Effectiveness of first-line anticancer treatment may predict treatment response in further lines in stage III/IV patients with non-small cell lung cancer

By the 2020s, lung cancer remains one of the most serious cancer diseases, claiming millions of lives worldwide. Despite notable progress in understanding lung cancer pathobiology, further therapeutic improvements are desired. Novel targeted treatments emerged during the last decade and the most apparent progress in treatment outcomes has been achieved in non-squamous non-small cell lung cancer (NSCLC). Importantly, the introduction of novel therapies resulted also in increased opportunities for treatment sequencing in multiple treatment lines.

In daily practice, the real-life effectiveness of various treatments may differ from the efficacy reported from clinical trials (Brat et al. 2020; Cramer-van der Welle et al. 2018), e.g., overall survival (OS) and progression-free survival (PFS) rates for pemetrexed, bevacizumab and tyrosine kinase inhibitors (TKIs) were higher than pooled OS and PFS from clinical trials in our previous study (Brat et al. 2020). Favorable treatment outcomes may be related to the existence of „good responders “—patients benefitting from most types of anticancer therapy. Understanding several new molecular pathways resulted in an increased opportunity for treatment response prediction; however, the relationships in sequenced multilinear treatment are more complex and poorly understood. Some patients with NSCLC respond favorably to multiple treatments and can be generally considered „good responders “. To date, we lack specific biomarkers of good treatment response and favorable outcomes within the use of multiple treatment lines.

The effectiveness of first-line anticancer therapy could be one of such aspects as demonstrated in a study by Bonotto et al. (Bonotto et al. 2015). In this study, the authors demonstrated that a 6-month benefit with the first line of anticancer treatment was associated with benefits in the second and further lines in patients with breast cancer (Bonotto et al. 2015). Among the modern-era treatments of NSCLC, pemetrexed is the oldest and most explored regime. A relation between response to the previous treatment line and subsequent treatment success with pemetrexed therapy has been described also in patients with NSCLC (Sun et al. 2010). Similarly, sensitivity to pemetrexed predicted therapeutic benefits from further treatment lines (Park et al. 2019).

In this study, we focused on various classes of first-line anticancer treatments in patients with NSCLC, including platinum-based chemotherapy, tyrosine kinase inhibitors (TKIs), anaplastic lymphoma kinase (ALK) inhibitors, and immunotherapy (IO). Our aim was to evaluate if therapeutic success with certain types of first-line anticancer treatments may predict treatment success in the following lines. We hypothesized that treatment success within first-line therapies may predict the probability of treatment success with subsequent lines.

We analyzed data from a total of 2317 patients with advanced-stage NSCLC treated in the first line of their anticancer therapy by afatinib (180 patients), gefitinib (340 patients), erlotinib (60 patients), platinum-based chemotherapy plus pemetrexed (1204 patients), platinum-based chemotherapy plus bevacizumab (451 patients), alectinib (24 patients), crizotinib (14 patients), or pembrolizumab (44 patients).

To our best knowledge, this was the first study attempting to assess survival benefits in its complexity during all lines of patients´ anticancer therapies in patients with NSCLC. A similar study has been performed by Bonotto et al. in 2015 (Bonotto et al. 2015). The authors of this study described the most frequent sequences/patterns of anticancer therapies in a cohort of 472 patients with breast cancer and assessed if treatment response of PFS ≥ 6 months within the first line of treatment resulted in a higher probability of survival benefit with further treatment lines. As an extension of this study design, we attempted to assess treatment responses for all lines in groups of patients with NSCLC treated by different first-line therapies.

The main finding of our study was that patients treated by certain groups of anticancer therapies (EGFR inhibitors, ALK inhibitors, IO) had an increased probability of experiencing a ≥ 6-month survival benefit not only in their first line of anticancer treatment but also in subsequent treatment lines. This observation was most apparent in patients treated with alectinib (ALK inhibitor). On the contrary, patients treated with chemotherapy-based regimens experienced the lowest rate of survival benefit in the first and also in the subsequent lines of their anticancer therapies.

The observed favorable outcomes with EGFR inhibitors, ALK inhibitors, and IO have been demonstrated previously in a number of studies.

For both EGFR- and ALK-positive patients, our data showed that the rate of good responders was significantly higher than in the chemotherapy-based group. We speculate that these tumor types may be composed of heterogenic (but dominantly EGFR- or ALK-mutant) cancer cells that are prone to significant treatment response with targeted therapies. Residual cancer tissue may harbor a broader number and spectrum of oncogenic driver mutations with an overall weaker potential for rapid progression of the disease after targeted treatment.

To date, the most frequently used biological therapy in patients with NSCLC is the group of EGFR inhibitors (TKIs). Several predictive markers exist, indicating a potential therapeutic benefit from TKIs. These include Exon 19 deletion as some subtypes of this mutation may have an important clinical impact (Huang et al. 2022) or the plasma level of circulating tumor DNA (ctDNA) as lower ctDNA during the treatment course is associated with better survival (Kallergi et al. 2022; Provencio et al. 2021).

Several TKIs (erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib) can be used in various treatment lines, and also in a sequence. The optimal sequencing strategy appeared to be the combination of afatinib in the first line, followed by second-line osimertinib in a case of a proven T790M mutation (Hirsh et al. 2020; Kim et al. 2023), until the results of the FLAURA study have been published, shifting osimertinib to the first-line therapy of EGFR positive NSCLC (Lorenzi et al. 2022). Exact recommendations on treatment after first- or second-line osimertinib failure were not formulated. Usually, a switch to chemotherapy or chemo-immunotherapy is preferred (Reck et al. 2019). In our study, we found larger numbers of treatment benefits and good responders among patients treated by osimertinib in the second line which is in accordance with current knowledge (Hirsh et al. 2020; Kim et al. 2023).

According to recent studies, PD-L1 expression of ≤ 1% (Lasvergnas et al. 2023) and concomitant genetic mutations AXIN2, P2CG, or RAD51C may predict a poor response to a first-line TKI therapy (Wen et al. 2023). On the other hand, post-treatment TKIs-resistant NSCLC tumors have recently been considered potentially targetable by MET-, HER2-, and HER3-directed therapies (Johnson et al. 2022).

For ALK-positive NSCLC, several ALK inhibitors can be used in a sequence (alectinib, ceritinib, crizotinib, brigatinib, lorlatinib) (Kauffman et al. 2021). Alectinib, brigatinib and lorlatinib, ALK inhibitors with high intracerebral penetration, are recommended as first-line drugs. Lorlatinib is preferred in the second line of treatment post-failure after a second-generation ALK inhibitor (ESMO guidelines 2023; Hochmair et al. 2020). On the other hand, a recent study by Takeyasu et al. found similar effectivity of second-line lorlatinib and pemetrexed-based chemotherapy after failure of alectinib (Takayasu et al. 2022).

After crizotinib failure, a variety of other ALK drugs can be used (ESMO guidelines 2023). Survival of patients with NSCLC harboring ALK mutation and receiving an ALK inhibitor seems to be independent of the fusion variants of ALK translocation (Tabbó et al. 2022). In contrast, other authors discuss worse effectiveness in patients harboring variant 3 of the ALK translocation (Lin et al. 2018). Further studies are needed to uncover the mechanisms of resistance in ALK-mutated NSCLC disease.

Another group of highly effective anticancer treatment for NSCLC is immunotherapy. It gains a still larger therapeutic scope not only in the treatment of NSCLC but also in small-cell lung cancer (SCLC) or malignant pleural mesothelioma. To date, expression of PD-L1 remains the key marker of treatment response to IO (Herbst et al. 2014; Kim et al. 2018). However, new markers of treatment response emerged, including ECOG PS, presence of brain metastases, molecular genetic factors, circulating regulatory T cells, and immune-related adverse events (irAEs). Circulating regulatory T cells are associated with better response during IO and may help to differentiate between disease pseudoprogression and hyperprogression (Kang et al. 2022). As to the molecular genetic factors, patients with a concurrent KRAS- or BRAF-positive disease experienced longer PFS when compared to those with an EGFR- or ALK-positive profile (Bodor et al. 2022). By contrast, ECOG PS ≥ 2 or the presence of brain metastases were associated with early progression of the disease (Dumenil et al. 2018). Patients developing irAEs are known to benefit more significantly compared to those without irAEs; the more irAEs the patient experiences, the higher the probability of a survival benefit from IO (Sonehara et al. 2021).

Similarly to our observation, better survival outcomes after first-line IO have also been reported in a retrospective multicenter study by Bersanelli et al. (Bersanelli et al. 2020). In this study, the authors observed improved survival and ORR after chemotherapy in patients pre-treated with IO, concluding that IO may increase the tumor´s sensitivity to the (subsequent) chemotherapy (Bersanelli et al. 2020). Our data seem to support this hypothesis.

In contrast, low TMB has been found a predictor of responsiveness to first-line chemotherapy (PFS 9.77 vs 6.33 months, HR = 0.523; p = 0.009) (Song et al. 2022) while other authors report the tumor mutation index model (based on total/sensitive TMB from blood and mutation score) as a potential predictor of response to chemotherapy or immunotherapy in the subsequent treatment lines (Lu et al. 2022). Nastase et al. identified a group of genes associated with a good response to platinum chemotherapy in IIIA stage NSCLC (Nastase et al. 2022). Genetic background of treatment response to adjuvant chemotherapy has also been observed in patients with low-stage NSCLC (Van Laar 2012).

In summary, the differences in treatment responses to various classes of first-line anticancer therapies observed in our study likely point out the complexity of mechanisms of tumor pathogenesis in NSCLC. Different tumor subpopulations may coexist in each individual patient, and this may evolve also during the course of their anticancer therapy. Further research is needed to understand the molecular and genetic mechanisms and the broader clinical context beyond our observation.

We concluded that the effectiveness of first-line therapies in patients with NSCLC may predict survival benefit in the subsequent lines, particularly in EGFR-, ALK-, or PD-L1-positive disease treated by targeted therapies. By contrast, chemotherapy-based regimens were associated with the highest rate of poor response in all lines of anticancer treatment. Further studies are needed to uncover and better understand the underlying mechanisms of increased treatment responsiveness in certain subgroups of patients with NSCLC.