Canadian consensus: a new systemic treatment algorithm for advanced EGFR- mutated non-small-cell lung cancer

Background Multiple clinical trials for the treatment of advanced EGFR- mutated non-small-cell lung cancer ( nsclc ) have recently been reported. As a result, the treatment algorithm has changed, and many important clinical questions have been raised: Canadian expert panel was convened to define the key clinical questions, review recent evidence, and discuss and agree on practice recommendations for the treatment of advanced EGFR- mutated nsclc . The published overall survival results for osimertinib, combined with its central nervous system activity, have led to osimertinib becoming the preferred first-line treatment for patients with common EGFR mutations, including those with brain metastasis. Other agents could still have a role, especially when osimertinib is not available or not tolerated. Treatment in subsequent lines of therapy depends on the first-line therapy or on T790M mutation status. Treatment recommendations for patients whose tumours harbour uncommon EGFR mutations are guided mainly by retrospective and limited prospective evidence. Finally, the evidence for sequencing and combining tki s with chemotherapy, angiogenesis inhibitors, checkpoint inhibitors, and other new therapeutics is reviewed. by significant advances in the treatment of EGFR- mutated nsclc .


BACKGROUND
Few therapeutic areas have experienced as much progress in recent times as EGFR-mutated non-small-cell lung cancer (nsclc). An estimated 15% of Canadians with nsclc tumours have an activating mutation in the EGFR gene in exons 18-21, the region encoding the tyrosine kinase domain 1 . Since the introduction of epidermal growth factor receptor (egfr) tyrosine kinase inhibitors (tkis) in 2010 in Canada, EGFR mutation testing for patients with advanced nonsquamous nsclc has been the standard of care, with results prompting a specific treatment algorithm for this subset of lung cancer.
More frequent in lifetime never-smokers, the most common EGFR mutations are the exon 19 deletion (exon 19del)

METHODS
An invited expert panel of thoracic medical oncologists was tasked with identifying key clinical questions, critically reviewing recent evidence related to the systemic treatment of EGFR-mutated nsclc, and summarizing evidenceinformed treatment recommendations. The first author drafted the manuscript with the assistance of a medical writer, and all authors provided feedback and revisions. Authors documented their level of agreement to each of the clinical recommendations using a 5-point Likert scale (5, strongly agree; 4, agree; 3, neutral; 2, disagree; 1, strongly disagree). The final level of agreement was an average of the responses from all authors. All authors approved the final manuscript and algorithm.

CLINICAL QUESTIONS, RECOMMENDATIONS, AND EVIDENCE
The 6 clinical questions and related recommendations are presented in the subsections that follow, together with a brief summary of the evidence for each point. The final recommendations are reflected in the algorithm shown in Figure 1.

Clinical Question 1
What is the optimal first-line treatment for patients with advanced nsclc whose tumours harbour common EGFR mutations?

Recommendation 1a
Osimertinib is the preferred first-line treatment for patients with advanced nsclc whose tumours harbour common EGFR mutations. -Level of consensus: 4.875 (7×5, 1×4) Evidence: The phase iii fl aur a trial randomized 556 patients with nsclc having common EGFR exon 19del and L858R mutations to receive either osimertinib or a first-generation egfr tki (gefitinib or erlotinib) 17 18 . That result is consistent with an earlier publication of the study showing superior, but nonsignificantly improved, os with osimertinib 19 . Although the objective response rates (orrs) were similar in the two arms, the duration of response was prolonged with osimertinib, at 17.2 months (95% ci: 13.8 months to 22.0 months) compared with 8.5 months with erlotinib or gefitinib (95% ci: 7.3 months to 9.8 months) 19 . Grade 3 or greater adverse events were less frequent with osimertinib.
A subgroup analysis in flaura showed that, despite experiencing a significant progression-free survival (pfs) benefit, patients of Asian ethnicity did not experience an os benefit 17 . However, that exploratory analysis was not powered to show os differences. Given the strong pfs benefit observed in that subgroup, specific groups are, until further data are available, not excluded from our recommendation of osimertinib as the preferred egfr tki.
Providing a third-generation agent in the first-line setting might lead to concerns about restricted options in later lines of therapy; however, up to 30% of patients with EGFR-mutated nsclc as seen in the flaura trial never received a second-line therapy 18 .

Recommendation 1b
First-and second-generation egfr tkis are reasonable first-line options for patients with advanced nsclc whose tumours harbour common EGFR mutations (exon 19del or L858R) when osimertinib is not available or for patients who had to discontinue osimertinib because of an adverse event.
-Level of consensus: 5 (unanimous) Evidence: The efficacy of the second-generation egfr tkis afatinib and dacomitinib, compared with gefitinib, in the first-line setting for patients with exon 19del and L858R EGFR-mutated nsclc were demonstrated in the lux-Lung 7 and archer 1050 trials respectively.
The phase iib randomized lux-Lung 7 trial demonstrated a statistically significant improvement in pfs with afatinib (hr: 0.73; 95% ci: 0.57 to 0.95; p = 0.017) and prolonged median time to treatment failure (hr: 0.73; 95% ci: 0.58 to 0.92; p = 0.0073). However, afatinib did not demonstrate a statistically significant os advantage (27.9 months with afatinib vs. 24.5 months with gefitinib; hr: 0.86; 95% ci: 0.66 to 1.12; p = 0.26) 20,21 . The trial was insufficiently powered for a proper os evaluation. lux-Lung 7, patients who received afatinib followed by a third-generation tki experienced prolonged survival, with os not reached at 4 years 25,26 . The reported rate of T790M mutation after gefitinib, erlotinib, and afatinib ranges from 40% to 60% and occurs in up to 73% of patients with an exon 19del mutation [27][28][29] . Data for the rate after dacomitinib are insufficient. Ultimately, it is impossible to know who will and will not acquire T790M secondary mutations. Nonetheless, a global debate continues.

Recommendation 1c
Inhibitors of PD-1/-L1 as single agents or in combination with a platinum doublet do not have a role in the first-line treatment of EGFR-mutated nsclc, and PD-L1 status should not be used to select first-line treatment for EGFR-mutated nsclc.
-Level of consensus: 5 (unanimous) Evidence: Recommendation 1c is based on 0 responses seen in a phase ii trial of pembrolizumab in PD-L1-positive EGFR-mutated nsclc in the first-line setting that was closed for futility. A potentially increased risk of autoimmune toxicity (pneumonitis and hepatitis) was also observed in The phase iii archer 1050 trial excluded patients with brain metastasis 22 . Although it reported a numeric improvement in os of 34.1 months for dacomitinib (95% ci: 29.5 months to 37.7 months) compared with 26.8 months for gefitinib (95% ci: 23.7 months to 32.1 months; hr: 0.760; 95% ci: 0.582 to 0.993), the trial had a hierarchical stratified statistical design, and given that it did not meet significance in orr, a p value could not be given to os 23 .
The toxicity profiles of second-generation agents vary. Their relative effects are described or discussed in detail elsewhere 19,20,24 , but are generally worse than those for the first-generation egfr tkis, resulting in more frequent dose reductions. When selecting between a first-and second-generation egfr tki, the toxicity profile should be considered in patient-specific decisions.
An important unresolved question is whether sequencing maximizes survival: Could initial treatment with a second-generation egfr tki, followed by osimertinib, compared with upfront osimertinib in patients with acquired T790M mutations ultimately lead to longer survival for the entire group? Unfortunately, randomized data to answer that question are not available. Based on the study when subsequent egfr tkis were administered close to or with an immune checkpoint inhibitor (particularly osimertinib) 30 . The panel thus strongly recommends waiting for EGFR results before exposing patients to PD-1/-L1 inhibitors.
High PD-L1 expression does not influence first-line therapy for patients with EGFR-mutated nsclc because those patients were excluded from all first-line studies of single-agent pembrolizumab 31,32 and nivolumab 33 , and of combination pembrolizumab-chemotherapy 34 and nivolumab-ipilimumab 35 . If treatment is urgently required before EGFR molecular results can be obtained, the group suggests starting platinum doublet chemotherapy without a PD-1/-L1 inhibitor.

Clinical Question 2
What is the preferred first-line systemic treatment for patients with central nervous system (cns) metastasis?

Recommendation 2a
Osimertinib is the preferred egfr tki for patients with brain metastasis or leptomeningeal disease (lmd).
-Level of consensus: 5 (unanimous) Evidence: Almost half the patients with metastatic EGFR-mutated nsclc develop brain metastasis during the course of their disease 36,37 , negatively affecting prognosis and quality of life. Osimertinib is the tki with the most compelling cns data [38][39][40] . The flaura trial permitted patients with stable or neurologically asymptomatic cns metastasis to enrol. However, the protocol contained no directions about how to follow patients without brain metastasis at baseline. Thus, conclusions can be based only on the group with baseline brain metastasis.
After the trial was initiated, an independent review committee was established to evaluate the measurable and non-measurable cns responses in 61 patients (22%) treated with 80 mg osimertinib and in 67 patients (24%) treated with either gefitinib or erlotinib (gefitinib/erlotinib) 38 . The cns pfs assessed by central blinded independent neuroradiologic review was not reached at median in the osimertinib arm [95% ci: 16.5 months to not calculable (nc)]; in the gefitinib/erlotinib arm, the cns pfs was 13.9 months (95% ci: 8.3 months to nc). A statistically significant and clinically relevant improvement in cns pfs was observed for osimertinib compared with gefitinib/erlotinib (hr: 0.48; 95% ci: 0.26 to 0.86; p = 0.014) 38 . In patients with 1 or more measurable cns lesions, the cns orr was 91% for osimertinib and 68% for gefitinib/erlotinib. The median cns pfs with osimertinib was not reached (95% ci: 16.5 months to nc); it was 13.9 months for gefitinib/erlotinib (95% ci: 8.3 to nc; hr: 0.48).
In the aura3 study, the cns orr was measured as part of a preplanned subgroup analysis 39 . Of 116 patients with measurable or unmeasurable brain metastasis, median cns pfs was longer for patients receiving 80 mg osimertinib than for those receiving chemotherapy, at 11.7 months compared with 5.6 months respectively, by blinded independent review committee (hr: 0.32; 95% ci: 0.15 to 0.69; p = 0.004) 39 . Of 46 patients with 1 or more measurable cns metastases, 30 patients had been treated with osimertinib, with 21 achieving a response (orr: 70%; 95% ci: 51% to 85%), and 16 had been treated with chemotherapy, with 5 achieving a response (orr: 31%; 95% ci: 11% to 59%) 39 .
Osimertinib has also been studied in patients with lmd. In the phase i bloom study, 21 patients who had lmd and stable extracranial disease, and who had received an egfr tki, were treated with 160 mg osimertinib daily 41 . Radiologic improvement was confirmed in 7, and 9 had stable disease. The trial did not compare the 80 mg and 160 mg doses. A more recent evaluation of 22 patients with lmd in the aura program of 80 mg osimertinib daily, reported an orr of 55% (95% ci: 32% to 76%). The median lmd pfs and os were 11.1 months (95% ci: 4.6 months to nc) and 18.8 months (95% ci: 6.3 months to nc) respectively 42 .
Thus, the group recommends standard-dose osimertinib 80 mg for patients with cns lmd metastasis until further studies are conducted to evaluate the additional benefit of the increased dose of 160 mg. There are no data to guide the treatment of patients with cns progression after osimertinib treatment, and there is no evidence that dose escalation would improve patient outcomes.
All tkis have demonstrated responses in cns metastases in retrospective case series 43 . Afatinib delayed the onset or progression of brain metastasis in a pooled analysis of the lux-Lung 3, 6, and 7 studies 41 and in a real-world population of patients with advanced nsclc 44 . The archer 1050 study of dacomitinib excluded patients with cns metastasis at baseline and did not mandate imaging of the brain, thus providing no evidence of whether dacomitinib prevents the development of brain metastasis 23 . However, the primary site of progression was noted for patients who progressed while on trial, and a brain site was recorded in only 1 of 227 patients in the dacomitinib arm and in 11 of 225 patients in the gefitinib arm 23 .

Clinical Question 3
What evidence do we have for treating patients whose tumours harbour uncommon EGFR mutations?
Uncommon EGFR mutations are heterogeneous, with various insertions or base substitutions observed in exons 18-21, and they can often be compound or complex, with 2 different mutations being present in the same tumour 2,3 . Patients with uncommon EGFR mutations are often excluded from clinical trials and primary analyses, and so much of what is known about their response to egfr tkis comes from post hoc 17 or retrospective analyses of trial data 2 or from clinical practice 3 . Uncommon mutations have historically been categorized into 3 subgroups based on in vitro and in vivo response to egfr tkis: ■ EGFR sensitizing mutations (G719X, S768I, and L861Q) ■ Exon 20 insertions ■ De novo T790M mutations.

Recommendation 3a
Afatinib is the preferred first-line treatment for patients with uncommon Evidence: The highest level of prospective data comes from studies of afatinib. Most evidence focuses on patients with the exon 18 G719X, exon 20 S768I, and exon 21 L861Q somatic mutations. For patients with tumours carrying G719X, S768I, or L861Q mutations treated with afatinib, median os durations were, respectively, 26.9 months (95% ci: months 16.4 to not evaluable), not evaluable (95% ci: 3.4 months to not evaluable), and 17.1 months (95% ci: 15.3 months to 21.6 months). For the lux-Lung 2, 3, and 6 trials, a pooled analysis 17 showed responses similar to those in patients having standard EGFR mutations 3 .
Studies of osimertinib in patients with uncommon mutations are ongoing. Patients with uncommon mutations were excluded from the flaura trial. Interim results of a phase ii single arm study of patients with treatment-naïve (61%) and pretreated disease demonstrated that osimertinib was active: the orr in patients with L861Q was 77.8%; with G719X, 52.8%; and with S768I, 37.5%; the median pfs was only 9.5 months (range: 1.0-20.1 months) 45 , however. The astris real-world treatment study measured outcomes in 53 patients with an acquired T790M mutation in the setting of uncommon mutations; those patients were treated with 1 or more lines of egfr tki followed by osimertinib, resulting in a median pfs of 8.1 months compared with the 11.1 months seen in the full dataset (n = 3015) 46,47 . Studies in patients with uncommon EGFR mutations who were naïve to egfr tkis are continuing (see NCT03434418 at https:// ClinicalTrials.gov/).

Recommendation 3b
Osimertinib is the preferred first-line treatment for patients with de novo T790M mutation. -Level of consensus: 5 (unanimous) Evidence: De novo T790M mutations occurring without prior egfr tki treatment are rare and result in a poor response to first-and second-generation egfr tkis 3 . Patients with germline T790M mutations might have an inherited propensity for lung cancer 48 . All patients with a de novo T790M mutation should also be referred to a hereditary cancer program, because standard tumour-based assays do not differentiate between a de novo somatic mutation and a germline mutation. Treatment evidence is lacking, and so patients with a de novo T790M mutation are usually empirically treated similarly to those with an acquired T790M mutation 1 .

Recommendation 3c
Patients with an exon 20 insertion (excluding T790M) should be treated with a platinum doublet or on a clinical trial. -Level of consensus: 4 (4×5, 1×4, 2×3, 1×2) Evidence: Patients with an exon 20 insertion are resistant to first-and second-generation egfr tkis 2,3,17 . Response to osimertinib has been reported in case studies, but the largest series to date suggests, at most, a 7.5% response rate 49 . The preferred treatment is a platinum doublet. As an alternative, numerous clinical trials with promising targeted therapeutics specifically designed to inhibit such mutations are in development 50 , including poziotinib 51,52 , TAK-788 53 , tarloxotinib 54 , and the JNJ-372 bi-specific antibody 55 . Whether affected patients should receive atezolizumab-bevacizumab-carboplatin-paclitaxel (abcp) remains controversial (lack of consensus to recommend for or against); the regimen is under active investigation (see NCT03991403 at https://ClinicalTrials.gov/).

Clinical Question 4
What is the preferred second-line treatment for patients who received a first-or second-generation tki in the firstline setting?
The development of acquired resistance is a key challenge in treating patients with EGFR-mutated nsclc. The most common resistance mechanism in patients treated with first-and second-generation egfr tkis is an acquired EGFR T790M (exon 20) mutation that changes a conserved threonine residue in the atp binding pocket to methionine and that occurs in 50%-60% of cases of acquired resistance [56][57][58] . The mutation results in a conformational change of the kinase binding pocket and prevents the activity of the inhibitors. The individuals who will develop a T790M mutation after progression on first-and second-generation egfr tkis cannot be predicted; thus, all patients treated with a first-or second-generation tki for common or uncommon mutations have to undergo T790M molecular testing on progression. Testing guidelines are beyond the scope of the present document and are published elsewhere 59 .

Recommendation 4a
Patients who received a first-or second-generation egfr tki in the first-line setting and who are T790M-positive should be treated with osimertinib or on a clinical trial. -Level of consensus: 5 (unanimous) Evidence: Several trials demonstrated the benefit of a third-generation tki after progression on a first-or secondgeneration tki. The phase iii aura3 trial randomized 419 patients with an acquired T790M mutation after progression on a first-or second-generation egfr tki to osimertinib versus chemotherapy (pemetrexed-carboplatin or pemetrexed-cisplatin) 60 . The primary endpoint of investigator-assessed pfs was significantly longer for osimertinib compared with chemotherapy (10.1 months vs. 4.4 months; hr: 0.30; 95% ci: 0.23 to 0.41; p < 0.001). The orr was 71% for osimertinib (95% ci: 65% to 76%) compared with 31% for chemotherapy (95% ci: 24% to 40%; odds ratio for orr: 5.39; 95% ci: 3.47 to 8.48; p < 0.001). Adverse events of grade 3 or greater were less frequent with osimertinib (23%) than with chemotherapy (47%). Median os was 26.8 months in the osimertinib arm (95% ci: 23.5 months to 31.5 months) compared with 22.5 months in the chemotherapy arm (95% ci: 20.2 months to 28.8 months; hr: 0.87; 95% ci: 0.67 to 1.12; p = 0.28) 61 .
The statistically and clinically significant pfs benefit associated with osimertinib in a comparison with platinum-pemetrexed did not result in a statistically significant improvement in os, possibly as a result of the high crossover rate (patients from the platinum-pemetrexed arm crossing to osimertinib).
Consistent results were observed in a post hoc analysis of the lux-Lung 7 trial, which examined os in patients treated with at least 1 line of post-progression therapy after discontinuing a first-or second-generation tki 21 . In patients who received a third-generation tki at some time as subsequent treatment, median os was 48.3 months for patients initially treated with gefitinib and is still not reached for those initially treated with afatinib 26 .
The benefit of subsequent second-and third-generation tkis has also been demonstrated in the GioTag real-world study 62 . That retrospective chart review examined 204 patients who had received first-line afatinib followed by second-line osimertinib. The time to failure with firstline afatinib was 11.9 months (90% ci: 10.9 months to 12.2 months), and with second-line osimertinib, it was 14.3 months (90% ci: 12.8 months to 15.9 months). The combined time to treatment failure was 27.6 months (90% ci: 25.9 months to 31.3 months). At data cut-off, 48% of the patients were still on treatment, with a 2-year os of 79% and a 30-month survival rate of 69% 62 .

Recommendation 4b
In patients who are progressing after a first-line first-or second-generation inhibitor and who are T790M-negative, the preferred second-line treatment is a platinum doublet or a clinical trial. Whether patients should receive abcp or other chemotherapy combinations [anti-PD-1, anti-vascular endothelial growth factor (vegf)] remains controversial (no consensus to recommend for or against); the regimen is under active investigation.
-Level of consensus: 4.125 (2×5, 5×4, 1×3) Evidence: Clinical trials are needed to develop more compelling recommendations for this patient population. Patients who do not acquire a T790M mutation at progression might develop alternative egfr-dependent and -independent resistance mechanisms, including phenotypic transformation, HER2 and MET amplification or activation, and activation of Raf, Ras, or vegfr pathways 59,63 . If available, comprehensive gene testing should be considered to look for alternative gene resistance mechanisms and the potential for clinical trial enrolment.
In the absence of trials, these patients should receive platinum-doublet chemotherapy as the standard or be enrolled on trials of chemotherapy combinations (for example, 4-drug or 3-drug regimens) or targeted therapies. The IMpower150 trial tested the combination of bevacizumab, an antibody against vegf, or atezolizumab, a PD-L1 antibody, with a carboplatin-paclitaxel chemotherapy backbone (bcp, acp), or the chemotherapy backbone with both antibodies (abcp) 64 . In a post hoc analysis, a trend toward longer os was observed in patients with EGFR-mutant lung cancer when treated with the quadruplet (hr for abcp compared with bcp: 0.61; 95% ci: 0.29 to 1.28), although the Kaplan-Meier curves favoured bcp in the first 4 months 65 . When only the 57 patients with EGFR sensitizing mutations, previously treated with a tki, were analyzed, the survival hr was 0.31 favouring abcp over bcp (95% ci: 0.11 to 0.83). Those data are compelling; however, based on existing evidence, a consensus could not be reached to recommend for or against abcp. A larger randomized study testing that question in patients with EGFR-or ALK-driven lung cancer is ongoing.

Clinical Question 5
What is the preferred treatment after osimertinib?
In the first-line flaura trial, none of the patients treated with first-line osimertinib acquired the T790M mutation 66 .
Patients treated with osimertinib develop resistance through several different mechanisms, including MET amplification 66 , acquisition of an exon 20 EGFR C797S point mutation 66 , or loss of the T790M mutation (in treated patients with already-acquired resistance), which does not re-sensitize patients to a first-or second-generation egfr tki 67 . The field is complex, and research into targeting resistant mutations is ongoing 68 .

Recommendation 5a
For patients treated with osimertinib in the first-line setting or in the second line after a first-or second-generation egfr tki, the preferred subsequent systemic treatment is a platinum doublet or a clinical trial. -Level of consensus: 4.375 (5×5, 1×4, 2×3) A platinum doublet or clinical trial is the preferred option. The panel could not reach consensus for or against platinum plus an anti-PD-1 antibody or abcp in this setting. Other options to consider in patients with a poor performance status include single-agent chemotherapy with pemetrexed, gemcitabine, or vinorelbine. For those with oligoprogressive disease, participation in trials of local therapy such as radiation-for example, stop (see NCT02756793 at https:// ClinicalTrials.gov/)-should be considered.

Upcoming Strategies
The upcoming strategies discussed here had not yet been approved by Health Canada at the time of writing.

Recommendation 6a
The combination of gefitinib plus chemotherapy could be considered in the first-line setting for patients not eligible for osimertinib or a clinical trial. -Level of consensus: 4 (1×5, 6×4, 1×3) Evidence: Two randomized phase iii trials demonstrated improved clinical outcomes for gefitinib plus chemotherapy compared with gefitinib monotherapy in treatment-naïve EGFR-mutated nsclc.
The Japanese NEJ009 phase iii study randomized 344 patients with common EGFR mutations to gefitinib or to gefitinib-carboplatin-pemetrexed, followed by maintenance pemetrexed 83,84 . Although pfs was significantly better and median os was numerically higher in the tkichemotherapy arm than in the gefitinib-alone arm, pfs2 was similar in the two arms and did not meet the endpoint necessary to formally analyze os because of a hierarchical statistical testing design. Most of the patients in the trial crossed over, and 22%-30% had brain metastasis, a group that normally experiences poorer outcomes.
A study from Mumbai, India, randomized 350 patients with sensitizing EGFR mutations (including uncommon ones) to gefitinib or to gefitinib-pemetrexed-carboplatin followed by pemetrexed maintenance 85 . The study included patients with treated brain metastases (18% of patients) and those with an Eastern Cooperative Oncology Group performance status of 2, who were excluded from the flaura trial. The addition of chemotherapy to the egfr tki was associated with significantly prolonged pfs and os 85 . At disease progression, the crossover rate from the gefitinib arm to chemotherapy was 32.4%. With adoption of the combination approach, higher toxicities were described.

Recommendation 6b
No consensus could be reached for or against a consideration of combining erlotinib with vegf inhibition in the first-line setting.
-Level of consensus: 3 (2×4, 4×3, 2×2) Evidence: Combinations of erlotinib with bevacizumab (anti-vegf antibody) or with ramucirumab (anti-vegf receptor antibody) are promising and have been associated with pfs improvements in first-line trials, including JO25567 (phase ii) 86 , nej026 (phase iii) 87 , and relay (randomized double-blind phase iii) 88 . Although os differences were insignificant in the JO25567 trial 89 , final os data from the nej026 and relay trials are awaited before a role as a firstline treatment option can be defined for erlotinib-vegf inhibitors. The data will also have to be assessed in context, because the comparator arm is erlotinib, which has an os inferior to that with osimertinib, the new standard of care. Additional trials in this area are ongoing.

DISCUSSION AND CONCLUSIONS
Patients with EGFR-mutated nsclc currently have many systemic treatment options available, and we encourage enrolment onto clinical trials when possible. Upcoming clinical trial results and the emergence of new agents and combinations will likely change the algorithm presented here. We look forward to potentially better survival options for our patients.