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Characteristics and Outcomes of Patients with Lung Cancer Harboring Multiple Molecular Alterations: Results from the IFCT Study Biomarkers France
Nicolas Guibert MD, Fabrice Barlesi MD, PhD, Renaud Descourt MD, Hervé Léna MD, Benjamin Besse MD, PhD, Michèle Beau-Faller MD, PhD, Jean Mosser MD, PhD, Eric Pichon MD, Jean-Philippe Merlio MD, PhD, L'Houcine Ouafik MD, PhD, François Guichard MD, Bénédicte Mastroianni MD, Lionel Moreau MD, Annie Wdowik MD, Jean-Christophe Sabourin MD, Antoinette Lemoine MD, PhD, Pascale Missy PhD, Alexandra Langlais MSc, Denis Moro-Sibilot MD, PhD, Julien Mazières MD, PhD
Journal of Thoracic Oncology, Volume 12, Issue 6, June 2017, Pages 963 - 973
Commentary by Stefan Zimmermann
You believe that oncogenic molecular alterations are mutually exclusive? There are exceptions. This largest-ever cohort of NSCLC patients harboring multiple molecular alterations represents 0.9% of the French Biomarkers France database, accounting for 162 out of 17’664 patients. Interestingly, while OS was not decreased by the presence of double mutations, PFS under first-line therapy was decreased, especially so for EGFR mutated tumors harboring a concomitant KRAS mutation. Concomitant mutations associated with KRAS account for two thirds of all multiple alterations, with a detrimental effect on prognosis and response to platinum-based chemotherapy independent of other oncogenes. Interestingly, about 1.5% of EGFR mutated tumors contained a coexisting ALK rearrangement, with numbers too small to allow any conclusion on the treatment efficacy. Allelic frequencies were not reported, precluding any conclusion in this dataset on the clonal or subclonal nature of these alterations; the recent publication of the TRACERx study do show that driver mutations in EGFR, MET, BRAF are almost always clonal, with heterogeneous driver alterations such as PIK3CA occurring later in evolution. This highlights the challenged posed by tumor heterogeneity, most obvious in the context of targeted therapy.
Long-Term Results of a Trial of Concurrent Chemotherapy and Escalating Doses of Radiation for Unresectable Non–Small Cell Lung Cancer: NCCTG N0028 (Alliance)
Steven E. Schild MD, Shauna L. Hillman MS, Angelina D. Tan MS, Helen J. Ross MD, William L. McGinnis MD, Yolanda A. Garces MD, David L. Graham MD, Alex A. Adjei MD, PhD, James R. Jett MD, Mayo Clinic, North Central Cancer Treatment Group.
Journal of Thoracic Oncology, Volume 12, Issue 4, April 2017, Pages 697 - 703
Commentary by Tom Stinchcombe
The publication by Schild et al reports the long-term results of a phase I/II trial concurrent chemotherapy (carboplatin and paclitaxel weekly) with escalating dose of radiation in unresectable non-small cell lung cancer (NSCLC). The phase 2 portion of the trial was never completed. The maximum tolerated disease was 74 Gy in 37 fractions. Of the 25 patients enrolled 20 patients had stage III disease. The median survival and 5-year survival among patients with stage III NSCLC was 39.8 months and 15%, respectively. Grade 5 adverse events occurred in 4 of the 25 patients and included pneumonitis, infection/febrile neutropenia (2 patients), and gastrointestinal hemorrhage. Importantly, each radiation treatment plan was reviewed for quality of assurance before any therapy and any deviations from the guidelines were corrected before treatment was initiated. The patients treated on this trial had numerically lower radiation dose to heart than patients in the RTOG 0617 high dose arm. The careful quality assurance of radiation treatment planning may have contributed to the good outcomes observed on this trial. The use of high dose thoracic radiation therapy should not be done outside of a clinical trial, based on the results of RTOG 0617 which revealed an inferior survival with 74 Gy compared to the 60 Gy.
Oncogene addiction in non-small cell lung cancer: Focus on ROS1 inhibition
Francesco Facchinettia, Giulio Rossi, , Emilio Bria, , Jean-Charles Soria, Benjamin Besse, Roberta Minari, , Luc Friboulet, Marcello Tiseo
Cancer Treatment Reviews 55 (2017) 83–95
Crizotinib is approved in the United States and Europe for treatment of ROS1 rearranged non-small cell lung cancer. The detection of this rare oncogenic driver can be challenging with concerns about false positive and false negative test results. The two molecular approaches for diagnosis include in-situ testing (fluorescence in situ hybridization and immunohistochemistry) and extractive testing (real time PCR and next generation sequencing). Each of these methods has strengths and weaknesses which are reviewed in this publication. The European Board of pathologists recently proposed a clinical practice algorithm of IHC screening and further confirmation by ROS1 FISH assay in the IHC positive and cases where there is doubt about the accuracy of the results. There is a tendency to think of ALK and ROS1 interchangeably since both are sensitive to crizotinib, but there are important differences. For example of the second generation ALK inhibitor ceritinib is only slightly more active than crizotinib and alectinib is inactive. Similar to ALK acquired resistance mutations develop and the specific mutation (e.g. L1951R, S1968Y/F, L2026M, G2032R, and D2033N) may impact the activity of tyrosine kinase inhibitors. A number of clinical trials are enrolling treatment naïve, and patients who have previous received crizotinib.
Randomized Phase III Trial of Erlotinib versus Docetaxel in Patients with Advanced Squamous Cell Non–Small Cell Lung Cancer Failing First-Line Platinum-Based Doublet Chemotherapy Stratified by VeriStrat Good versus VeriStrat Poor. The European Thoracic Oncology Platform (ETOP) EMPHASIS-lung Trial
Solange Peters MD, PhD, Rolf A. Stahel MD, Urania Dafni ScD, Santiago Ponce Aix MD, Bartomeu Massutí MD, Oliver Gautschi MD, Linda Coate MD, Ana López Martín MD, PhD, Robbert van Heemst MD, Thierry Berghmans MD, PhD, Peter Meldgaard MD, PhD, Manuel Cobo Dols MD, Javier Garde Noguera MD, Alessandra Curioni-Fontecedro MD, Daniel Rauch MD, Michael T. Mark MD, Sinead Cuffe MD, Bonne Biesma MD, PhD, Arjen M.J. van Henten MD, Óscar Juan Vidal MD, PhD, Ramón Palmero Sanchez MD, José Carlos Villa Guzmán MD, Ricardo Collado Martin MD, Sergio Peralta MD, Amelia Insa MD, Yvonne Summers MD, István Láng MD, PhD, ScD, Anne Horgan MB, Fortunato Ciardiello MD, PhD, Sander de Hosson MD, Remge Pieterman MD, PhD, Harry J.M. Groen MD, PhD, Paul M. van den Berg MD, Christoph C. Zielinski MD, Yojena Chittazhathu Kurian Kuruvilla MD, Adriana Gasca-Ruchti MD, Marie Kassapian PhD, Silvia Novello MD, PhD, Valter Torri MD, Zoi Tsourti PhD, Vanesa Gregorc MD, Egbert F. Smit MD, PhD, for the, EMPHASIS-lung Collaborative Group.
Journal of Thoracic Oncology, Volume 12, Issue 4, April 2017, Pages 752 - 762
Commentary by Solange Peters
The use of erlotinib (E) in the late-line setting for patients with EGFR WT squamous cell carcinoma of the lung sq NSCLC remains a valid clinical option, possible in third line in patients with PS 0-1 (selected PS2) and second line in PS2-3, taking into account the available options of docetaxel (D) as well as checkpoint inhibitors.
Despite a series of clinical trials attempting to compare the standard second line chemotherapy D to E in second line treatment of unselected NSCLC, no formal difference in their respective antitumor activity could be clearly demonstrated to date. A recent meta-analysis of relevant clinical trials was concluding that among patients with advanced NSCLC harboring wt EGFR, conventional chemotherapy, compared with first-generation EGFR TKI, was associated with improvement in PFS but not OS. Therefore, any parameter or biomarker supporting strategy decision would be of help in this late line scenario in unselected advanced sqNSCLC.
The clinically validated serum proteomic test Veristrat (VS) is used to classify patients as Veristrat good (VSG) or poor (VSP). Retrospective studies have shown that patients with VSG have a significantly better outcome than do those classified as VSP when treated with EGFR tyrosine-kinase inhibitors (TKI). In the randomized Phase III study PROSE, patients with a proteomic test classification of poor (VSP) had worse OS on E than on chemotherapy, while there was no significant difference in OS between treatments for patients with a proteomic test classification of good (VSG).
The final analysis of EMPHASIS did not show a differential activity on PFS of E vs D in SqNSCLC pts by VS status. These results are at variance with previous early retrospective studies and the PROSE trial. In the combined sqNSCLC cohort of EMPHASIS and PROSE- VSG patients demonstrated a significantly lower risk of progression and death compared to VSP, but the combined analysis of EMPHASIS and PROSE-Sq- was not able to reproduce a predictive ability of the VS test, showing a differential activity of E vs D for different VS classification in advanced SqNSCLC.
This analysis is relevant, suggesting that the FDA-approved Veristrat test should not be used in advanced sqNSCLC for treatment decision making process.
Synergy between next generation EGFR tyrosine kinase inhibitors and miR-34a in the inhibition of non-small cell lung cancer
Jane Zhao, Adriana Guerrero, Kevin Kelnar et al.Lung Cancer, Volume 108, June 2017, Pages 96-102
Commentary by Solange Peters
In this article, aiming at addressing the low sensitivity of EGFR wild-type (WT) NSCLC patients to EGFR TKIs as well as the inevitable scenario of EGFR TKI resistance in mutated EGFR NSCLC, authors explore a combination of miRNAs and EGFR TKIs in EGFR mutated and WT cell lines. Human NSCLC cell lines with varying degrees of primary and acquired resistance to erlotinib are assessed for sensitivity to a broad set of combined doses of miR-34a mimic and EGFR TKI afatinib, rociletinib or osimertinib. Various analytical approaches are used to characterize effects on cancer cell proliferation demonstrating a synergistic effect across a broad range of dose levels and drug ratios, with maximal synergy at doses yielding high levels of inhibition beyond those possible to be induced by the single agents alone.
MicroRNAs (miRNAs) are naturally occurring, short non-coding RNAs that modulate the expression of hundreds of genes across distinct cellular pathways, governing a plethora of cellular processes including tumor suppression. Recently, miRNAs were detected in serum and plasma of humans and animals, opening the possibility of using miRNAs as diagnostic biomarkers of various diseases.
Evidence that dysregulated miRNAs play a role in diseases such as cancer has positioned miRNA-seq to potentially become an important tool in the future.
Bioinformatic target prediction is often the first step toward defining the function of a specific miRNA. Currently, there are a number of freely available programs, such as miRanda (http://www.microRNA.org), microCosm (http://www.mirbase.org), Targetscan (http://www.targetscan.org), or PicTar (http://pictar.mdc-berlin.de) that will help predict which mRNAs a miRNA can potentially target or which miRNAs might be able to target a certain gene of interest. Combining the results of different target prediction programs to look for overlap in predicted targets between the different programs will result in the highest specificity but lowest sensitivity.
The tumor suppressor miR- 34a represses the expression of >30 oncogenes as well as genes involved in tumor immune evasion (e.g. PD-L1).
While these data are of great interest, two challenges remain to be urgently faced. Firstly, the mechanism of action of miR-34a in general and in this specific context is unknown. Synergy in these cells derives from the fact that the tumor suppressive mechanisms of miR-34 and EGFR TKIs are substantially different: miR-34 represses many oncogenes in various pathways – the specific activity of which should be studied in this model. Its activity might be completed by the EGFR pathway inhibition, which remains to be shown. The focus should now be on better understanding the molecular mechanisms that drive a potential in vitro synergism.
Second, the therapeutic opportunities and in particular limitations should be discussed. The relative ease by which miRNAs can be manipulated pharmacologically provides interesting therapeutic opportunities. There are several tools available to selectively target miRNA pathways, but, by far, the most widely used approach to regulate miRNA levels in vivo is by using antimiRs. AntimiRs are modified antisense oligonucleotides harboring the full or partial complementary reverse sequence of a mature miRNA that can reduce the endogenous levels of a miRNA
Recently, the therapeutic applicability of LNA-antimiR technology has been reported in rodents and nonhuman primates. The LNA modification leads to a thermodynamically strong duplex formation with complementary RNA, and systemic delivery of unconjugated LNA-antimiR potently antagonized the liver-expressed miR-122 in mice and nonhuman primates. However, although these antimiR approaches are very effective in inhibiting a miRNA in vivo, one should consider that systemic delivery might induce unknown off-target effects and that the effect observed might be attributable to effects outside of the target tissue. Development paths of such technologies should be evoked.
Patterns of initial and intracranial failure in metastatic EGFR-mutant non-small cell lung cancer treated with erlotinib
Suchit H. Patel, Andreas Rimner, Amanda Foster et al.Lung Cancer, Volume 108, 1 June 2017, Pages 109-114
Commentary by Nir Peled
Most, if not all EGFR+ patients will progress on EGFR TKI and therefore understanding the mode of progression is important. Local control seems to be the main site of progression in 60% of those pts who were treated by erlotinib and therefore it might be that there is a role for palliative therapy for the main disease site. However, such therapy should show an added clinical valued e.g. survival or symptomatic benefit, as exists in extensive SCLC.
Masha Zeltsman, Jordan Dozier, Erin McGee et al.Translational Research, Available online 26 April 2017 https://doi.org/10.1016/j.trsl.2017.04.004
Commentary by Nir Peled
Immunotherapy has changed the treatment paradigm in lung cancer, however hardly half of the patients respond to immunotherapy in the best current circumstances (PDL1>50% 1st line for pembrolizumab). In the 2nd line setting and when lowering the bar of PDL1, most of the patients do not respond and only the minority of the patients will have a durable respond. Therefore, the current UNMET need is to find further ways to engage the immune system upfront and on progression. The use of common tumorous antigen combined with synthetic receptors that enhance T-cell antitumor effect seems to be a promising avenue for those cases that need immune accelerator if of checkpoint inhibitors are not enough. This is only one further mechanism which indicates that the PD1 story is only the beginning.
Clinical Outcome of ALK-Positive Non–Small Cell Lung Cancer (NSCLC) Patients with De Novo EGFR or KRAS Co-Mutations Receiving Tyrosine Kinase Inhibitors (TKIs)
Sabine Schmid MD, Oliver Gautschi MD, Sacha Rothschild MD, Michael Mark MD, Patrizia Froesch MD, Dirk Klingbiel Dsc, Hermann Reichegger MD, Wolfram Jochum MD, Joachim Diebold MD, Martin Früh MD
Journal of Thoracic Oncology, Volume 12, Issue 4, April 2017, Pages 681 - 688
Commentary by Stefan Zimmermann
How should you treat your patients with NSCLC harboring both an ALK rearrangement and a KRAS mutation? We do know that intratumor heterogeneity will fuel drug resistance and tumor evolution. Recent efforts have highlighted the patterns of NSCLC evolution, with early clonal genome doubling followed by subsequent subclonal diversification. (For a most interesting read, please peruse “Tracking the Evolution of Non–Small-Cell Lung Cancer” by Jamal‑Hanjani et al, New England Journal of Medicine 2017) The resulting evolutionary side-branches may rarely lead to the co-occurrence of a targetable alteration in ALK or EGFR, and a currently un-targetable alteration in KRAS. The present series, the largest to date, presents the clinical outcomes of patients treated with TKIs, and strongly suggests a high degree of resistance to ALK TKIs in this setting. Patients with co-occurring EGFR and KRAS mutations seem to fare better with EGFR TKIs, although the sample size is admittedly too small to draw firm conclusions.
A Dose Escalation Clinical Trial of Single-Fraction Carbon Ion Radiotherapy for Peripheral Stage I Non–Small Cell Lung Cancer
Naoyoshi Yamamoto MD, PhD, Tadaaki Miyamoto MD, PhD, Mio Nakajima MD, PhD, Masataka Karube MD, Kazuhiko Hayashi MD, PhD, Hiroshi Tsuji MD, PhD, Hirohiko Tsujii MD, PhD, Tadashi Kamada MD, PhD, Takehiko Fujisawa MD, PhD
Journal of Thoracic Oncology, Volume 12, Issue 4, April 2017, Pages 673 - 680
Commentary by Stefan Zimmermann
Compared with conventional radiotherapy, particle beam radiotherapy, and in particular heavy-ion radiotherapy such as carbon-ion radiotherapy (CIRT) possess unique physical and biological characteristics: low entry dose but high energy release at the end of the flight path (the famed “Bragg peak”), sharper dose distribution with less scatter and little penumbra, as well as no oxygen-dependence and little cell-cycle radio-sensitivity. This makes CIRT uniquely suited for otherwise untreatable radio-resistant disease, hypoxic tissues, and targets located close to vital radiosensitive normal tissue. While Japan has pioneered in the development of CIRT, the technology is garnering worldwide interest, and several European, Asian, and American projects are underway. The Heidelberg center in Germany is conducting several randomized trials. How the technique compares with conventional therapies is of obvious interest: hypofractionated stereotactic radiotherapy is a de facto standard in inoperable patients with early NSCLC, and a serious challenger in operable patients, although the question is unlikely to get a clear cut answer due to sluggish patient enrollment in randomized trials. In the present series, interesting results are reported by the Japanese National Institute of Radiological Sciences, demonstrating the feasibility of a single fraction, the safety of dose-escalation and very encouraging local control and survival data in the higher-dose cohorts.
Mok TS, Wu Y-L, Ahn M-J et al.New England Journal of Medicine, Volume 376, Issue 7, 16 February 2017, Pages 629-640
Commentary by Nir Peled
The clinical evidence for targeted therapy has gotten another strong validation by this phase III randomized study, comparing osimertinib to platinum doublet in EGFR+ T790M positive NSCLC patients who progressed on EGFR related therapy. Osimertinib succeeded to duplicate the 1st line results and further shows an excellent response in the CNS. This study also provides a support for the decision makers who approved osimertinib for this indication upon the previous phase II study. The latter emphasizes the power of precision medicine and may indicate that drug approval may bypass the need for long-term big phase III studies. The current challenges would be to incorporate liquid biopsy for fast diagnosis of the T790M resistant mutation, to reimburse the drug and to face with the next resistant mechanism such as C797S.
Vandetanib in patients with previously treated RET-rearranged advanced non-small-cell lung cancer LURET: an open-label, multicentre phase 2 trial
Yoh K, Seto T, Satouchi M et al.The Lancet Respiratory Medicine, Volume 5, Issue 1, 1 January 2017, Pages 42-50
Commentary by Solange Peters
Cabozantinib and vandetanib are multitarget tyrosine kinase inhibitors (TKIs), being used for the treatment of metastatic medullary thyroid carcinoma harbouring RET mutations or chromosomal rearrangements of the RET receptor tyrosine kinase. RET fusion is a rare event, identified in less than 2% of unselected NSCLC, with an enrichment in never smokers and younger patients subpopulations.
Drilon et at report the activity of cabozantinib in 26 patients with RET fusion-positive NSCLC, namely a RR of 28%, a median PFS of 5·5 months and a median OS of 9·9 months.
Yoh et al report the activity of vandetanib in 19 RET fusion-positive 17 patients, with an objective RR of 47%, and a median PFS of 4·7 months.
Interestingly, in both trials, different types of RET fusions were demonstrating different sensitivities to RET inhibitors.
Both trials pave the way for tailored treatment in patients with RET fusion-positive NSCLC, although clinical benefit of both TKIs was some disappointing as compared to the EGFR, ALK or ROS1 oncogene addiction. RET rearrangements are structurally similar to ALK and ROS1 rearrangements in that they retain an intact tyrosine kinase domain fused to a variety of upstream gene partners.
Of note, Cabozantinib also inhibits MET, VEGFR2, ROS1, and AXL, whereas vandetanib is also an EGFR, and VEGFR inhibitor. A rational argument for a somehow weaker activity than what could be expected would be that some of these drugs were not optimally designed to inhibit RET, or alternatively that their lack of specificity might significantly limit their therapeutic window. Another option might be that drug combinations are needed to sufficiently block RET downstream signalling, as observed in the context of BRAF driver mutations.
Several multikinase inhibitors with activity against RET are currently in preclinical and clinical testing for patients with RET-rearranged lung cancers, including lenvatinib, ponatinib, and alectinib.