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The use, safety and effectiveness of crizotinib as part of the management of ROS1-rearranged NSCLC patients in a real-world Canadian clinical cohort was the focus of this retrospective review. Twenty-one ROS1-rearranged patients with advanced/metastatic disease receiving crizotinib between 2014-2020 were identified; crizotinib demonstrated tolerability and effectiveness in this population where outcomes were similar to those described in other crizotinib-treated real-world cohorts, but lower than those of the PROFILE 1001 clinical trial population. Systemic anti-cancer therapy prior to crizotinib initiation occurred in half of the study cohort, with platin-pemetrexed and immune checkpoint inhibitors being most common. Platin-pemetrexed showed good effectiveness in this cohort, but despite high prevalence of upregulated PD-L1 expression, immune checkpoint inhibitors showed poor effectiveness in his cohort. Among all systemic therapies received, crizotinib showed the most effective disease control, although longer intervals between diagnosis and crizotinib initiation were more common among those showing a lack of clinical response to crizotinib, and patients with brain metastases at the time of crizotinib initiation also showed increased diagnosis to crizotinib initiation intervals and decreased clinical response to crizotinib. This study reveals crizotinib has clinical benefit, but timely identification of ROS1-rearrangements and initiation targeted therapies appears important to maximize outcome in this population.

Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) have limited treatment options, particularly if they are transplantation or chimeric antigen receptor (CAR) T-cell ineligible, and novel therapeutics are needed. An 86-year-old woman with relapsed DLBCL received a novel, first-in-class small molecule inhibitor of N-myristoyltransferase (NMT) as the initial patient on a phase I dose escalation trial. Daily oral administration of 20 mg PCLX-001 tablets produced a pharmacokinetic profile suitable for single daily dosing: rapid oral absorption, followed by an apparent elimination half-life of 16 h, without systemic accumulation of drug by day 15. Pharmacodynamic tests showed no clear change in NMT1 and NMT2 levels or selected NMT substrate Lyn and HGAL protein levels in normal circulating blood mononuclear cells, suggesting a higher dose will be required for normal tissue toxicity. The patient did not experience any dose-limiting toxicities but had disease progression after 28 days of study therapy. Dose escalation continues in other patients in this first-in-human study of a new class of anticancer drug. We conclude that PCLX-001 oral monotherapy has suitable pharmacokinetic parameters for dose escalation, and that higher doses are required to achieve pharmacodynamic evidence of on-target activity in normal tissues. The current protocol is appropriately designed to achieve these ends, and the study proceeds without modification.

Diffuse large B cell lymphoma (dlbcl) is an aggressive non-Hodgkin lymphoma, accounting for approximately 30% of lymphoma cases in Canada. Although most patients will achieve a cure, up to 40% will experience refractory disease after initial treatment, or relapse after a period of remission. In eligible patients, salvage therapy followed by high-dose therapy and autologous stem-cell transplantation (asct) is the standard of care. However, many patients are transplant-ineligible, and more than half of those undergoing asct will subsequently relapse. For those patients, outcomes are dismal, and novel treatment approaches are a critical unmet need. In this paper, we present available data about emerging treatment approaches in the latter setting and provide a perspective about the potential use of those approaches in Canada., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare the following interests: Medical writing support provided by Anna Christofides of impact Medicom Inc. was funded by Hoffmann–La Roche Canada Inc. SA has received honoraria for consulting purposes from Janssen, Gilead, and Hoffmann–La Roche. DM has received honoraria for consulting purposes from Hoffmann–La Roche/Genentech, AbbVie, Amgen, AstraZeneca, Celgene, Gilead, Janssen, Lundbeck, Merck, and Seattle Genetics. AP has received honoraria for consulting purposes from AstraZeneca and AbbVie. RS has received honoraria for consulting purposes from Pfizer, Boehringer Ingelheim, AstraZeneca, Hoffmann–La Roche/Genentech, Lundbeck, Eli Lilly, Bristol–Myers Squibb, Merck, AbbVie, Novartis, and Takeda. BAM is an employee of Hoffmann–La Roche Canada Inc. LHS has received honoraria for consulting purposes from Hoffmann–La Roche/Genentech, AbbVie, Amgen, Apobiologix, AstraZeneca, Acerta Pharma, Celgene, Gilead, Janssen, Kite, Karyopharm, Lundbeck, Merck, MorphoSys, Seattle Genetics, Teva, Takeda, TG Therapeutics, and Versatem Oncology. She has also received research funding from Hoffmann–La Roche/Genentech. PS has no conflicts to disclose.

Immune checkpoint inhibitors have revolutionized care for many cancer indications, with considerable effort now being focused on increasing the rate, depth, and duration of patient response. One strategy is to combine immune strategies (for example, ctla-4 and PD-1/L1-directed agents) to harness additive or synergistic efficacy while minimizing toxicity. Despite encouraging results with such combinations in multiple tumour types, numerous clinical challenges remain, including a lack of biomarkers that reliably predict outcome, the emergence of therapeutic resistance, and optimal management of immune-related toxicities. Furthermore, the selection of ideal combinations from the myriad of immune, systemic, and locoregional therapies has yet to be determined. A longitudinal network-based approach could offer advantages in addressing those critical questions, including long-term follow-up of patients beyond individual trials. The molecular cancer registry Personalize My Treatment, managed by the Networks of Centres of Excellence nonprofit organization Exactis Innovation, is uniquely positioned to accelerate Canadian immuno-oncology (io) research efforts throughout its national network of cancer sites. To gain deeper insight into how a pan-Canadian network could advance research in io combinations, Exactis invited preeminent clinical and scientific advisors from across Canada to a roundtable event in November 2017. The present white paper captures the expert advice provided: leverage longitudinal patient data collection; facilitate network collaboration and assay harmonization; synergize with existing initiatives, networks, and biobanks; and develop an io combination trial based on Canadian discoveries., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare the following interests outside the submitted work: VH is an employee of Exactis Innovation; RF is the ceo of Exactis Innovation; GB has received research funding from several pharmaceutical companies and is the cmo of Exactis Innovation; PKC has received fees as an advisory board member for Bristol–Myers Squibb, Merck, AstraZeneca, Pfizer, and Roche; HLM has received fees as an advisory board member for Merck, Spectrums, Syndax Pharmaceuticals, obi Pharma, Calithera, Roche, Lilly, Peregrine, TapImmune, Amgen, Puma, Pfizer, and Immunomedics, and has received research funding from Bristol–Myers Squibb, MedImmune, Ziopharm, Eli Lilly, and Merck; TMP has received advisory board member fees from Bristol–Myers Squibb, Merck, and Incyte, and a grant from Roche; RS has received honoraria from Pfizer, and honoraria or advisory board fees from Boehringer Ingelheim, AstraZeneca, Roche, Lundbeck, Bristol–Myers Squibb, Merck, AbbVie, and Takeda; MFS has received honoraria from Amgen; JS is a permanent member of the scientific advisory board of Surface Oncology and owns stock in Surface Oncology; DJS has received honoraria or consulting or advisory board fees from Roche, Boehringer Ingelheim, Novartis, Merck, AstraZeneca, Bristol–Myers Squibb, and Exactis, and scientific writing or clinical trials support from Boehringer Ingelheim, AstraZeneca, Novartis, Bristol–Myers Squibb, and Celgene; SV has received fees as an advisory board member for Amgen, Lilly, AstraZeneca, Novartis, Pfizer, and Roche, and is the co-founder and medical director of OncologyEducation.com (uncompensated). BM, DM, and SSS have no conflicts of interest to disclose.

Background: Inhibition of the anaplastic lymphoma kinase (alk) oncogenic driver in advanced non-small-cell lung carcinoma (nsclc) improves survival. In 2015, Canadian thoracic oncology specialists published a consensus guideline about the identification and treatment of ALK- positive patients, recommending use of the alk inhibitor crizotinib in the first line. New scientific literature warrants a consensus update., Methods: Clinical trials of alk inhibitor were reviewed to assess benefits, risks, and implications relative to current Canadian guidance in patients with ALK- positive nsclc., Results: Randomized phase iii trials have demonstrated clinical benefit for single-agent alectinib and ceritinib used in treatment-naïve patients and as second-line therapy after crizotinib. Phase ii trials have demonstrated activity for single-agent brigatinib and lorlatinib in further lines of therapy. Improved responses in brain metastases were observed for all second- and next/third-generation alk tyrosine kinase inhibitors in patients progressing on crizotinib. Canadian recommendations are therefore revised as follows:■ Patients with advanced nonsquamous nsclc have to be tested for the presence of an ALK rearrangement.■ Treatment-naïve patients with ALK- positive disease should initially be offered single-agent alectinib or ceritinib, or both sequentially.■ Crizotinib-refractory patients should be treated with single-agent alectinib or ceritinib, or both sequentially.■ Further treatments could include single-agent brigatinib or lorlatinib, or both sequentially.■ Patients progressing on alk tyrosine kinase inhibitors should be considered for pemetrexed-based chemotherapy.■ Other systemic therapies should be exhausted before immunotherapy is considered., Summary: Multiple lines of alk inhibition are now recommended for patients with advanced nsclc with an ALK rearrangement., Competing Interests: CONFLICT OF INTEREST DISCLOSURES BM serves on advisory boards for Novartis, Pfizer, and Roche; JA serves on advisory boards for Novartis, Pfizer, Takeda, and Roche, and has given talks for, or served on advisory boards for, Astra-Zeneca, Boehringer Ingelheim, Bristol–Meyers Squibb, Merck, Novartis, and Pfizer; RA serves on advisory boards for Novartis, Pfizer, and Roche; DGB serves on advisory boards for Novartis, Pfizer, and Roche; NB serves on advisory boards for Takeda, Novartis, Pfizer, and Roche; RB serves on advisory boards for Roche, Takeda, Merck, and AstraZeneca; CB serves on advisory boards for AstraZeneca, Boehringer Ingelheim, Bristol–Meyers Squibb, Merck, and Pfizer; VH serves on advisory boards for Amgen, Astra-Zeneca, Boehringer Ingelheim, Bristol–Meyers Squibb, Eli Lilly, Merck, Novartis, Roche, and Pfizer; RJ serves on advisory boards for Novartis, Pfizer, and Roche; DNI has received honoraria from, or has been part of an advisory board for, AstraZeneca, Boehringer Ingelheim, Bristol–Myers Squibb, Eli Lilly, Merck, Novartis, and Pfizer; WM serves on advisory boards for Novartis, Pfizer, and Roche; ZP has served on advisory boards for AstraZeneca, Merck, and Roche; RS serves on advisory boards for AstraZeneca, Boehringer Ingelheim, Bristol–Myers Squibb, Merck, Novartis, AbbVie, Roche, and Takeda; MT has served on advisory boards for Takeda; MST has received research funding from Roche; MV serves on advisory boards for Amgen, AstraZeneca, Bristol–Myers Squibb, Boehringer Ingelheim, Celgene, Novartis, Eli Lilly, Takeda, Taiho, Hoffman–La Roche, Pfizer, and Merck, and is a member of the speaker’s bureau for AstraZeneca, Boehringer Ingelheim, Amgen, Merck and Eli Lilly; ZX serves on the advisory board for and has received grants from Pfizer; GL serves on advisory boards for and has received honoraria from AstraZeneca, Novartis, Pfizer, Roche, Merck, AbbVie, Bristol–Myers Squibb, and Takeda, and has received grants from AstraZeneca and Roche; the remaining authors have no conflicts of interest to disclose.

Starting in the early 2000s, non-small-cell lung cancer (nsclc) subtypes have evolved from being histologically described to molecularly defined. Management of lung adenocarcinomas now generally requires multiple molecular tests at baseline to define the optimal treatment strategy. More recently, second biopsies performed at progression in patients treated with tyrosine kinase inhibitors (tkis) have further defined the continued use of molecularly targeted therapy. In the present article, we focus on one molecular subtype: EGFR- mutated nsclc. For that patient population, multiple lines of tki therapy are now available either clinically or in clinical trials. Each line of treatment is guided by the specific mutations (for example, L858R, T790M, C797S) identified in EGFR. We first describe the various mechanisms of acquired resistance to EGFR tki treatment. We then focus on strategies that clinicians and pathologists can both use during tissue acquisition and handling to optimize patient results. We also discuss future directions for the molecular characterization of lung cancers with driver mutations, including liquid biopsies. Finally, we provide an algorithm to guide treating physicians managing patients with EGFR- mutated nsclc. The same framework can also be applied to other molecularly defined nsclc subgroups as resistance patterns are elucidated and additional lines of treatment are developed., Competing Interests: We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare the following interests: MST declares research grants from AstraZeneca, Pfizer, and Merck, and honoraria from AstraZeneca, Pfizer, Merck, Hoffman–La Roche, Bristol–Myers Squibb, and Boehringer Ingelheim; RS declares honoraria from AstraZeneca, Boehringer Ingelheim, Pfizer, Merck, Bristol–Myers Squibb, Roche, Eli Lilly, and Novartis; SKR declares a research grant from Pfizer and honoraria from AstraZeneca, Pfizer, Bristol–Myers Squibb, Roche, and Novartis; AK declares honoraria from AstraZeneca, Pfizer, Merck, Hoffman–La Roche, and Bristol–Myers Squibb; MP declare honoraria from AstraZeneca; DI declares honoraria from AstraZeneca, Pfizer, Merck, Hoffman–La Roche, and Bristol–Myers Squibb; RAJ declares a research grant from AstraZeneca and honoraria from AstraZeneca, Boehringer Ingelheim, Bristol–Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer, and Roche; CB declares honoraria from AstraZeneca, Pfizer, Merck, Bristol–Myers Squibb, and Boehringer Ingelheim; MC, BSS, and MS have no declarations to make.

Targeting the epidermal growth factor receptor (egfr) pathway has become standard practice for the treatment of advanced non-small-cell lung cancer. Compared with chemotherapy, egfr tyrosine kinase inhibitors (tkis) have been associated with improved efficacy in patients with an EGFR mutation. Together with the increase in efficacy comes an adverse event (ae) profile different from that of chemotherapy. That profile includes three of the most commonly occurring dermatologic aes: acneiform rash, stomatitis, and paronychia. Currently, no randomized clinical trials have evaluated the treatments for the dermatologic aes that patients experience when taking egfr tkis. Based on the expert opinion of the authors, some basic strategies have been developed to manage those key dermatologic aes. Those strategies have the potential to improve patient quality of life and compliance and to prevent inappropriate dose reductions.