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Feature: 2020 View on Updates in the Treatment of Lung Cancer

Chung-Shien Lee, PharmD BCOP BCPS
Assistant Professor St. John’s University College of Pharmacy
Queens, NY

Lung cancer remains the deadliest form of cancer in the United States, accounting for approximately 135,720 deaths with an estimated 228,850 new cases in 2020.1 Lung cancer can be classified as two major histological groups, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Treatment of NSCLC has become dependent on molecular profiling since many cases harbor a drivergenetic alterations, most notably mutations in the epidermal growth factor receptor (EGFR) or rearrangements of the anaplastic lymphoma kinase (ALK) gene and ROS1 genes.2,3 The year 2020 was a year of tremendous growth for lung cancer treatment with several new drug approvals and lung cancer trials maturing.

Treatments Targeting ALK
ALK rearrangements are present in 3-5% of NSCLC and are effectively treated with ALK tyrosine kinase inhibitors (TKI).4,5,6

Brigatinib
Brigatinib is a second-generation ALK TKI that was originally approved for the treatment of patients with metastatic ALK-positive NSCLC who had progressed on or were intolerant to crizotinib.7,8 Subsequently, brigatinib received approval as first-line therapy in ALK-positive metastatic NSCLC in May 2020 as a result of the AL-TA-1L trial.9,10 This was an open-label trial, evaluating 275 patients with locally advanced or metastatic ALK-positive NSCLC who were naïve to ALK-targeting therapy. Patients were randomized to receive either brigatinib (n=137) or crizotinib (n=138). The primary endpoint was progression-free survival (PFS). The estimated median PFS was 24.0 months (95% CI, 18.5 to not reached) in the brigatinib group compared to 11.0 months (95% CI, 9.2 to 12.9) in the crizotinib group [HR=0.49, (95% CI, 0.35 to 0.68); p<0.0001]. This benefit was consistent across subgroups, including those with baseline brain metastases.9 The NCCN clinical practice guidelines currently recommend brigatinib as a first-line option in patients with an ALK rearrangement.11

Ensartinib
Ensartinib is a second-generation ALK TKI that was recently shown to be superior to crizotinib. Interim results of eXalt3 study, which was a randomized, open-label, phase III study was presented at the IASLC World Conference on Lung Cancer Virtual Presidential Symposium.12 Ensartinib demonstrated a benefit in the primary endpoint, median PFS (25.8 months vs 12.7 months) with a 49% reduction in the risk of disease progression or death (HR=0.51, 95% CI, 0.35 to 0.72; p=0.0001) in patients with locally advanced or metastatic ALK-positive NSCLC who were naïve to ALK-targeting therapy.

Other efficacy outcomes, such as duration of response and overall survival were not yet mature, but favored ensartinib. In addition, ensartinib demonstrated CNS activity in a small subgroup. Ensartinib had similar rates of serious treatment-related adverse events (TRAEs) (8% vs 6%), dose reductions (24% vs 20%), and drug discontinuations (9% vs 7%) compared to crizotinib.12 The results of the eXalt3 study demonstrate ensartinib as a potential new first-line treatment option for patients with ALK-positive NSCLC.

Treatments Targeting EGFR
EGFR mutations have been found in up to 50% of Asian patients with NSCLC.13 Deletion in exon 19 (45%) and L858R point mutation in exon 21 (40%) are the two most common types of mutations found.14,15 EGFR TKIs have shown to be an effective treatment option for these patients.

Osimertinib
Osimertinib is a third-generation EGFR TKI that was approved as first-line therapy in patients with metastatic EGFR mutated NSCLC in 2018. This approval was based on results of the FLAURA trial, which was a double-blind, phase III trial that demonstrated an improvement in PFS with osimertinib compared to first-generation EGFR TKIs (gefitinib or erlotinib) in 556 patients with advanced EGFR mutated NSCLC. The median PFS was found to be18.9 months and 10.2 months, respectively; HR=0.46; 95% CI, 0.37 to 0.57; p<0.001).16 Recently, long-term follow up of this study also demonstrated an improvement in OS with a median OS of 38.6 months in the osimertinib group compared to 31.8 months in the first-generation EGFR TKI group (HR=0.80, 95.05% CI, 0.64 to 1.00; p=0.046).17

After showing benefit in the advanced EGFR mutated NSCLC setting, osimertinib was investigated in the adjuvant setting. Recently, results of the ADAURA study were disseminated. This was a randomized, double-blinded, placebo-controlled phase III trial comparing osimertinib to placebo in patients with EGFR mutated NSCLC in the adjuvant setting. There was an 83% improvement in disease free survival (DFS) with the osimertinib group (HR=0.17, 95% CI, 0.12 to 0.23; p<0.0001) in stage II to IIIA patients. When patients with stage IB NSCLC were added to the analysis, osimertinib improved DFS by 79% (HR=0.21, 95% CI, 0.16 to 0.28; p<0.0001).18 These results demonstrate osimertinib effectiveness in the adjuvant setting with patients with EGFR mutated NSCLC.

Ramucirumab + Erlotinib
The combination of ramucirumab and erlotinib is the first approval of a vascular endothelial growth factor receptor (VEGFR) inhibitor with an EGFR TKI for first-line treatment of metastatic EGFR mutated NSCLC. The RELAY trial was a randomized, double-blind, placebo-controlled phase III trial investigating the addition of ramucirumab to erlotinib in treatment naïve, EGFR mutated, advanced NSCLC.

The primary endpoint of PFS was significantly longer in the combination group [19.4 months (95% CI, 15.4 to 21.6)] compared to the erlotinib alone group [12.4 months (95% CI, 11.0 to 13.5)] [HR=0.59 (95% CI, 0.46 to 0.76; p<0·0001)]. Severe TRAEs were higher in the combination group compared to the erlotinib alone group (72% vs 54%). The most common severe TRAEs in the ramucirumab plus erlotinib group were hypertension (24%) and derma-titis acneiform (15%).19 Currently the combination of ramucirumab and erlotinib is an option for patients with advanced EGFR mutated NSCLC, but osimertinib is the preferred option according to the NCCN guidelines.11

Treatments Targeting RET
RET rearrangements are less common than ALK rearrangements and EGFR mutations and have been reported to be present in 1-2% of NSCLC cases.20SelpercatinibSelpercatinib is a novel, highly selective RET TKI that was granted accelerated approval by the FDA for adult patients with metastatic RET fusion-positive NSCLC and select patients with RET-mutant or RET fusion-positive thyroid cancer. This approval was based on the results of the LIBRETTO-001 study, which was a phase 1/2 trial that included patients 12 years of age or older with a RET positive advanced or metastatic solid tumor. Drilon and colleagues reported the results for 144 patients with NSCLC (39 previously untreated and 105 patients who had received at least platinum-based chemo-therapy). Among the patients who had previously received treatment, many were heavily pretreated with a median of three previous treatments (range, 1 to 15) and over half previously received immunotherapy. Previously treated patients had an objective response rate of 64% (2% complete response) and a median duration of response of 17.5 months [95% CI, 12.0 to not estimable (NE)]. In the treatment naïve group, the objective response rate (ORR) was 85%. The median PFS was 16.5 months (95% CI, 13.7 to NE) in all patients. Selpercatinib was generally well tolerated with the most common TRAEs being dry mouth (36%), diarrhea (25%), increased liver enzymes (20-22%) and hypertension (17%). The most com-mon severe TRAEs were hypertension (14%) and increased liver enzymes (6-9%). Four patients discontinued selpercatinib due to TRAEs.21 Selpercatinib is currently a preferred option for advanced NSCLC with a RET rearrangement.11PralsetinibSimilar to selpercatinib, pralsetinib is a highly selective RET TKI that was granted accelerated approval by the FDA for adult patients with metastatic RET fusion-positive NSCLC. The phase I/II ARROW trial was a multicenter, open-label, multi-cohort clinical trial evaluating the use of pralsetinib in patients with advanced RET fusion-positive solid tumors. In a recent report, 87 NSCLC patients previously treated with platinum-based chemotherapy had an ORR of 57% (95% CI, 46% to 68%). Median duration of response was not estimable (95% CI, 15.2 months to not estimable). The ORR was 70% (95% CI, 50% to 86%) with a median duration of response of 9.0 months (95% CI, 6.3 months to not estimable) in 27 treatment-naive patients who were ineligible for platinum-based chemotherapy. The most common TRAEs included increased aspartate aminotransferase (31%), anemia (22%), increased alanine amino-transferase (21%), constipation (21%) and hypertension (20%). Four percent of patients discontinued pralsetinib due to TRAEs.22,23Pralsetinib is currently a preferred option for advanced NSCLC with a RET rearrangement.11

Treatments Targeting Mesenchymal-epithelial transition (MET)
Recently, MET has presented itself as another actionable tar-get mutation. MET exon 14 skipping mutations occur in 3-4% of NSCLC patients and MET amplification occurs in 1-6% of NSCLC patients.24,25

Capmatinib
Capmatinib is a potent, selective MET TKI that was granted accelerated approval by the FDA for adult patients with metastatic NSCLC whose tumors have a mutation that leads to MET exon 14 skipping. This approval was based on the GEOMETRY mono-1 study, which was an open-label, multiple-cohort, phase 2 study that investigated the use of capmatinib in patients with advanced NSCLC with a MET exon 14 skipping mutation or MET amplification. The primary end point was ORR, which was 68% (95% CI, 48 to 84) in 28 patients who were treatment naïve and 41% (95% CI, 29 to 53) in 69 patients who were previously treated. Median duration of response was 12.6 months (95% CI, 5.6 not estimable) and 9.7 months (95% CI, 5.6 to 13.0), respectively. Median PFS was 12.4 months (95% CI, 8.2 to not estimable) and 5.4 months (95% CI, 4.2 to 7.0), respectively. There was a limited response in previously treated patients with MET amplification who had a gene copy number of <10 orr="7-12%)." the="" most="" commonly="" reported="" adverse="" events="" were="" peripheral="" edema="" 51="" nausea="" 45="" increase="" serum="" creatinine="" 24="" and="" dyspnea="" 23="" which="" mostly="" of="" grade="" 1="" or="" 2="" sup="">26 Capmatinib is currently the preferred option for advanced NSCLC with a MET mutation.11

Tepotinib
Tepotinib is a selective MET inhibitor that was recently shown to be efficacious in advanced NSCLC patients with MET exon 14 skipping mutations. The VISION study was a multicohort, open-label, phase II study evaluating tepotinib in advanced NSCLC patients with MET alterations. One hundred and fifty-two patients were treated with tepotinib (safety population) and out of these, 99 had a confirmed biopsy (liquid or tumor) and at least 9 months of follow-up (efficacy population). The primary end point was confirmed ORR, which was 46% (95% CI, 36 to 57) with no complete responses. Responses were similar in both biopsy groups, 48% (95% CI, 36 to 61) in the liquid biopsy group and 50% (95% CI, 37 to 63) in the tissue biopsy group. Median PFS was 8.5 months (95% CI, 6.7 to 11.0). The most commonly reported adverse events were peripheral edema (63%), nausea (26%) and diarrhea (22%) with 7% of patients experiencing FEATURE (continued)24FEATURE (continued)severe peripheral edema. The VISION study demonstrated tepotinib to be a well-tolerated efficacious agent for advanced NSCLC patients with MET exon 14 skipping mutation.27

Lurbinectedin for SCLC
Lurbinectedin is an alkylating agent and a selective inhibitor of oncogenic transcription, which binds preferentially to guanines located in the GC-rich regulatory areas of DNA gene promoters leading to tumor cell apoptosis. It was granted accelerated approval for adult patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy.

In a single-arm, open-label, phase II basket trial, lurbinectedin demonstrated an overall response of 35.2% (95% CI, 26.2 to 45.2) in 105 patients who were pre-treated with only one previous chemo-therapy containing treatment line (immunotherapy was allowed). The most common adverse events observed were anemia (87%), elevated creatinine (83%), elevated alanine aminotransferase (67%), leucopenia (50%), elevated γ-glutamyl transferase (50%), fatigue (50%), elevated aspartate aminotransferase (43%), and thrombocytopenia (37%). Severe adverse events were mostly hematological.28 Lurbinectedin is currently the preferred regimen for SCLC patients who have relapsed within 6 months of first line treatment.29

Durvalumab for SCLC
Durvalumab is a PD-L1 inhibitor, which was approved as first-line treatment of patients with extensive-stage SCLC in combination with etoposide and a platinum agent. The CASPIAN trial was a randomized, open-label, phase III trial that investigated durvalumab in treatment naïve extensive-stage SCLC. Durvalumab plus platinum etoposide demonstrated a significant improvement in OS compared to platinum etoposide alone [HR = 0.73 (95% CI, 0.59 to 0.91; p=0·0047)]; median OS of 13.0 months (95% CI, 11.5 to 14.8) vs 10.3 months (95% CI, 9.3 to 11.2). The rate of severe adverse events was similar in the two groups.30 Durvalumab plus platinum etoposide is currently a preferred first line regimen for extensive-stage SCLC patients.29

Immunotherapy for NSCLC
Immunotherapy has become the mainstay of treatment for patients with NSCLC in the absence of a driver mutation.11 Several approvals with various immunotherapy agents have occurred in this patient population in 2020:

  • Nivolumab plus ipilimumab was approved as first-line treatment for patients with metastatic NSCLC whose tumors express ≥1% PD-L1 with no EGFR or ALK genomic tumor aberrations.31
  • Atezolizumab was approved as first-line treatment of adult patients with metastatic NSCLC whose tumors have high PD-L1 expression (PD-L1 stained ≥ 50% of tumor cells [≥ 50%] or PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 10% of the tumor area [IC ≥ 10%]), with no EGFR or ALK genomic tumor aberrations.32
  • Nivolumab plus ipilimumab was approved with 2 cycles of platinum doublet chemotherapy as first-line treatment for patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations.33

Data from the phase III ORIENT-11 trial was recently presented at the IASLC Virtual Presidential Symposium 2020. This trial demonstrated sintilimab, an anti-PD-1 inhibitor, when added to pemetrexed and platinum-based therapy significantly improved PFS compared to chemotherapy alone in patients with locally advanced or metastatic nonsquamous NSCLC. Median PFS was 8.9 months (95% CI, 7.1 to 11.3) compared to 5.0 months (95% CI, 4.8 to 6.2), respectively (HR=0.482, 95% CI, 0.362 to 0.643]; p<0.00001). This benefit was seen across all subgroups and increased with higher PD-L1 tumor expression. Sintilimab was well tolerated, with similar incidence of overall adverse events (AEs; 99.6% vs 100%), severe adverse events (61.7% vs 58.8%), and adverse events leading to treatment discontinuation (6.0% vs 8.4%).34 Sintilimab provides a treatment option for patients with nonsquamous NSCLC with no EGFR mutations or ALK rearrangements, where treatment options are limited.

Conclusion
A plethora of much-needed, new treatment options and approvals for lung cancer have occurred in 2020. These include various oral TKIs for driver mutations, as well as combination immunotherapy treatments. As further data matures, the treatment paradigm for SCLC and NSCLC will continue to shift and improve patient out-comes.

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  31. U.S. Food and Drug Administration. FDA approves nivolumab plus ipilimumab for first-line mNSCLC (PD-L1 tumor expression ≥1%). Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-plus-ipilimumab-first-line-mnsclc-pd-l1-tumor-expression-1
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  34. Zhang L, Yang Y, Wang Z, et al. ORIENT-11: Sintilimab + pemetrexed + platinum as first-line therapy for locally advanced or metastatic non-squamous NSCLC. 2020 World Conference on Lung Cancer. Presidential Symposium. Abstract 1.
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