Making the first move in EGFR-driven or ALK-driven NSCLC: first-generation or next-generation TKI?

The publication of two studies in 2004 (refs^31,32) describing the predictive value of sensitizing mutations in EGFR on the activity of EGFR inhibitors is a key landmark in the development of potent drugs to treat molecularly selected patients with NSCLC^31,32. Multiple phase III trials comparing the first-generation EGFR TKIs erlotinib, gefitinib, or icotinib, as well as the second-generation TKI afatinib, with platinum-based chemotherapy as frontline therapies for patients with advanced-stage disease have been reported^33‐50 (Table 1). A consistent benefit in favour of EGFR TKIs is observed across studies in terms of progression-free survival (PFS), response rates, and disease control rates. The median PFS with these compounds ranged from 8.0–13.1 months, compared with 4.6–6.9 months with chemotherapy (range of HRs 0.16–0.48). Given this impressive PFS benefit, an important overall survival benefit was expected⁵¹. Nevertheless, median overall survival durations were equivalent for both trial arms across studies (19.3–34.8 months), predominantly owing to the high rates of treatment crossover (54−95%). The findings of these studies also provided the first demonstration that, in the context of oncogene addiction, the clinical benefit derived from treatment with TKIs is independent of whether the patients were treated upfront or after first-line chemotherapy.

For the treatment of patients with the most frequent EGFR mutations (L858R and exon 19 deletions), the choice of a first-generation or second-generation EGFR inhibitor depends on the physician’s preference, the toxicity profile, and the local availability of each agent. No differences in the efficacy of erlotinib, gefitinib, or afatinib in terms of PFS and overall survival have been detected in comparative studies (CTONG 0901 (ref.⁵²) and LUX-Lung 7 (refs^53,54)). Icotinib has been demonstrated to be non-inferior to gefitinib, leading to its approval in 2014 in China as a frontline treatment for patients with advanced-stage EGFR-mutant NSCLC but its development in Western countries was not pursued⁴⁵. In the ARCHER 1050 trial, dacomitinib, another second-generation irreversible EGFR TKI, was associated with longer PFS and overall survival durations than gefitinib (34.1 months versus 26.8 months, HR 0.76; P = 0.044)^55,56 (Table 1). This improvement was achieved at the cost of higher toxicity (frequency of grade 3 adverse events 63% versus 41%) and a detrimental effect on quality of life (QOL)⁵⁵. Similarly, the addition of erlotinib to bevacizumab extended PFS duration for an average of 6 months compared with erlotinib monotherapy⁴⁷, although again at the expense of increased toxicity (frequency of grade 3 adverse events 91% versus 53%); the combination regimen was approved by the EMA in 2016 as a first-line treatment option⁴⁶.

For patients treated with first-line EGFR TKIs, blood-based and/or tumour sampling analysis upon disease progression is mandatory to study the T790M mutational status, owing to the clinical benefits shown for patients in this subgroup who received sequential treatment with osimertinib in multiple studies^{18,21,57‐59} (Table 1). In the AURA 3 randomized phase III trial²¹, for example, osimertinib was associated with better median PFS durations and overall response rates (ORRs) than cisplatin plus pemetrexed in the second-line setting (Table 1). In comparison with the chemotherapy regimen, patients receiving osimertinib also had an improved QOL, with better scores for lung cancer symptoms and a lower incidence of grade ≥3 adverse events (23% versus 47%). At a median follow-up duration of 8.3 months, 71% of patients receiving chemotherapy had crossed over to receive osimertinib after disease progression, and the median overall survival had not been reached in either treatment arm. The extended benefit of the sequential administration of a first-generation EGFR TKI followed by osimertinib observed in this study²¹ drove the approval of this compound for patients with NSCLC harbouring the T790M mutation and disease progression after treatment with first-generation or second-generation EGFR TKIs.

Crizotinib is a first-generation TKI of ALK, MET, and ROS1, and was the first agent to be approved for the treatment of patients with NSCLC harbouring ALK translocations^60‐63. Two randomized phase III trials established the superiority of crizotinib over chemotherapy in patients with advanced-stage NSCLC, either as a first-line therapy²² or in patients with disease progression after receiving a platinum-based regimen⁶⁴. In the PROFILE 1014 study²², greater response rates and median PFS durations were achieved with crizotinib than with platinum-based therapy (Table 2). Again, no significant differences in overall survival were observed, with a 4-year survival of 56.6% with crizotinib and 49.1% with chemotherapy⁶⁵. This effect was mostly due to the high crossover rates (84.2%) from crizotinib to the experimental arm. In an exploratory analysis, after adjusting for crossover, the median overall survival was 59.8 months with crizotinib and 19.2 months with chemotherapy.

Sequential treatment strategies with ALK inhibitors have been developed with the aim of extending overall survival durations^{61‐63,66‐81} (Table 2). Unlike EGFR inhibitors, a wide repertoire of ALK TKIs is available for patients with disease progression after treatment with crizotinib; the second-generation ALK TKIs ceritinib, alectinib, and brigatinib have been developed to overcome most resistance mechanisms^24‐26. Treatment with ceritinib was associated with improved outcomes compared with second-line chemotherapy (ORR 39.1% versus 6.9%, and a median PFS gain of ~4 months) in patients with disease relapse after receiving crizotinib and platinum-based chemotherapy⁷² (Table 2). In the same disease setting, the results of the phase III ALUR trial⁷⁷ and the phase II ALTA trial⁷⁶ demonstrated beneficial outcomes with alectinib and brigatinib, respectively (Table 2). The third-generation ALK TKI lorlatinib has activity against resistance mutations arising after treatment with first-generation and/or second-generation TKIs, including the G1202R mutation²⁷. Lorlatinib has been tested in a dose-escalation phase I study⁶⁶ and in a phase II trial⁸¹ (Table 2).

One of the major concerns in the management of patients with ALK-translocated tumours is the high risk of developing brain metastases; 22–33% of patients present with central nervous system (CNS) involvement at diagnosis, and the prevalence of brain metastases increases to 45–70% upon progression on crizotinib treatment^{68,69,73,75,82}. The improved CNS activity of second-generation and third-generation ALK TKIs results from both their higher CNS penetration and increased potency compared with crizotinib²⁷. Intracranial responses have been observed in 45% of patients receiving ceritinib⁶⁹, 64% of those receiving alectinib⁸³, and 67% treated with brigatinib⁸⁴. Brigatinib was associated with an intracranial PFS of 18.4 months with the standard dose⁸⁴. Importantly, even 42% of patients in a heavily pretreated cohort (≥2 lines of ALK TKIs) had intracranial disease control with lorlatinib, and the cerebrospinal fluid concentration documented for lorlatinib was 75% of the plasma concentration⁶⁶.

In the randomized phase III FLAURA study²⁸, osimertinib was compared as a frontline therapy with the standard choice of gefitinib or erlotinib in patients with NSCLC harbouring EGFR exon 19 deletions or L858R point mutation²⁸. As expected, the median PFS was significantly prolonged by almost 9 months with osimertinib compared with first-generation TKIs (HR 0.46; P < 0.001), although the ORRs were similar between trial arms (Table 3). The median time to second-line treatment or death was 23.5 months with osimertinib and 13.8 months with first-line EGFR TKI, and the median time to third-line treatment was not reached and 25.9 months, respectively. Brain imaging was mandatory at study entry, as well as during the course of the study for patients with brain metastases; at study entry, 19% of patients in the osimertinib arm and 23% in the control arm had brain metastases. Fewer patients treated with osimertinib had disease progression in the CNS (6% versus 15%) or extracranial disease progression (38% versus 54%), compared with the control arm²⁸. The benefit in PFS was maintained for patients with brain metastases (15.2 months with osimertinib versus 9.6 months with first-generation TKIs; HR 0.47; P < 0.001). Osimertinib was better tolerated than first-line TKIs (34% versus 45% of patients had grade 3 adverse events). Accordingly, the rate of treatment discontinuation was 13% in the osimertinib arm compared with 18% in the control arm. Of note, QT interval prolongations were more frequent with osimertinib than with first-line TKIs (10% versus 4%). In this trial, crossover to subsequent treatment with osimertinib was permitted in patients in whom the T790M mutation was detected after progression upon treatment with first-generation EGFR TKIs. Among the 129 patients who received treatment after disease progression in the control arm, 48 patients (37%) crossed over to receive treatment with osimertinib; data on the overall survival of patients who received treatment after disease progression are eagerly awaited.

Ceritinib was the first second-generation TKI approved as a first-line treatment option for patients with ALK-rearranged NSCLC on the basis of the superior efficacy over platinum-based chemotherapy observed in the ASCEND-4 study⁷¹ (Table 2). In this study, the incidence of grade 3–4 adverse events was higher with ceritinib than with chemotherapy (65% versus 40%), but treatment discontinuations owing to toxicity occurred in 5% of patients treated with ceritinib versus 11% in the control arm. This study was designed before crizotinib was established as standard first-line therapy in this disease setting; taking toxicities into consideration, ceritinib remains a valid option for first-line treatment. Encouraging results from a phase I/II trial of brigatinib (NCT01970865) include a median PFS of 34.2 months in 8 patients treated upfront with this agent⁷⁸. In another phase II trial, the ORR was 90% in a cohort of 30 patients receiving frontline lorlatinib and the median PFS had not been reached at the time of reporting; mature results of this ongoing study will provide further insight into the clinical outcomes derived from lorlatinib treatment⁸¹.

Alectinib is the first ALK inhibitor that was compared against crizotinib in the first-line setting in two randomized studies: the phase III trials J-ALEX³⁰, conducted in Japan, and the international ALEX trial²⁹ (Table 3). None of the patients enrolled in J-ALEX had been previously treated with an ALK TKI, but 36% of them had received chemotherapy. Alectinib was associated with a significant PFS benefit (Table 3), as well as a more favourable toxicity profile than crizotinib: grade 3 adverse events were reported in 26% of patients receiving alectinib versus 52% of those receiving crizotinib, and fewer patients required dose interruptions (29% versus 74%) or toxicity-related treatment suspensions (9% versus 20%).

All the patients enrolled in the ALEX trial²⁹ received alectinib in the frontline setting. The median PFS duration and ORR were higher with alectinib than with crizotinib; according to the last update¹²¹, median PFS was 34.8 months with alectinib and 10.9 months with crizotinib (HR 0.43; 95% CI 0.32–0.58 months). Crossover was not permitted in the study protocol, hampering the direct comparison of outcomes obtained by administering alectinib using sequential or upfront strategies. One strength of this study²⁹, however, was the evaluation of CNS activity through mandatory brain MRI at study entry and every 8 weeks during treatment. Baseline brain metastases were detected in 42% of patients allocated to receive alectinib and in 38% of patients in the crizotinib group. Patients with measurable CNS metastases had an intracranial response rate of 81% (45% of them being complete responses) with alectinib and 50% (9% complete responses) with crizotinib. The median duration of CNS responses was 17.3 months with alectinib and 5.5 months with crizotinib, and the 12-month cumulative incidence of brain metastases was significantly lower with alectinib than with crizotinib (9.4% versus 41.4%), showing that alectinib provides superior control against the development of brain metastases compared with crizotinib. Interestingly, the difference in PFS between arms can be mainly attributed to the higher rates of CNS-related disease progression with crizotinib, because no significant differences in extra-CNS progression rates were observed between arms (24% and 22% with alectinib and crizotinib, respectively). Comparative trials of crizotinib with brigatinib (NCT02737501), lorlatinib (NCT03052608), or ensartinib (NCT02767804) will provide further information on the efficacy of all next-generation ALK TKIs in the first-line setting.

This approach has been in place for a longer time than the next-generation upfront strategy, and, thus, sufficient data support an impressive long-term survival with therapies involving sequencing TKIs. The long-term benefit of providing sequential therapies is based on the response rates and the duration of PFS that can be achieved with next-generation inhibitors upon resistance to first-generation TKIs. In patients with NSCLC harbouring mutations in EGFR^T790M, a pooled analysis update of the AURA 2 and AURA extension studies⁵⁹ revealed a median global overall survival of 26.8 months. The 2-year overall survival was 56% for the entire cohort. The mature survival outcomes of the AURA 3 study²¹ and data on treatment outcomes from the ASTRIS study¹²² have not yet been published; these results should provide insight into the clinical benefits derived from osimertinib treatment in patients with EGFR^T790M-mutated NSCLC.

In patients with ALK-rearranged NSCLC, results from the PROFILE 1014 trial showed, at a median follow-up duration of 46 months, that median survival was not reached (95% CI 45.8 months–not reached) and that 4-year overall survival was 56.6% in patients treated with crizotinib, of whom 33% received subsequent next-generation TKIs⁶⁵. The French national IFCT-1302 retrospective study¹²³ analysed the survival outcomes of 318 patients with ALK-rearranged NSCLC involved in an expanded crizotinib access programme¹²³. In this study, 31.9% of patients received the second-generation ALK inhibitors ceritinib or alectinib after disease progression on frontline crizotinib. The median overall survival duration from the first dose of crizotinib was not reached for patients who received sequential treatment, and 3-year survival was 59.2% (both ceritinib and alectinib analysed together). Impressively, the median overall survival from the time of diagnosis of metastatic NSCLC was 89.6 months. This duration is highly superior to that observed in patients with NSCLC not driven by alterations in EGFR or ALK and treated with chemotherapy in ‘real-world’ settings (~10 months)¹²⁴.

The studies discussed support the notion that effective sequential strategies with upfront first-generation inhibitors can lead to impressive overall survival in some patients with NSCLC in which the driver alterations have been characterized; whether upfront next-generation inhibitors could provide a similar long-term benefit remains to be established. The available preclinical and clinical evidence suggests that no clinical benefit is derived from treatment with first-generation TKIs after disease progression on next-generation TKI treatment, with the exception of ALK L1198F¹⁰⁸, MET amplification^125, and EGFR C797S mutation in trans⁹⁵, thus limiting the availability of targeted therapeutic options when next-generation inhibitors are used upfront.

This therapeutic option is associated with prolonged PFS durations, improved disease control in the CNS, and a more favourable toxicity profile than treatment with first-generation TKIs — providing a major argument in favour of upfront treatment with next-generation TKIs. In the ALEX²⁹ and FLAURA²⁸ studies, the difference in the incidence of grade 3 adverse events with first-generation versus next-generation TKIs was ~10%, favouring the latter. With the upfront administration of next-generation TKIs, T790M or secondary ALK mutational screening does not need to be performed on a continuous basis, an approach that is convenient in centres where repeated molecular diagnosis is not available. Indeed, the medical practice environment needs to be considered in decisions of the best therapeutic strategy for patients. Close monitoring and timely access to molecular diagnostics and treatment options are essential to providing optimal care.

In the ALEX²⁹ and FLAURA²⁸ studies, alectinib and osimertinib showed greater efficacy in the treatment of brain metastases than first-generation TKIs; thus, these agents should be considered for patients in this setting^126‐128. The prevention or delay of the onset of brain metastases is key to controlling morbidity and reducing the needs and costs for localized CNS therapies¹²⁹. In this context, the results of the ongoing evaluation of responses to frontline lorlatinib are awaited⁸¹. Indeed, results from studies in mouse models suggest that frontline lorlatinib could dramatically delay the emergence of resistance, including those with brain metastases²⁷. Despite having superior potency and the widest spectrum of activity against secondary mutations, lorlatinib might not replace alectinib as the standard-of-care ALK TKI in the first-line setting because of its association with an increased incidence of neurological adverse effects; lorlatinib, however, might represent the ideal second-line treatment option after disease progression on alectinib.

An important argument in favour of using next-generation upfront originates from the emerging evidence from studies of persister cells. An intuitive hypothesis is that a ‘hitting hard first’ strategy would help to limit the number of drug-tolerant cells that would later lead to disease progression; however, to our knowledge, direct comparisons of the persistence capacities of cancer cells treated with first-generation or next-generation TKIs have not been performed. Understanding the molecular mechanisms supporting the viability of these cells and how they can be targeted therapeutically are key questions that have not yet been solved.

Another key aspect that remains to be elucidated is whether frontline treatment with next-generation TKIs can decrease the emergence of subclonal heterogeneity involving TKI resistance mechanisms, either with a mutational or non-mutational component. Importantly, the existence of intratumour heterogeneity is evidenced by simultaneous oncogenic alterations that can mediate resistance to EGFR or ALK TKIs, including the co-occurrence of EGFR with ALK alterations or ALK with KRAS alterations, which present a challenge for treatment selection^23,130‐134. To address this issue, multiple combinations of ALK or EGFR TKIs with other kinase inhibitors targeting MET (NCT02143466), MEK (NCT03392246, NCT03087448, NCT03202940, and NCT02143466), JAK (NCT02917993 and NCT03450330), mTOR (NCT02503722 and NCT02321501), SRC (NCT02954523), AXL (NCT03255083) or CDK4/6 inhibitors (NCT03455829 and NCT02292550), or apoptotic modulators, such as navitoclax (NCT02520778), are ongoing. The aim of these strategies is to revert, delay or prevent the onset of off-target resistance. In addition, several studies have intended to modulate the antitumour immune response by combining an EGFR or ALK TKI with anti-programmed cell death 1 (PD-1) and/or anti-programmed cell death 1 ligand 1 (PD-L1) monoclonal antibodies, which generally lack efficacy as single agents in patients with oncogene-addicted NSCLC¹³⁵. Nevertheless, toxicity issues have already hampered the development of combinations of osimertinib with durvalumab and of crizotinib with nivolumab. In the phase Ib TATTON study, recruitment into the combination arm (osimertinib plus durvalumab) was closed owing to the occurrence of interstitial lung disease in 38% of patients¹³⁶. In the multicohort phase I/II CheckMate 370 trial, the combination of nivolumab and crizotinib was associated with severe hepatic toxicity in 38% of patients, with two adverse-event-related deaths¹³⁷. By contrast, preliminary data of the combination of crizotinib or lorlatinib with avelumab and of alectinib with atezolizumab have shown an acceptable safety profile^138,139.

In the absence of survival data after disease progression from head-to-head comparative trials, investigators rely on the sum of PFS from studies held in different therapy lines to establish comparisons. This provocative approach is not supported statistically¹⁴⁰ but can provide an estimation, in the absence of valid surrogates, of the theoretical benefit of sequential targeted therapies in patients with advanced-stage NSCLC (Fig. 2).

Relying on the results from clinical trials^{22,69,72,77,80}, patients with ALK-translocated NSCLC would derive a median PFS of 16–25 months from frontline crizotinib followed by a next-generation ALK TKI, compared with 34.8 months with alectinib¹²¹. Likewise, patients with EGFR-mutated NSCLC would derive a PFS benefit ranging from 21–27 months^{21,36,41,47,53} with sequential treatment, a value close to the 18.9 months reported for frontline osimertinib in the FLAURA study²⁸. Of note, chemotherapy is the standard treatment for patients with T790M-negative NSCLC with disease progression after receiving first-generation EGFR TKIs. For these patients, the median PFS with cisplatin-based chemotherapy after progression upon treatment with first-line EGFR TKIs was reported to be 5.4 months¹⁴¹; thus, frontline treatment with a first-generation TKI would provide a slightly inferior sum of PFS than frontline osimertinib.

In addition, a subset of patients treated with TKIs can develop oligoprogressive disease. In this scenario, and especially in the setting of brain metastasis, patients can benefit from a 6-month gain in PFS when local ablative treatments (such as surgery or radiotherapy) are applied¹⁴². These local ablative treatments are crucial because they enable the continuation of previously administered systemic therapies, delaying the switch to the next treatment line and prolonging systemic disease control.

The economic burden of novel drugs can also influence the choice of upfront TKIs — for example, osimertinib is more expensive than afatinib¹⁴³. In the absence of definitive evidence of meaningful overall survival benefits, the prolonged administration of costly therapeutic agents might not be easily accepted by regulatory authorities.

In this new era, a growing need exists for the development of clinical trials to enable further understanding of the best sequential therapeutic strategy in the setting of advanced-stage NSCLC. Monitoring resistance onset using sequencing of circulating cell-free DNA can provide new insights into the effect of early treatment of subclinical resistance¹⁴⁴. In the setting of EGFR-mutated NSCLC, the ongoing phase II APPLE trial¹⁴⁵ will shed light on this matter, evaluating the overall survival outcomes of patients treated sequentially with a first-line EGFR TKI and switching to osimertinib upon progression, compared with treatment with osimertinib upfront.