ALK inhibitors and checkpoint blockade: a cautionary tale of mixing oil with water?

Patel, Malini; Jabbour, Salma K.; Malhotra, Jyoti

doi:10.21037/jtd.2018.06.118

Cited by 15 publications

(12 citation statements)

References 15 publications

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“…Reversible elevations in transaminase levels were the most common treatment-related adverse events (AEs) for both drugs. Severe hepatotoxicity resulting in death and grade ≥ 3 elevated transaminase rates of 10%-46% have been reported with other PD-1 inhibitor/ALK TKI combinations in ALK-positive or -negative NSCLC [6,9]. In our small study, the rate of elevated transaminases was within this range, and all resolved after permanent treatment discontinuation.…”

Section: Discussionsupporting

confidence: 47%

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Phase Ib Study of Crizotinib plus Pembrolizumab in Patients with Previously Untreated Advanced Non-Small Cell Lung Cancer with ALK Translocation

et al. 2020

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This study evaluating first-line crizotinib plus pembrolizumab in patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) was terminated early because increased availability of second-generation ALK inhibitors resulted in difficulty identifying and accruing eligible patients. • In the small number of patients enrolled, elevated transaminases were the most common treatment-related toxicity. No other relevant toxicities were observed. • Although no definitive conclusions could be drawn because of the small number of patients studied, the higher frequency of severe transaminase increases noted in this sample should be of concern if ALK inhibitor and PD-L1/PD-1 inhibitor combinations are tested in future studies.

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Section: Discussionsupporting

confidence: 47%

“…Although ALK TKIs, including crizotinib, are effective in ALKpositive NSCLC [1,5], the potential relationship between ALK rearrangements and PD-L1 expression and resistance to single-agent ALK TKIs suggests synergistic effects with targeted ALK TKI therapy plus anti-PD-1 inhibitor immunotherapy, such as pembrolizumab [6,7].…”

Section: Discussionmentioning

confidence: 99%

Phase Ib Study of Crizotinib plus Pembrolizumab in Patients with Previously Untreated Advanced Non-Small Cell Lung Cancer with ALK Translocation

et al. 2020

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“…177,178 Hepatotoxicity, in particular, has emerged as an important consideration across numerous studies combining immunotherapy with molecularly targeted therapy, either concomitantly or sequentially. 173,184,185 Targeted therapies may also play a role in altering the tumor endothelium, allowing T cell and NK cell infiltration, and tolerogenic cell infiltration may be decreased. [186][187][188][189] Combination trials of VEGF-targeting therapy plus ICI have been fruitful.…”

Section: Metabolismmentioning

confidence: 99%

The future of cancer immunotherapy: microenvironment-targeting combinations

2020

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Immunotherapy holds the potential to induce durable responses, but only a minority of patients currently respond. The etiologies of primary and secondary resistance to immunotherapy are multifaceted, deriving not only from tumor intrinsic factors, but also from the complex interplay between cancer and its microenvironment. In addressing frontiers in clinical immunotherapy, we describe two categories of approaches to the design of novel drugs and combination therapies: the first involves direct modification of the tumor, while the second indirectly enhances immunogenicity through alteration of the microenvironment. By systematically addressing the factors that mediate resistance, we are able to identify mechanistically-driven novel approaches to improve immunotherapy outcomes.

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“…Based on a similar rationale, maintenance durvalumab treatment of stage III NSCLC for 1 year after completion of chemoradiotherapy has doubled PFS and OS and is currently standard (in Europe restricted by the EMA to PD-L1 + cases only) [303]. In contrast, trials testing combinations of PD-L1 with tyrosine kinase inhibitors for oncogene-driven EGFR + /ALK + NSCLC showed disappointing results, that is lack of benefit and increased toxicity [304-306]. Despite endogenous PD-L1 expression induced by oncogenic signaling (Fig.…”

Section: Therapeutic Immunomodulationmentioning

confidence: 99%

Immune Modulation in Lung Cancer: Current Concepts and Future Strategies

Gaissmaier

Christopoulos

2020

Respiration

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Cancer immunotherapy represents the most dynamic field of biomedical research currently, with thoracic immuno-oncology as a forerunner. PD-(L)1 inhibitors are already part of standard first-line treatment for both non-small-cell and small-cell lung cancer, while unprecedented 5-year survival rates of 15–25% have been achieved in pretreated patients with metastatic disease. Evolving strategies are mainly aiming for improvement of T-cell function, increase of immune activation in the tumor microenvironment (TME), and supply of tumor-reactive lymphocytes. Several novel therapeutics have demonstrated preclinical efficacy and are increasingly used in rational combinations within clinical trials. Two overarching trends dominate: extension of immunotherapy to earlier disease stages, mainly as neoadjuvant treatment, and a shift of focus towards multivalent, individualized, mutatome-based antigen-specific modalities, mainly adoptive cell therapies and cancer vaccines. The former ensures ample availability of treated and untreated patient samples, the latter facilitates deeper mechanistic insights, and both in combination build an overwhelming force that is accelerating progress and driving the greatest revolution cancer medicine has seen so far. Today, immune modulation represents the most potent therapeutic modality in oncology, the most important topic in clinical and translational cancer research, and arguably our greatest, meanwhile justified hope for achieving cure of pulmonary neoplasms and other malignancies in the next future.

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ALK inhibitors and checkpoint blockade: a cautionary tale of mixing oil with water?

Cited by 15 publications

References 15 publications

Phase Ib Study of Crizotinib plus Pembrolizumab in Patients with Previously Untreated Advanced Non-Small Cell Lung Cancer with ALK Translocation

Phase Ib Study of Crizotinib plus Pembrolizumab in Patients with Previously Untreated Advanced Non-Small Cell Lung Cancer with ALK Translocation

The future of cancer immunotherapy: microenvironment-targeting combinations

Immune Modulation in Lung Cancer: Current Concepts and Future Strategies

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