sheweidin Azkia, Ema Shofiana Babak Mirzashahi, Babak Badal, Tanya Bader, Khaldoun Badhiwala, Jetan Baharudin, Azmi Baisden, Jamie Baklanov, Andrey Baldew, Vyaas Balioglu, Mehmet Bulent Ballesteros, Vicente Banerjee, Purnajyoti Banta, Aditya Bao, Hongda Barbagallo, Giuseppe Barbero, Andrea Bari, Tanvir Johanning Barimani, Bardia Barna, Michal Barrey, Cedric Barry, Sean Barsotti, Carlos Eduardo Bartos, Marton Barzilai, Ori Basankin, Igor Bashir, Muhammad Farrukh Basiński, Krzysztof Basso, Marco Basu, Saumyajit Batista, Bernardo Batista, Marianna Batista, Mário Batista Jr, José Lucas Bayram, Serkan BC, Sureshkumar BCM, Prasad Becker, Christopher Beckerman, Daniel Beckett, Joel Bedoya, Maria Constanza Behr, Robert Beland, Benjamin Belatka, Jaroslav Bellabarba, Carlo Berbeo Calderon, Miguel Enrique Beretta, Matteo Berg, Andrew James Bernard, Jason Bernd, Wegener Berry, Abigale Global Spine Journal 2018, Vol. 8(1S) 375S-383S a The Author(s) 2018 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/2192568218777251 journals.sagepub.com/home/gsj

Skin cancer: Golden age of melanoma therapy

We have reached a golden era in oncology with exciting rapid developments in immunotherapy and targeted therapies that are providing significant survival improvements. Two papers recently published in the New England Journal of Medicine exemplify progress in the oncology field, and highlight new standards of treatment only a couple of years after other first-line therapies were approved in this setting, illustrating the speed at which these therapies have galvanized our treatment armamentarium. The global incidence of melanoma continues to increase, and although patients treated with the monoclonal antibody anti-CTLA-4 targeted agent ipilimumab have demonstrated improvements in both response rate and survival, the median duration of these responses is often less than 1 year. Although the use of combination therapy with BRAF and MEK inhibitors have provided good responses, only 40% of patients who harbour a BRAF V600 mutation benefit from such an approach. Thus, there remains an unmet medical need for improved therapies. Nivolumab, a fully human IgG4 antibody that inhibits the immunecheckpoint by targeting the programmed death 1 (PD-1) protein had previously shown very promising efficacy and safety results in a phase I study. Now, Caroline Robert and co-authors report the results of a phase III, randomized, doubleblind study that compared nivolumab with the commonly used chemotherapy agent dacarbazine (which remains a first-line therapy in many countries) in patients with previously untreated advancedstage melanoma who lacked BRAFV600 mutations and were thus unlikely to benefit from other targeted therapies. A total of 418 patients were randomly assigned to receive either nivolumab or dacarbazine: the 1-year overall survival rate was 72.9% for those receiving nivolumab compared with 42.1% in patients treated with dacarbazine. Median progression-free survival (PFS) was 5.1 months for patients in the nivolumab arm and 2.2 months for patients in the dacarbazine arm. Objective response rates were also substantially greater for nivolumab compared with dacarbazine (40.0% versus 13.9%). These results translate to a 58% decreased risk of death or disease progression with nivolumab compared with dacarbazine. Acquired resistance to BRAF inhibitors often develops owing to paradoxical activation of the MAPK compensatory pathway, and patients can also develop secondary skin tumours. However, combining a BRAF inhibitor with a MEK inhibitor can address the limitations of single-agent therapy. As Robert explains, “the strategy in this second trial is based on targeted therapy that combines antiBRAF and anti-MEK agents. The objective was to delay resistance and to fight the paradoxical activation of the MAPK pathway that is induced by anti-BRAF agents when used as monotherapy, and can lead to epithelial skin tumours.” In the second open-label, randomized, phase III study, 704 patients with metastatic melanoma and a BRAF V600 mutation were randomly assigned to receive the BRAF inhibitor dabrafenib and MEK inhibitor trametinib, or the BRAF inhibitor vemurafenib as monotherapy. At the preplanned interim analysis, the study protocol was amended to allow patients in the vemurafenib arm to crossover to the combination therapy arm. At 12 months, the overall survival rate was 72% in patients treated with the combination and 65% in those who received vemurafenib. Median PFS was 11.4 months for the combination therapy arm and 7.3 months for patients treated with vemurafenib. The rate of adverse effects were similar in both groups. The relative reduction in the risk of death was 31%. Skin adverse effects were less frequent with the combination therapy than with vemurafenib monotherapy, as were secondary skin tumours. The clinical findings in this trial correlates with preclinical data showing that addition of a MEK inhibitor can downregulate the BRAF-induced paradoxical activation of the MAPK pathway. Importantly, both studies were stopped before they reached the total number of events as a result of the impressive efficacy outcomes, and both trials demonstrated an overall survival benefit and met their primary end points. Robert provides some context regarding the impressive results of these two trials: “these studies represent new important steps forward not only in the field of melanoma, but also cancer in general. Less than 3 years and 4 years after vemurafenib and ipilimumab, respectively, were the first drugs to demonstrate an overall survival benefit in patients with metastatic melanoma, we now have two treatments that provide significantly better outcomes and will probably also be effective in other cancers.”

Personalized cancer medicine: era of promise and progress

Nowhere has the evolution of personalized medicine been more rapid than the field of oncology. advances in drug development, identification of multiple disease subtypes, and available high-throughput technologies have allowed treatment progress and a better understanding of cancer heterogeneity. successful personalized medicine requires a global collaborative effort so that diverse populations of cancer patients have the opportunity to participate in clinical trials with the latest innovative drugs. such a global effort was the basis for the generation of the worldwide innovative networking (win) Consortium, initiated by the institut Gustave roussy (iGr) and the mD anderson Cancer Center. the Consortium facilitates the collaboration between clinical cancer centers, industry, patient advocacy groups, government institutions and other stakeholders to enhance patient access to clinical trials and the latest therapies. in July 2010, win held its second annual conference, prompting Nature Reviews Clinical Oncology to commission a special focus issue on personalized medicine to highlight the latest advances, opportunities and challenges. a systems approach to medicine that includes predictive, personalized, preventive and participatory (P4) aspects was first described by leroy Hood more than 5 years ago to explain the growing trend that medicine is “moving from a reactive to a proactive discipline.” the ultimate goal of P4 medicine is to understand completely the complexity of biological networks that govern the carcinogenic process and to harness this information to provide better patient care. implementing P4 medicine in clinical practice requires that technical and societal barriers are overcome. in this issue, leroy Hood and stephen Friend discuss these challenges and posit that a systems approach to disease will provide new insights via the power ful new diagnostics and therapeutics available. However, the mining and integration of the billions of data points for each individual in order to construct models representing each patient’s wellness or disease continuum is key to achieving P4 medicine. as a testament to the participatory aspect of P4 medicine, Hood and Friend note that patients are already becoming partners in oncology trials, with trial participation and accrual being driven by patients—the million women study is a pertinent example. each cancer is as individual as the patient and continually evolves, and responses to therapies are equally varied—these facts will have a huge impact on the design of clinical trials, especially when thousands of patients are required to detect a small survival or clinical benefit. the business approach for drug development by pharmaceutical companies, and the FDa approval process, will need a radical change to synergize with the ever increasing pace and complexity of how to test the multitude of drugs in so many diseases. Conducting clinical trials with such high patient numbers to detect relatively small efficacy changes will become prohibitive. effective collaboration and innovative clinical trial designs are needed. researchers at the iGr offer their own perspective and novel suggestions as to how this could be achieved. they suggest patients who could be cured with available treatments should be treated at local, high-volume hospitals. For patients with a high risk of relapse who cannot be cured with conventional agents, newer effective drugs are needed; these patients will be included in trials evaluating new drugs and referred to specialized centers that have the capabilities to use high-throughput technologies for patient management. tursz et al. envisage biology-driven phase i and ii trials that include patient populations that are enriched for the candidate marker. if responses are observed in phase ii trials, in situations where a high sensi tivity to the drug is demonstrated, they believe it is not ethical to propose further phase iii testing but that conditional approval together with data from large phase ii trials should be sought to consolidate efficacy and safety findings. this would increase the number of biology-driven phase ii trials while decreasing the need for randomized phase iii studies. a key component to implementing this approach will require that biomarker data are accessible, consistently reported and that negative data relating to biomarker outcomes are published. with so many biomarker studies published, selective publication bias—leading to falsepositive findings—and complexities associated with multiple hypothesis testing can distort the true value of a biomarker. Fabrice andre and coauthors propose that a comprehensive biomarker registry be created for all biomarker studies (including negative data), which would initially focus on using specimens from randomized trials to help reduce bias and allow a standardized, highly accessible and more balanced evaluation of promising candidate biomarkers. appropriate biomarker testing and independent validation are critical to ensure that the biomarker registry fulfils its full potential, but i welcome the premise behind this initiative and look forward to more progress in the field of personalized medicine.

Oncology trials—the elephant in the room

Each year, when new annual cancer incidence and mortality statistics are published, the media are quick and happy to report that cancer mortality is reducing, despite some increases in incidence. There is a lot for the oncology community to celebrate and be proud of in these declining mortality rates and the decades of work that have produced them. However, late-phase clinical trials for anticancer drugs have the highest failure rates of all the clinical areas.1 Furthermore, those drugs that are successful often do not provide sufficient improvement on already available therapies, meaning that health-care providers often cannot afford to make them available to the patients they were designed for.2 Against this backdrop, it is time to discuss oncology clinical trials—the elephant in the room.

Can exemestane improve adjuvant treatment for postmenopausal women with primary breast cancer

Can exemestane improve adjuvant treatment for postmenopausal women with primary breast cancer?

Targeted therapies: Lapatinib is effective in patients with p95HER2-positive tumors

overexpression of Her2 occurs in approximately 20% of human breast cancers and is associated with a poor prognosis. although the anti-Her2 monoclonal antibody trastuzumab has improved survival outcomes, treatment resistance remains a challenge. trastuzumab resistance is partly explained by the coexpression of p95Her2, a truncated receptor fragment of Her2 that retains kinase activity but lacks the extracellular binding domain. p95Her2 is expressed in 30% of Her2-positive breast cancers and is associated with a reduced disease-free survival.

Targeted therapies: Activated PI3K/AKT confers resistance to trastuzumab but not lapatinib

Despite clinical benefits of Her2-targeted therapies in breast cancer, little progress has been made in understanding the resistance to such therapies. now a study by o’Brien and coauthors has unraveled the role of Pi3K/aKt signaling. “we observed that the majority of our trastuzumab resistant cell lines remain sensitive to lapatinib, providing further evidence that these two agents have independent mechanisms of resistance.” a major limitation of previous studies is that they have used only one or two cell models to identify specific alterations. to address this issue, o’Brien’s team adopted rigorous screening of 18 Her2positive breast cancer cell lines by twodimensional and three-dimensional drug response assays. “we calculate the growth rate of cells in the presence and absence of drug, which allows for any error in cell seeding,” o’Brien explains. Cell lines with increased Pi3K/aKt activity were resistant to trastuzumab TargeTed Therapies