*3.3. Patients Outcome in Relation to TP53 Mutations*

No statistically significant associations were found between *TP53* mutations and ORR and DCR (Table S3). When considering any type of *TP53* mutation with regard to PFS, no association was found; however, significant results were observed considering only *TP53* exon 8 mutations. As previously reported [6], patients with this gene mutation showed a shorter median PFS than non-exon 8 mutated and wild type *TP53* patients: 5.8 months (95% CI: 2.4–10.2) vs. 14.4 (95% CI: 6.7–21.8) and 12.4 (95% CI: 10.0–15.0), respectively (Figure 1A). These patients also showed a poorer OS as compared with the other groups, even though this result was not statistically significant: median OS were 18.53 months (95% CI: 7.3–NR), 34.8 (95% CI: 21.6–NR), 27.3 (95% CI: 20.2–52.9), respectively (Figure 1B).

The presence of *TP53* exon 8 mutation seemed to be associated with a worse prognosis in a similar way in the patients with the different *EGFR* mutations, both in terms of PFS and OS.

In particular, patients with wild type *TP53* exon 8 had a better clinical outcome independently by *EGFR* status: median PFS and OS were 12.9 (95% CI: 10.0–16.3) and 29.7 months (95% CI: 23.0–60.5) for patients with *EGFR* exon 19 deletion vs. 12.4 months (95% CI: 7.9–15.0) and 23.2 months (95% CI: 19.2–63.7) for those with other *EGFR* mutations, respectively; in the subgroup of patients with *TP53* exon 8 mutations, median PFS and OS were 5.8 months (95% CI: 2.5–NR) and 21.9 months (95% CI: 7.3–NR) for patients with *EGFR* exon 19 deletion vs. 6.4 (95% CI: 2.4–NR) and 18.5 months (95% CI: 7.6–NR) for those with other *EGFR* mutations. In Table S4, the univariate Cox analysis results are reported.

**Figure 1.** Progression-free survival (**A**) and Overall Survival (**B**) of patients according to *TP53.*


*3.1. Study of the Chemical Composition and Nanostructure of the Ti-TiN-(Ti,Cr,Mo,Al)N Coating*

According to the results of 20 conducted measurements, the average hardness of the coating was 42 ± 1.3 GPa, which is fairly high for nitride coatings. The coating structure includes an adhesion layer of Ti with the thickness of about 50 nm, a transition layer of TiN with the thickness of about 600 nm, and a wear-resistant layer of (Ti,Cr,Mo,Al)N with the thickness of about 2700 nm (Figure 1). The thickness of the functional layers of the coating was selected based on their optimal ratio [32,35]. The wear-resistant layer of (Ti,Cr,Mo,Al)N is formed by a 22-nanolayer period with λ of about 120 nm [11,33].

**Figure 1.** General structure of the Ti-TiN-(Ti,Cr,Mo,Al)N coating (TEM).

The nanostructures of the studied coating Ti-TiN-(Ti,Cr,Mo,Al)N in comparison with the (Ti,Al)N monolayer coating are presented in Figure 2.

Figure 2a illustrates that the nanostructure of Ti-TiN-(Ti,Cr,Mo,Al)N coating includes nanolayers with the high content of Al (lighter bands) and nanolayers with the high content of Cr-Mo and Ti (darker bands). For Ti-TiN-(Ti,Cr,Mo,Al)N coating, the value of nanolayer period λ [11,33] is about 120 nm, and the thicknesses of nanolayers are within a range of 1–8 nm. The results of the studies of the coatings phase compositions using the Selected Area Electron Diffraction (SAED) method are presented in Figure 2c,d.

The analysis of the SAED patterns for coatings Ti-TiN-(Ti,Cr,Mo,Al)N (Figure 2c) detected the presence of two phases. The analysis also found the main cubic phase (Ti,Nb,Zr,Al)N with Fm3m space group. Weak reflections with P6.3mc space group belong to the h-AlN phase. Rings of the h-AlN phase are barely noticeable, and that fact may indicate an extremely insignificant volume of the phase.

**Figure 2.** *Cont*.

**Figure 2.** (**a**,**b**) TEM micrograph of coating and (**c**,**d**) SAED patterns of the coatings: (**a**,**c**) Ti-TiN- (Ti,Cr,Mo,Al)N and (**b**,**d**) (Ti,Al)N monolayer coating (TEM).

The studies of the chemical composition of the coatings (Figure 3a) found the average contents of elements as follows in coating Ti-TiN-(Ti,Cr,Mo,Al)N:

**Figure 3.** Distribution of chemical elements over the thickness (**a**) and change in the content of different elements in nanolayers (**b**) of coating Ti-TiN-(Ti,Cr,Mo,Al)N.

Ti—22 at.%, Cr—38 at.%, Al—11 at.%, Mo—10 at.%.

The study of the nature of the distribution of elements in the nanolayer periods (Figure 3b) finds that the content of each element changes significantly within a nanolayer period. In particular, the content of Ti changes from 7 to 60 at.%, and the content of Al—from 3 to 27 at.%. The above ensures a smooth, gradient transition from harder and more wear-resistant layers with the high Al content to more ductile layers with the low Al content.

Let us consider the influence of the nanolayer structure of the coating on its crystalline structure. Earlier, it has been found that the nanolayer structure affects the grain sizes by reducing them [11,33]. At the same time, the grain size of the coating is not always limited by the boundaries of a nanolayer or a nanolayer period [11]. The Ti-TiN-(Ti,Cr,Mo,Al)N coating under study demonstrates columnar crystals with sizes noticeably larger than the value of nanolayer period (Figure 4a), and the grain structure of the coating can be seen more clearly in the reverse contrast image (Figure 4b). The nanolayer structure of this coating does not stop the growth of crystals (Figure 4c). However, as noted earlier [11,33],

the presence of the nanolayer structure allows the formation of crystals with significantly smaller sizes than crystals in coatings with monolayer structures. A comparison of SAED patterns on the Ti-TiN-(Ti,Cr,Mo,Al)N nanolayer coating (Figure 2c) and on the (Ti,Al)N monolithic coating (Figure 2d) demonstrates the significantly smaller size of crystals in the Ti-TiN-(Ti,Cr,Mo,Al)N coating.

**Figure 4.** TEM micrograph of Ti-TiN-(Ti,Cr,Mo,Al)N coating and study of the influence of the nanolayer structure of the coating on its crystalline structure. (**a**) nanostructure (**b**) nanostructure in reverse contrast image (**c**) individual grain in a nanostructure.

Figure 5 presents the high-resolution TEM images of coating Ti-TiN-(Ti,Cr,Mo,Al)N, with noticeable crystals with sizes of 5–15 nm. The analysis of interplanar spacing revealed the presence of two phases of h-AlN and c-(Cr,Ti,Mo,Al)N. The obtained results are in line with the SAED pattern presented in Figure 2c.

**Figure 5.** Crystalline structure of coating Ti-TiN-(Ti,Cr,Mo,Al)N (HR TEM).

*3.2. Study of the Cutting Properties and the Wear Pattern on Tools with the Ti-TiN-(Ti,Cr,Mo,Al)N Coating*

The studies of the cutting properties of the carbide tools found that the use of Ti-TiN-(Ti,Cr,Mo,Al)N coating can significantly reduce the flank wear compared to the tools with the (Ti,Al)N commercial coating. Figure 6 illustrates that after 7 min of operation, the wear of the carbide inserts with the (Ti,Al)N coating increases sharply, while the inserts with Ti-TiN-(Ti,Cr,Mo,Al)N coating demonstrate much lower wear, and the wear rate decreases.

**Figure 6.** Relation between cutting time and flank wear (VB) on coated carbide tools during the turning of AISI 1045 steel: vc = 300 m/min, f = 0.25 mm/rev, ap = 1.0 mm.

The good wear resistance of the Ti-TiN-(Ti,Cr,Mo,Al)N coating can be explained by the formation of tribological oxide films of MoO3 and Cr2O3, which favourably transform the cutting conditions [42–47].

The investigation of wear areas on the rake face of the carbide inserts after 16 min of operation (Figure 7) found that the tool with coating (Ti,Al)N demonstrated the higher rake wear, which manifested itself in the formation of a crater and a notch wear compared to the tool with Ti-TiN-(Ti,Cr,Mo,Al)N coating.

**Figure 7.** Contact pads on the rake faces of the carbide tools with coatings (**a**) Ti-TiN-(Ti,Cr,Mo,Al)N and (**b**) (Ti,Al)N after 16 min of cutting.

Figures 8 and 9 exhibit the results of the investigation of the fracture pattern on the rake and flank faces of the carbide tools.

**Figure 8.** Fracture patterns for Ti-TiN-(Ti,Cr,Mo,Al)N coating (**a**,**b**) on the flank faces of the tools (90◦ counterclockwise, top left (SEM).

The study of the fracture pattern finds that, given the noticeable microdeformations in the structure of the carbide substrate, Ti-TiN-(Ti,Cr,Mo,Al)N coatings are characterised by sufficient ductility and resistance to brittle fracture.

The study of the fracture patterns on the Ti-TiN-(Ti,Cr,Mo,Al)N coatings on the rake faces of the tools (Figure 9) finds that the fracture process is accompanied by active cracking. The Ti-TiN-(Ti,Cr,Mo,Al)N coating exhibits both inclined and transverse cracks (Figure 9). On the Ti-TiN-(Ti,Cr,Mo,Al)N coating, the brittle fracture accompanied by chipping of some fragments is typical (Figure 9b–e). Figure 9a illustrates that the wear surface of the coating on the boundary of its fracture is quite smooth and there are signs of local chipping of coating fragments.

**Figure 9.** Fracture pattern for coating Ti-TiN-(Ti,Cr,Mo,Al)N on the rake face of the carbide tool (SEM), (**a**) the nature of destruction of the coating at the boundary of the crater of wear, (**b**–**e**) the nature of cracking in the structure of the coating.

After cutting, delaminations and longitudinal cracks also occur in the structure of the coating on the cutting tool, and the study of them on the rake face of the tool is depicted in Figure 10. The upper part of the image demonstrates a delamination between nanolayers (see Box A for a larger scale). The delamination occurs not only along the border of two nanolayer periods, but also along the border of individual nanolayers. At the same time, the delamination does not transform into a longitudinal crack, that it, does not cut the nanolayers. As noted earlier [8,30,31,35], such delaminations can reduce the level of internal stresses and can thus play some positive role by slowing down the process of coating fracture. The lower part of the image depicts a delamination transforming into a transverse crack (see Box B for details). The formation of such cracks may be associated with the effect of residual longitudinal compressive stresses. Another reason for the formation of delaminations and longitudinal cracks can be transverse cyclic tensile stresses formed under the influence of adhesive fatigue wear processes arising during cutting [8,30,31,35,48].

**Figure 10.** Pattern of the formation of longitudinal cracks and delaminations in the Ti-TiN- (Ti,Cr,Mo,Al)N coating on the rake face of the tool (TEM). (**A**) inter nanolayer delamination (**B**) nanolayer cut by a crack.