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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.
Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study
Goss, G.a , Tsai, C.-M.b, Shepherd, F.A.c, et al.The Lancet Oncology, Volume 17, Issue 12, 1 December 2016, Pages 1643-1652
Commentary by Solange Peters
Patients with advanced NSCLC with a mutated EFGR tend to respond well to first-line EGFR TKIs but most progress after 9–13 months. The Thr790Met (T790M) mutation of the epidermal growth factor receptor (EGFR) gene is the most common mechanism underlying resistance to first- or second-generation EGFR tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). Repeated biopsy indicate that it is responsible for approximately 50–60% of acquired resistance cases, reducing binding of EGFR-TKIs to the receptor ATP-binding pocket and restoring affinity to ATP,
Osimertinib is an oral EGFR-TKI that is selective for both EGFR-TKI sensitising and showing robust clinical efficacy in patients with T790 M-mutated lung cancer
In this phase 2, open-label, single-arm study (AURA2), patients with centrally confirmed T790M EGFR -positive mutations who progressed on previous EGFR tyrosine-kinase inhibitor therapy received osimertinib 80 mg orally once daily; treatment could continue beyond progression if the investigator observed a clinical benefit. Patients with asymptomatic, stable CNS metastases not requiring steroids were allowed to enrol.
140 (70%; 95% CI 64–77) of 199 patients achieved an objective response by blinded independent central review: confirmed complete responses were achieved in six (3%) patients and partial responses were achieved in 134 (67%) patients. Osimertinib showed manageable side-effects.
Shortly after Aura 2, the Aura 3 trial was presented and published. In that trial patients with EGFR- T790M mutated advanced NSCLC given osimertinib had longer PFS and were more likely to respond to treatment than those given platinum plus pemetrexed after first-line EGFR tyrosine kinase inhibitor (TKI) therapy. Median PFS was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10·1 vs 4·4 months, hazard ratio 0·30, 95% CI 0·23–0·41, p<0·001), and was doubled in the 144 patients with CNS metastases (8·5 months with osimertinib vs 4·2 months with standard therapy).
These findings now firmly establish osimertinib as the routine treatment of choice in the setting of acquired resistance and T790M+ disease.
Pooled analysis of CNS response to alectinib in two studies of pretreated patients with ALK-positive non-small-cell lung cancer
Gadgeel, S.M. , Shaw, A.T., Govindan, R., Gandhi, L. et al.Journal of Clinical Oncology, Volume 34, Issue 34, 1 December 2016, Pages 4079-4085
Commentary by Tom Stinchcombe
Approximately 25% of patients with ALK rearranged NSCLC have brain metastases at the time of diagnosis.1 CNS progression is a common occurrence and is the only site of disease progression in approximately 25% of patients treated with crizotinib due to the to the relatively low CSF concentrations of crizotinib.2,3 This is a pooled analysis of two trials of alectinib in patients with progressive disease after receiving crizotinib, and evaluated the activity of alectinib for patients with CNS metastases. Of the 225 patients enrolled, 136 patients had CNS metastases (60% of the study population), and 95 patients had prior CNS radiation therapy (70%). For patients with baseline measurable CNS disease (n= 50), the CNS objective response rate by independent radiological review was 64% (95% CI, 49.2 to 77.1%) and the CNS disease control rate was 90.0% (95% CI, 78.2 to 96.7%). For the 41 patients without prior CNS radiotherapy the CNS objective response rate was 58.5% (95% CI, 42.1 to 73.7%) and the CNS disease control rate was 82.9% (95% CI, 67.9 to 92.9%). In the study population (n=225), 17% of patients had progressive disease in the CNS and for 11% of patients CNS was the sole cite of progression.
This combined analysis of alectinib trials demonstrates activity of alectinib in the treatment of CNS metastases, and high rate of disease control. The patients who did not receive prior CNS radiation therapy were most likely patients with asymptomatic CNS disease and smaller size of CNS metastases. The patients who received radiation include patients who received radiation > 6 months and ≤ 6 months. Thus, there is significant heterogeneity in the clinical characteristics of the patient population included in the analysis and clinicians should assess each patient individually when considering this data.
The use of first-line alectinib has the potential to reduce the rate of CNS disease progression and provide a longer duration of disease control for patients with CNS metastases. A carefully selected group of patients may be able to delay or avoid CNS radiation therapy and receive systemic therapy alone.
Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 InvestigatorsNew England Journal of Medicine, Volume 375, Issue 19, 10 November 2016, Pages 1823-1833
Commentary by Nir Peled
The success of this milestone study is an additional proof for the strength of precision medicine. The power to predict a positive response to pembrolizumab by PDL1>50% improved not only PFS, rather also overall survival although cross over was allowed for progressors. It may also suggest that we may have missed some patient who could have had a clinical benefit (PFS & QOL) from pembrolizumab even with a lower PDL1 cut-off. However, this is further to be investigated.
Another interesting perspective of this study is that it seems that ~50% of the NSCLC populations should not get chemotherapy for first line therapy (~20% fits for targeted therapy and 30% of the screened patients had PDL1>50%). In regions where EGFR+ is more frequent, it might be even a higher proportion of patients. Therefore, the urgent UNMET worldwide needs are immediate implementation of PDL1 staining and working hard on drugs' availability through risk sharing models between the industry and the payers with the assistance of the medical community.
Interpreting survival data from clinical trials of surgery versus stereotactic body radiation therapy in operable Stage I non-small cell lung cancer patients
Samson P, Keogan K, Crabtree T, Colditz G, Broderick S, Puri V, Meyers BLung Cancer, Volume 103, January 2017, Pages 6–10
Commentary by Stefan Zimmermann
Should operable stage I NSCLC patients undergo SBRT instead of surgery? This most debated question remains open, as landmark phase 3 randomized controlled trials fail to accrue. The north-american STARS trial randomized 36 patients out of 1030 planned, and the European ROSEL trial enrolled 22 patients out of 960 planned. This has not prevented the publication of a pooled post-hoc analysis by Chang and colleagues in the Lancet Oncology, suggesting a better 3-year OS in the SBRT “arm” (93%) compared with the 27-patients surgical “arm” (79%). Samson and colleagues elegantly suggest that these small sample sizes preclude any meaningful conclusion beyond hypothesis generation. By performing 10’000 resampling of 27 surgical patients out of a single-institution database of 749 clinical stage I, surgically resected NSCLC patients meeting the inclusion criteria of STARS and/or ROSEL, the resulting variability of 30-day mortality and 3 year OS was so large that conclusions can only be considered exploratory. Possible values for 3-year OS ranged from 46% to 100%. I regret that the clinical characteristics of the clinical stage I NSCLC used for the study do not mention the percentage of patients that were eventually surgically upstaged to N+; yet this does not change the bottomline: additional studies comparing SBRT with surgery in operable patients are warranted.
Activity of Erlotinib When Dosed Below the Maximum Tolerated Dose for EGFR-Mutant Lung Cancer: Implications for Targeted Therapy Development
Lampson BL, Nishino M, Dahlberg SE, Paul D, Santos AA, Jänne PA, Oxnard GRCancer, Volume 122, Issue 22, 15 November 2016, Pages 3456-3463
Commentary by Stefan Zimmermann
What do alectinib, brigatinib, gefitinib, osimertinib, dabrafenib have in common? Their package insert dose or dose under development lies below their maximum tolerated dose. Administering a targeted drug at its maximum tolerated dose might well reduce the main benefit of this type of therapy, namely increased efficacy AND decreased toxicity. With this in mind, Lampson and colleagues queried their single-institution database at the Dana-Farber Cancer Institute for patients treated with erlotinib for advanced EGFRm NSCLC, and examined the relationship of dose and response rate, PFS and OS. While arguably the sample size limits the statistical power to detect subtle differences, the findings are enlightening: reduced doses of ≤100mg daily result in a high response rate comparable with that reported at the maximal tolerated dose, PFS does not significantly differ, while there is a trend towards higher rates of progression within the central nervous system suggesting earlier pharmacokinetic failure. The study highlights the components that current dose-finding studies absolutely need to incorporate: target modulation endpoints, and multiple dose-expansion cohorts at various dose levels.
The race to target MET exon 14 skipping alterations in non-small cell lung cancer. The Why, the How, the Who, the Unknown, and the Inevitable
Thanyanan Reungwetwattana, Ying Liang, Viola Zhu, Sai-Hong Ignatius OuLung Cancer, Volume 103, January 2017, Pages 27-37
Commentary by Stefan Zimmermann
The development of MET inhibitors has been marred by the failure of multiple high-profile trials, most of them sharing a common flaw: inadequate biomarker-driven patient selection. Some have narrowed in on MET over-expression, some others on MET amplification, in spite of an incidence of de novo MET amplification below 1%, and MET amplification as a resistance mechanism to EGFR TKIs of only 5%. The resulting pessimism regarding MET as an actionable target is now being salvaged by our new-found understanding of MET exon 14 skipping alterations, which define a subgroup, 3% of both non-squamous and squamous advanced NSCLC, amenable to MET TKI therapy. Reungwetwattana and colleagues provide a timely and in-depth review of MET inhibitors currently in development, address the clinic-pathologic characteristics of METex14+ NSCLC patients, and potential strategies to overcome the inevitable resistance to MET TKIs. A nice read indeed.
The potent ALK inhibitor brigatinib (AP26113) overcomes mechanisms of resistance to first- and second-generation ALK inhibitors in preclinical models
Zhang S, Anjum R, Squillace R, Nadworny S, Zhou T, Keats J et al.Clinical Cancer Research, 2016 Oct 25. [Epub ahead of print]
Commentary by Tom Stinchcombe
Currently patients with ALK rearranged NSCLC receive crizotinib as first-line therapy and then at the time of disease progression receive a second generation ALK inhibitor (alectinib or ceretinib). Recent phase 3 trials have suggested a role for first-line use of second-generation ALK Inhibitors.4,5 The rate of ALK tyrosine kinase resistance mutations increases after the use of second-generation ALK inhibitors.6 Brigatinib (AP26113) inhibited the 17 clinically and preclinically observed resistance mutations, and demonstrated activity against the G1202R resistance mutation in cell line and xenograft models. Mouse models demonstrated CNS activity, and brigatinib may be able to achieve IC 90 concentrations in patients better than other ALK inhibitors These promising preclinical results will need to be validated clinically. The optimal sequence of ALK inhibitors is unknown, and further research into the mechanisms of resistance is required. Unlike EGFR mutant NSCLC there does not seem a single dominant mechanism of resistance.
1. Solomon BJ, Mok T, Kim DW, et al: First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 371:2167-77, 2014
2. Costa DB, Kobayashi S, Pandya SS, et al: CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol 29:e443-5, 2011
3. Solomon BJ, Cappuzzo F, Felip E, et al: Intracranial Efficacy of Crizotinib Versus Chemotherapy in Patients With Advanced ALK-Positive Non-Small-Cell Lung Cancer: Results From PROFILE 1014. J Clin Oncol 34:2858-65, 2016
4. Nokihara H, Hida T, Kondo M, et al: Alectinib (ALC) versus crizotinib (CRZ) in ALK-inhibitor naive ALK-positive non-small cell lung cancer (ALK+ NSCLC): Primary results from the J-ALEX study. Journal of Clinical Oncology 34:abstract 9008, 2016
5. De Castro Jr G, Shao-Weng Tan D, Crinò L, et al: First-line ceretinib versus chemotherapy in patients with ALK-rearranged (ALK+) NSCLC: A randomized phase 3 study (ASCEND-4) Journal of Thoracic Oncology 12:S4 (abstract PLO3.07), 2016
6. Gainor JF, Dardaei L, Yoda S, et al: Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer. Cancer Discov 6:1118-1133, 2016
Relationship between Overall Survival and Response or Progression-Free Survival in Advanced Non–Small Cell Lung Cancer Patients Treated with Anti–PD-1/PD-L1 Antibodies
Takehito Shukuya MD, PhD, Keita Mori PhD, Joseph M. Amann PhD, Erin M. Bertino MD, Gregory A. Otterson MD, Peter G. Shields MD, Satoshi Morita PhD, David P. Carbone MD, PhD
Journal of Thoracic Oncology, Volume 11, Issue 11, November 2016, Pages 1927 - 1939
Commentary by Nir Peled
Immunotherapy has been implemented and approved for 1st and 2nd line therapies in NSCLC, and PDL1 IHC staining has a strong positive prediction power for PD1/PDL1 efficacy. Upon this new player, immunotherapy, we should re-define the term "efficacy" as one of its most important measures is a long tail of overall survival, which may not be reflected sufficiently by the previous measures of overall response rate (ORR), progression free status (PFS) or even median overall survival (MOS). This is also important for the community to understand the relevant measures to assess the efficacy of the new agents.
Shukuya et al, have performed a systematic review of their prospective studies extracted from 12 arms in 10 reported clinical trials using PD1/PDL1 therapies. They showed that while ORR and median PFS had moderate association with median OS, disease control rate and PFS status at 8, 16 and 24 months were the best predictors for OS. This data may indicate for the need to develop new tools to better quantify the effect of these drugs.