Oligoprogression in Patients Harboring ALK Rearrangements: Comparison
Please note this is a comparison between Version 1 by Marco De Filippis and Version 2 by Yvaine Wei.

The growing efficacy and availability of new targeted systemic therapies have markedly improved the prognosis of metastatic lung cancer patients harboring ALK rearrangements. The use of effective targeted therapies capable of maintaining a prolonged control of disease, for as long as possible, is paramount to ensure the best survival outcomes. In this regard, in cases of oligoprogression, “beyond progression” systemic treatment added to local ablative therapies is considered a feasible option in an attempt to improve the quality and quantity of patients’ lives, even if based on retrospective data. Certainly, treatment of ALK rearranged lung cancer patients with oligoprogressive disease must be individualized and based on multidisciplinary decisions. Above all, when further molecular targeted therapies are available, options must always be evaluated, especially in case of cerebral progression.

  • oligoprogression
  • ALK rearrangement

1. Introduction

Over the last two decades the application of personalized therapies based on molecular features has radically changed the diagnostic and therapeutic approach in advanced non-small cell lung cancer (NSCLC). Specific oncogenic drivers have been identified and several targeted drugs are now available, thus allowing a significant improvement in terms of response rate, survival and quality of life in molecularly selected patients.
Epidermal growth factor receptor (EGFR) mutations, followed by anaplastic lymphoma kinase (ALK) rearrangements, are the pillars of precision medicine in thoracic oncology, being the first molecular targets identified with substantial clinical implications.
ALK rearrangements are detected in 3–7% of advanced NSCLC and are typically associated with young age, non-smoking and adenocarcinoma histology [1]. ALK chromosomal rearrangements in NSCLC were first reported in 2007, and revolutionized the treatment of ALK+ patients. Several types of ALK translocation have been discovered, all resulting from the fusion between ALK gene portion encoding for the intracellular tyrosine kinase domain (exons 20–29) and different partners, of which echinoderm microtubule-associated protein like-4 (EML4) is involved in 90% of cases. This leads to the production of a chimeric protein with a constitutive tyrosine–kinase activity responsible for uncontrolled cellular proliferation [2]. Depending on the specific breaking point of the EML4 gene, more than 13 EML4-ALK fusion variants have been identified, with V1 (exons 1–13), V2 (exons 1–20) and V3 (exons 1–6) being the most common. A rapid bench to bedside approach from the detection of the ALK translocation in NSCLC has permitted the development of several effective targeted therapy options.
Under drug pressure, however, the emergence of molecular resistance finally occurs with a median time to disease progression from 10.9 to 34.8 months [3][4][3,4]. Sequential administration of ALK tyrosine kinase inhibitors (TKIs) (from second to third generation) up to chemotherapy (platinum–pemetrexed) represents a common therapeutic approach. In this context, extending the benefit deriving from targeted treatment is paramount, above all when disease progression occurs in a limited number of sites, defining the so-called oligoprogressive state. Oligoprogression is, indeed, relatively common in oncogene-addicted NSCLC, involving about 30–50% of patients in the course of targeted treatment, a higher percentage if compared to patients treated with immunotherapy or chemotherapy [5], raising the crucial question regarding the best treatment approach: change of systemic treatment or treatment prosecution beyond progression combined with local ablative therapy.

2. Oligoprogression in Oncogene-Addicted Disease: Focus on ALK-Rearranged NSCLC

In 1995, Hellman and Weichselbaum first introduced the concept of oligometastatic disease (OMD), an intermediate state between localized and widespread tumor in which metastases are limited in number and location; compared with more advanced stages, OMD is more indolent and it is more amenable to ablative therapy for metastatic lesions [6]. Patients may present with de novo OMD (synchronous OMD) or with limited relapse after treatment with curative purpose (metachronous OMD). Ablative local treatment (e.g., radiotherapy, radiofrequency, crioablation and surgery) to all metastatic sites with radical intent has been shown to be potentially curative and associated with long-term survival benefit in several types of cancers, including NSCLC [7]

The concept of OMD led to the recognition of other disease states in which local ablative therapies (LATs) may have a potentially curative role. Oligopersistent or oligoresidual disease definition refers to patients who present with oligometastatic disease after an excellent response to systemic therapy [8].

Oligoprogression is a common phenomenon in patients with oncogene-driven NSCLC treated with TKIs. Despite optimal initial response, progression eventually develops and, in roughly half of cases, relapse is limited to a few sites [9]. This pattern of progression is essentially explained by two mechanisms. (1) Pharmacokinetic failure: differently from next-generation TKIs, first-generation EGFR and ALK-TKIs have inadequate blood–brain barrier (BBB) penetration, hence isolated central nervous system (CNS) progression is easily detected [10][11][10,11]. (2) Intratumor and intertumor heterogeneity: resistant sites of disease may harbor a unique genomic profile, different from the primary tumor; drug pressure resulting from systemic targeted treatment prompts both the selection of intrinsically resistant cell clones and, after prolonged exposition, the development of acquired resistance mechanisms [12].

In contrast to widespread systemic progression, oligoprogression may be managed by not only changing systemic therapy, but also by maintaining the same systemic treatment beyond progression and adding metastasis-directed therapy to primary systemic treatment. Although most of the evidence derives from studies conducted in patients with EGFR-mutated NSCLC, the same approach can be extended to other molecular driver alterations, such as ALK, ROS1, BRAF and other less common genetic aberrations.

3. Local Ablative Therapies in Oligoprogressive ALK-Rearranged NSCLC

LATs to all progressing lesions in oligoprogressive, molecularly driven NSCLC is thought to potentially eradicate the TKI-resistant subclones, prevent secondary seeding and restore overall sensitivity of metastatic sites to the ongoing systemic treatment, until new resistant subclones emerge. Metastases-directed therapy approaches enable the extension in the duration of targeted therapy and delay the switch to the next systemic treatment as long as possible, thus prolonging the benefit of TKIs and improving survival. Stereotactic radiotherapy (SRT), an advanced radiotherapy technique with high local tumor control rates and low toxicity, is the most frequently adopted method in case of oligoprogressive, oncogene-driven NSCLC [13][17]. SRT includes stereotactic body radiation therapy (SBRT), which delivers high doses in divided portions, and stereotactic radiosurgery (SRS), which delivers a single ablative dose and is especially used for brain lesions. The addition of ALK-TKIs to radiotherapy can increase radiosensitivity of tumor cells strengthening the rational for combined strategies. Indeed, in preclinical studies, it has been shown that crizotinib elicits beneficial effects in combination with radiotherapy in ALK-positive NSCLC cell lines by reducing tumor proliferation, microvascular density and perfusion [14][15][18,19]. In another study, the antiproliferative effect of TAE684, a potent second generation ALK inhibitor that overcomes crizotinib resistance, was augmented by radiotherapy in EML4-ALK positive lung cancer cells [16][20]. On the other hand, another recent preclinical study reported that treatment with ALK-inhibitors combined with 10 Gy-irradiation led to similar effects to those of sole radiotherapy, with no clear evidence of sensitization to radiation by treating EML4-ALK mutated cells with ALK inhibitors [17][21].

4. The Importance of Managing CNS Disease: Local Therapy and Systemic Treatment

ALK+ NSCLC is characterized by a marked neurotropism due to an intrinsic high affinity for nervous tissue of ALK rearranged cancer cells. Isolated CNS progression with controlled extracranial disease is a common event on first-generation TKI treatment because of its reduced BBB penetration. Crizotinib activity on brain tissue is, indeed, modest with an ORR of 18% and a time to progression of 7 months [18][30]. In this context, SBRT and SRS have assumed a pivotal role in the multidisciplinary approach of oligoprogressive oncogene-driven NSCLC, with the aim of improving not only survival but also quality of life through a reduced impact on neurocognitive functions. Although SRS is routinely used for the treatment of a limited number of brain metastases, studies have shown that this technique can also be successfully used for the management of more than 10 metastases and limited disease burden, without increasing late neurocognitive toxicity [19][31].  The “beyond progression” strategy and the use of LAT in cases of oligoprogressive disease also remain common with second generation ALK TKIs in a first-line setting, the current therapeutic standard. The landscape in which LAT is placed is characterized, however, by deeper intracranial efficacy and disease control because of the higher CNS penetration of newer generation ALK TKIs. 

5. Systemic Treatment Algorithm: Waiting for a Guide

Considering the availability of further systemic treatment options is crucial to recognize the most effective and safe therapeutic strategy in oligoprogressive disease. However, as is well known, new generation ALK TKI selection and sequencing is still challenging because of the absence of head-to-head comparisons. In fact, second and third generation ALK TKIs, with an approximately 50% reduction in the risk of progression or death compared with crizotinib and with an impressive intracranial activity, overcame a first-line crizotinib approach (Table 13) [4][20][21][22][23][24][25][4,28,35,40,41,46,48].
Table 13.
 Comparison of first-line phase III trials in advanced ALK-rearranged NSCLC patients.
  PROFILE 1014 [3] ALEX [11] ALTA-1L [12] eXalt3 [26][13] ASCEND-4 [27][15] CROWN [28][22]
  Crizotinib Chemotherapy Alectinib Crizotinib Brigatinib Crizotinib Ensartinib Crizotinib Ceritinib Chemotherapy Lorlatinib Crizotinib
ORR 74% 45% 83% 76% 74% 62% 74% 67% 72.5% 26.7% 76% 58%
mPFS (months) 10.9 7 34.8 10.9 29.4 9.2 25.8 12.7 16·6 8.1 NR 9.3
PFS HR 0.45; 95% CI, 0.35–0.60 0.43; 95% CI 0.32–0.48 0.43; 95% CI, 0.31–0.61 0.51; 95% CI, 0.35–0.72 0·55; 95% CI 0·42–0·73 0.28; 95% CI, 0.19–0.41
Intracranial response rate - - 81% 50% 78% 26% 63.6% 21.1% 72·7% 27.3% 82% 23%
Frequency of dose reduction - - 20% 20% 38% 25% 24% 20% 80% 45% 21% 15%
Frequency of discontinuation 12% 14% 15% 15% 13% 9% 9% 7% 5% 11% 7% 9%
Key adverse events dision disorders, diarrhea, nausea, and edema nausea, fatigue, vomiting, and decreased appetite myalgia, increased blood bilirubin, increased ALT nausea, diarrhea, and vomiting ILD/pneumonitis, nausea, CPK increase, ALT increase, lipase increase nausea, diarrhea, edema Rash, pruritus, nausea, pyrexia, ALT and AST increase liver toxic effects, nausea, edema, and constipation diarrhea, nausea, vomiting, AST and ALT increase nausea, vomiting and anemia Edema, Hypercholesterolemia, hypertriglyceridemia, increased weight, neuropathy, cognitive effects, speech effects Diarrhea, vision disorder, vomiting, increased alanine aminotransferase level, fatigue, constipation, increased aspartate aminotransferase level, decreased appetite, dysgeusia, and bradycardia
ORR, objective response rate; PFS, progression-free survival; NR, not reached; CNS, central nervous system; HR, hazard ratio; CI, confidence interval.
Following “the-best-first” theory, lorlatinib could be considered as the preferred frontline TKI because of its higher activity in terms of PFS HR and CNS efficacy [5]. Preclinical and retrospective data demonstrated that sequential use of ALK TKIs could favor lorlatinib-resistant compound mutations, indicating that the most potent TKI used in first line treatment might better prevent acquired resistance mechanisms [29][30][49,50].
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