First-line therapy - Clinical Tree

CLINICAL PEARLS

In advanced non−small cell lung cancer, when an actionable oncogenic driver is present, regardless of the PD-L1 tumor proportion score (TPS), targeted therapy is the preferred option.
In the absence of an oncogenic driver, currently PD-L1 TPS drives decision making. For those with PD-L1 TPS ≥50% and no contraindication to immunotherapy, immunotherapy monotherapy is the preferred option, although chemoimmunotherapy combinations may be considered.
In the absence of an oncogenic driver and PD-L1 <50%, combination anti-PD-1 plus platinum doublet therapy is preferred. Currently approved regimens include histology-based platinum-doublet chemotherapy in combination with pembrolizumab, atezolizumab plus bevacizumab, or nivolumab plus ipilimumab.
PD-L1 TPS remains the key factor for selecting combination chemoimmunotherapy over monotherapy (i.e., TPS <50%). Patients with PD-L1 TPS ≥50% may derive preferential benefit from combination therapy in selected cases (e.g., high disease burden, liver metastasis, never-smokers). First-line combination chemoimmunotherapy significantly improves survival, progression-free survival, and response rates in both nonsquamous and squamous advanced lung cancer patients irrespective of PD-L1 TPS compared with chemotherapy.
Combination immunotherapy with nivolumab/ipilimumab is the only chemotherapy-sparing option for patients irrespective of PD-L1 tumor expression levels, including those with PD-L1 <1%.

Until recently, the standard first-line therapy for patients with advanced non−small cell lung cancer (NSCLC) has been platinum-doublet chemotherapy. Survival advances have previously been seen in patients with nonsquamous NSCLC, including pemetrexed/platinum with maintenance pemetrexed therapy, and bevacizumab/paclitaxel/carboplatin. The evolution of targeted therapy has led to major changes in lung cancer diagnosis, treatment algorithms, and improved patient outcomes. More recently, anti-PD-1/PD-L1 agents have demonstrated improved survival as monotherapy in first-line treatment. ^, Combination anti-PD-1 plus chemotherapy has also shown improved survival compared with first-line chemotherapy alone.

Treatment selection in patients with advanced disease relies on both patient and tumor factors. In addition to pathological subtype, molecular profiling is now a standard part of lung cancer diagnosis. Guidelines recommend testing for multiple genomic targets, including epidermal growth factor receptor (EGFR) sensitizing, BRAF V600E and MET exon 14 (METex14) skipping mutations, and anaplastic lymphoma kinase (ALK), ROS1, RET , KRAS G12C , and NTRK translocations at a minimum in patients with nonsquamous NSCLC and clinically selected patients with other subtypes (e.g., never-smokers with squamous carcinoma diagnosed with small samples or mixed histology). ^, Many additional emerging targets and therapies are also in development with relevant drug approvals expected in the near future (e.g. mutations in ERBB2 or MET amplifications ). If patients have an activating mutation ( EGFR, BRAF V600E, METex14 skipping) or translocation ( ALK, ROS1, RET, TRK ) present in tumor, it is recommended that they receive appropriate targeted therapy initially rather than immunotherapy or chemotherapy. Although it is recommended to test for KRAS G12C mutations at diagnosis, targeted therapy for KRAS G12C is not approved until the second line setting.

In the absence of an actionable oncogenic driver, treatment selection is based on pathological subtype (histology) and PD-L1 tumor proportion score (TPS). The TPS represents the percentage of viable tumor cells showing partial or complete membrane staining for PD-L1 protein expression. Choice of treatment is also influenced by patient and disease factors, including patient performance status, patient preferences, the extent of disease and metastatic sites, and the presence of symptoms. Toxicity and quality of life are also important considerations in the treatment decision. An algorithm for treatment in good performance status patients is shown in Fig. 8.1 , with highlights of recent studies in Fig. 8.2 .

Lung cancer epidemiology varies between western and eastern countries and by the prevalence of tobacco use. In North America, approximately 85% of lung cancer cases are non–small cell. Of these patients, 60% are adenocarcinoma, 30% are squamous carcinoma, and 10% are large cell (poorly differentiated) carcinoma. In North America and Europe, approximately 15%–20% of patients have EGFR mutant lung cancer, while this is much higher in Asian countries, where the incidence is approximately 60%. The incidence of ALK translocations is 3%–7%, ROS1 translocations 1%–2%, BRAF V600E mutations ~2%, and MET exon 14 skip mutations at 3%–4%. KRAS is the most common molecular mutation seen in patients with adenocarcinoma (~25%); however, targeted treatment options are just now emerging for patients who have a KRAS G12C (~15%) mutation. With respect to PD-L1 TPS, although proportions vary across studies, approximately one third of advanced NSCLC patients have PD-L1 TPS ≥50%, one third have PD-L1 TPS 1-49% and another third have PD-L1 TPS <1%. There are several assays for tumor PD-L1 expression, with different antibodies and different thresholds across drug development programs ( Table 8.1 ). While the Dako 22C3 PD-L1 IHC assay has been approved as a companion diagnostic in several jurisdictions, the BLUEPRINT study has demonstrated concordance for tumor cell staining across different PD-L1 testing platforms and antibodies used in various trials. ^, Results with immune cell staining were more variable, with the SP142 antibody (Ventana, atezolizumab program) demonstrating the greatest sensitivity for immune cell staining but the least for tumor cell staining.

TABLE 8.1 ■

Programmed Death−Ligand 1 Immunohistochemistry Assays in Lung Cancer

Agent	Assay	Indications
Pembrolizumab	22C3 DAKO	TPS ≥1% second-line therapy, first-line therapy (US) TPS ≥50% first-line therapy
Nivolumab	28-8 PharmDx	Not required for second-line therapy TC ≥1% for nivolumab plus ipilimumab first-line therapy (US)
Atezolizumab	SP142 Ventana22C3 DAKO	Not required for second-line therapy TC≥50%, IC≥10% First-line therapy
Durvalumab	SP263 Ventana	Not required for stage III consolidation therapy in US TC ≥1% for stage III consolidation therapy in Europe (EMA)
Avelumab	73-10 DAKO	Not approved in NSCLC

EMA, European Medicines Agency; IC, immune cell; NSCLC, non−small cell lung cancer; TC, tumor cell; TPS, tumor proportion score.

Anti-PD-1/PD-L1 monotherapy as first-line therapy in patients with advanced non–small cell lung cancer without oncogenic drivers ( EGFR, ALK wild type)

The identification of those most likely to benefit from anti-PD-1 therapy stems from initial studies in the second-line setting, where PD-L1 tumor expression was associated with greater response to monotherapy. The PD-L1 TPS cutoff of 50% was derived from the phase I KEYNOTE-001 study of pembrolizumab and later validated in the KEYNOTE-024 trial. There have been several studies of first-line anti-PD-1 therapy or combination immunotherapy compared with chemotherapy, with KEYNOTE-024 being the first to change the standard of care.

Pembrolizumab

The phase III open-label KEYNOTE-024 study led to the approval of first-line pembrolizumab as standard in this population. This study enrolled 305 patients with PD-L1 TPS ≥50%, 16% of 1934 patients screened for the study, including those with squamous and nonsquamous subtype. They were randomized to receive either pembrolizumab monotherapy (200 mg IV every 3 weeks for up to 35 cycles or 2 years) or platinum-doublet chemotherapy (investigator’s choice, 4–6 cycles with maintenance therapy as appropriate). Median survival in those treated with pembrolizumab was 30 months compared with 14.2 months for those treated with chemotherapy (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.47−0.86; P = 0.005), with 54% of patients in the chemotherapy arm receiving a subsequent checkpoint inhibitor. Progression-free survival (PFS) was also improved, 10.3 months with pembrolizumab versus 6.0 months with chemotherapy (HR, 0.50; 95% CI, 0.47−0.86, P < 0.001). The overall response rate (ORR) was 44.8% for pembrolizumab compared with 27.8% with chemotherapy, similar to the pembrolizumab response rate seen in KEYNOTE-001. Patients also had better quality of life and less toxicity with pembrolizumab versus chemotherapy. Severe grade ≥3 events were less common, 27% in the pembrolizumab group, compared with 53% with chemotherapy. The rate of severe immune-related events in the pembrolizumab arm included pneumonitis in 2.6%, rash in 5.2%, and colitis in 1.9%. On the basis of these results, first-line pembrolizumab in patients with PD-L1 TPS ≥50% is now standard of care.

KEYNOTE-042 was a phase III open-label study comparing pembrolizumab monotherapy versus platinum-doublet chemotherapy in patients with advanced NSCLC and PD-L1 TPS ≥1%. Although the HR for survival was 0.81 (95% CI, 0.71−0.93; P = 0.0018) in the total study population, the Kaplan-Meier curves cross between 6 and 12 months and the survival benefit was largely driven by the subgroup of PD-L1 TPS ≥50% (OS HR TPS ≥50%, 0.69 (95% CI, 0.56−0.85; P = 0.0003); HR TPS ≥20%, 0.77 (95% CI, 0.56−0.85; P = 0.0020). In an exploratory analysis in those with PD-L1 TPS 1%−49%, survival was not significantly improved versus chemotherapy. It is also important to note that crossover to pembrolizumab was not allowed in the control group, and only 20% of these patients received subsequent immunotherapy. Pembrolizumab monotherapy was better tolerated than chemotherapy, with treatment-related grade ≥3 adverse events in 18% versus 41% of patients, respectively. This led to the approval of pembrolizumab as initial therapy in patients with PD-L1 TPS ≥1% by the US Food and Drug Administration (FDA). However, most clinicians and guidelines continue to use the 50% PD-L1 TPS cutoff for selecting patients for upfront pembrolizumab or anti-PD-1 monotherapy. A recent presentation explored the impact of KRAS G12C mutations on outcomes in this study. Those with KRAS mutant lung cancer, in particular G12C mutations ( n = 29), had higher response rates (67% pembrolizumab vs. 24% chemotherapy) and longer survival (HR OS 0.28; 95% CI, 0.09−0.86). However, this analysis was not controlled for PD-L1 TPS; thus its relevance to daily practice remains unclear.

Nivolumab

CheckMate-026 was a phase III study comparing nivolumab with platinum-doublet chemotherapy in treatment-naïve patients with a PD-L1 tumor cell expression of 1% or more using the 28-8 (DAKO) assay. Patients were stratified by PD-L1 <5% and ≥5%. Survival was not improved, although the curves overlap, in those with a PD-L1 score of ≥5%, with a survival HR of 1.02 (95% CI, 0.80−1.30), median survival and PFS of 14.2 months and 4.2 months with nivolumab versus 13.2 months and 5.4 months with chemotherapy. Approximately 60% of patients starting chemotherapy crossed over to nivolumab.

The CheckMate-227 study has also examined the role of first-line nivolumab versus chemotherapy in patients with tumor PD-L1 ≥1%. Unfortunately, these data did not show significantly improved outcomes in patients treated with nivolumab monotherapy versus chemotherapy in this population.

Atezolizumab

The IMpower 110 study, a phase III trial of first-line atezolizumab versus platinum-based chemotherapy, included treatment-naïve NSCLC patients irrespective of PD-L1 status. In the entire study population, survival was not significantly improved. However, in the subgroup of patients with high PD-L1 expression (≥50%) in tumor cells using the SP142 assay, median survival with atezolizumab was 20.2 months, and 13.2 months with chemotherapy (HR, 0.59; 95% CI, 0.40−0.89; P = 0.0106). Similar findings were seen using the 22C3 assay (HR, 0.60; 95% CI, 0.42−0.86). However, although 28.5% of the study population had high PD-L1 expression using both assays, more patients (48.7%) had PD-L1 ≥50% using that 22C3 assay than using the SP142 assay (37.1%). Greater concordance was seen between the 22C3 and SP263 assay, although outcomes were not as favorable using the SP263 (HR, 0.71; 95% CI, 0.50−1.00). This has been approved by the FDA for those with PD-L1 tumor cell (TC) ≥50% (22C3 or SP142) or tumor-infiltrating immune cell (IC) ≥10% (SP142). Severe adverse events were less common with atezolizumab treatment than with chemotherapy (grade 3 or 4 adverse events in 12.9% vs. 44.1%).

Durvalumab

Recent studies of front-line durvalumab in PD-L1 unselected patients include MYSTIC and NEPTUNE. The MYSTIC study reported results last year, comparing durvalumab, durvalumab/tremelimumab versus platinum-doublet therapy as first-line advanced NSCLC patients with any PD-L1 status. There was no significant improvement in survival or PFS with first-line durvalumab versus chemotherapy.

Cemiplimab

The EMPOWER-1 study demonstrated that the anti-PD-1 monoclonal antibody cemiplimab improved survival compared with platinum chemotherapy as initial treatment in patients with advanced NSCLC and PD-L1 TPS ≥50%. The HR for survival in the intention-to-treat analysis was 0.68 (95% CI, 0.53−0.87; P = 0.0022), with a median survival of 22.1 months with cemiplimab and 14.3 months with chemotherapy. With central review to confirm PD-L1 expression ≥50%, the median survival with cemiplimab was not reached and the HR improved to 0.57 (95% CI, 0.42−0.77; P = 0.0002). PFS was also improved, median 8.2 months in those with central PD-L1 testing receiving cemiplimab versus 5.7 months with chemotherapy (HR, 0.54; 95% CI, 0.43−0.68; P < 0.0001). Response rate was also significantly higher, 35%−39% versus 20% with chemotherapy alone, with a median duration of response with cemiplimab of 16.7 to 21 months. Global quality of life scores were significantly improved in the cemiplimab arm, and treatment was well tolerated. This has been approved by the FDA for those with PD-L1 TC ≥50%.

Summary

In patients with TPS ≥50% and no evidence of targetable genomic alterations, single-agent anti-PD-1 agents such as pembrolizumab, atezolizumab, and cemiplimab are standard of care versus chemotherapy. The use of pembrolizumab in those with PD-L1 TPS 1%−49% is approved but not widely recommended, and our understanding of who should have anti-PD-1 monotherapy versus combination with chemotherapy or other checkpoint inhibitors is evolving.

Anti-PD-1/PD-L1 combinations with chemotherapy as first-line treatment in patients with advanced NSCLC

Multiple trials have compared combination platinum chemotherapy doublet plus PD-1 axis inhibitors to standard platinum doublet therapy alone. While four trials have demonstrated significant improvement in survival, three have had a significant impact on practice and redefined the standard of care in those with advanced nonsquamous and squamous lung cancer, particularly in patients with PD-L1 TPS <50%. ^,

Pembrolizumab combinations

Two studies with pembrolizumab plus chemotherapy have changed practice, KEYNOTE-189 in those with nonsquamous lung carcinoma and KEYNOTE-407 in those with squamous carcinoma. ^, In KEYNOTE-189, patients with advanced nonsquamous NSCLC ( EGFR, ALK wild type) and no previous treatment were randomized to receive either chemotherapy (pemetrexed and platinum) plus pembrolizumab (at a fixed dose of 200 mg IV) or placebo every 3 weeks for 4 cycles, followed by maintenance pembrolizumab or placebo for up to 35 cycles (2 years) plus pemetrexed maintenance until disease progression or unacceptable toxicity. Survival was improved with a median overall survival (OS) of 22.0 months with the addition of pembrolizumab, with 1-year survival estimated at 69.2% versus 49.4 % with chemotherapy alone (HR, 0.49; 95% CI, 0.38−0.64; P < 0.001). Forty-one percent of those randomized to chemotherapy alone subsequently received anti-PD-1 therapy. Survival benefit was seen irrespective of patient PD-L1 TPS score, including TPS <1%. The most dramatic benefit appeared to be in those with PD-L1 TPS ≥50%, although the appropriate comparator today would be single-agent pembrolizumab in this group rather than chemotherapy. Response rate (47.6% vs. 18.9%, P < 0.001) and PFS were also improved with the addition of pembrolizumab (median PFS 9.0 vs. 4.9 months; HR, 0.48; 95% CI, 0.40−0.58; P < 0.0001). The rate of severe adverse events was similar in both arms, although patients receiving pembrolizumab plus chemotherapy were more likely to experience diarrhea (31% vs. 21% any grade), rash (20% vs. 11%, any grade), and acute kidney injury (5.2% vs. 0.5%). Quality of life and symptom improvement trended to superiority in the pembrolizumab combination arm.

KEYNOTE-407 has a similar design but was conducted in patients with advanced squamous lung carcinoma, demonstrating similar improvements in survival, response, and PFS with the addition of pembrolizumab (up to 35 cycles) to 4 cycles of paclitaxel or nab-paclitaxel plus carboplatin. Study results were reported after the second interim analysis as recommended by the external data monitoring committee, after a median follow-up of 7.8 months (range 0.1–19.1). Median survival time was 15.9 months in the combination arm compared with 11.3 months with chemotherapy alone (HR, 0.64; 95% CI, 0.49–0.85; P < 0.0001). Approximately 32% of patients crossed over from the chemotherapy arm to receive subsequent anti-PD-1 therapy. The survival benefit was observed across PD-L1 TPS subgroups with a similar effect size. Response rate was significantly higher with combination therapy, 58% versus 38%, and PFS was also improved (median PFS, 6.4 vs. 4.8 months; HR, 0.56; 95% CI, 0.45–0.70; P < 0.001). The rate of severe adverse events was similar in both arms and consistent with known safety profiles of the combinations. Outcomes were similar whether paclitaxel or steroid-sparing nab-paclitaxel was used; thus use of either agent as part of the pembrolizumab/carboplatin combination appears safe and efficacious.

Atezolizumab combinations

There have been two studies of atezolizumab plus chemotherapy that demonstrated improved survival in patients with advanced nonsquamous lung cancer (IMpower150 and IMpower130). ^, Two other studies have demonstrated improved PFS, one in patients with nonsquamous lung cancer (IMpower132) and the other in squamous carcinoma (IMpower131). ^,

Socinski and colleagues have reported the results of the IMpower 150 trial, in which 1202 patients with chemotherapy-naïve advanced nonsquamous lung cancer were randomized to either bevacizumab/paclitaxel/carboplatin (BPC), BPC plus atezolizumab (ABPC), or atezolizumab plus paclitaxel/carboplatin (APC). Patients were required to be bevacizumab eligible (i.e., no significant hemoptysis nor central cavitary lesions), and those with EGFR/ALK -deranged tumors after TKI failure were included and represented approximately 10% of the total study population. Patients in the ABCP arm had the longest survival and PFS, with a survival HR of 0.78 (95% CI, 0.64−0.96) and PFS HR of 0.62 (95% CI, 0.52−0.74) compared with BPC. Those in the APC and BPC arms had similar outcomes, suggesting the potential for interaction between VEGF and PD-1 inhibition, which has been demonstrated preclinically. Improved outcome with ABCP was observed across all tumor and immune cell PD-L1 categories (TC0/IC0 to TC3+/IC3+, SP142 assay). Subgroup analysis demonstrated major benefit in those with liver metastases at baseline treated with ABCP, with improved survival compared with BPC. Median survival was 13.3 months compared with 9.4 months (HR 0.52; 95% CI, 0.33−0.82). Response rate and PFS were also improved. No significant differences were seen between the APC and BPC arms, raising questions about the importance and potential synergy of atezolizumab and bevacizumab. Another subgroup that derived benefit was patients with EGFR mutant or ALK -rearranged lung cancer. Further analysis of the 10% of study patients with EGFR mutant lung cancer reveals that 73% had sensitizing mutations and 63% had received prior TKI. A trend to improved survival was seen in the ABCP arm, HR 0.61 (95% CI, 0.29–1.28), but further post-hoc analysis of 58 patients suggests improved survival in those with sensitizing mutations (median survival not reached with ABCP; 17.5 months with BPC; HR, 0.31; 95% CI, 0.11–0.83). These differences were not seen in the APC arm compared with BPC. The most common severe adverse events were neutropenia, febrile neutropenia, and hypertension. The incidence of rash, stomatitis, febrile neutropenia, and hemoptysis was higher among those receiving ABCP than those in the BPC group.

IMpower132 was an unblinded study that enrolled 578 patients with nonsquamous, EGFR/ALK wild-type lung cancer, and patients were randomly assigned to receive pemetrexed/platinum (cis- or carboplatin) with or without atezolizumab for 4 cycles and then maintenance pemetrexed with or without atezolizumab until progression. While survival was not significantly improved, median PFS of 7.6 months was observed with atezolizumab versus 5.2 months with chemotherapy alone (HR, 0.60; 95% CI, 0.49–0.72; P < 0.0001). The overall response rate was higher, 47% in the atezolizumab group compared with 32% with chemotherapy, and the safety profile of the combination was manageable and consistent with known risks of each agent, with no new safety signals.

IMpower130 was a similarly designed, open-label randomized study in the same population, in which nonsquamous advanced lung cancer patients were randomized to nab-paclitaxel/carboplatin with or without atezolizumab. Of note, patients with EGFR or ALK -deranged lung cancer that had failed all standard TKI therapies were also permitted to enroll. After 4 to 6 cycles of combination therapy, patients continued atezolizumab in the experimental arm, and in the standard arm they were observed or received maintenance pemetrexed until progression. Data on how many received pemetrexed maintenance therapy are not available, but 41% of patients in the standard arm later crossed over to receive atezolizumab. Survival was improved in patients without oncogene addiction, median 18.6 months versus 13.9 months with chemotherapy alone (stratified HR, 0.79 [95% CI, 0.64–0.98]; P = 0.033). PFS was also improved, with a median PFS of 7.0 months versus 5.5 months (stratified HR, 0.64 [95% CI, 0.54–0.77]; P < 0·0001]). No survival benefit was seen in the subgroups of those with baseline liver metastases or EGFR mutant lung cancer. Treatment-related serious adverse events were higher, 24%, with atezolizumab versus 13% with chemotherapy alone. Thus while this regimen may be an option in patients with advanced nonsquamous lung cancer, most clinicians favor pemetrexed-based regimens.

One study has evaluated the combination of atezolizumab with chemotherapy in patients with squamous lung carcinoma. IMpower131 is a phase III randomized trial comparing chemotherapy plus atezolizumab with chemotherapy alone as first-line treatment in 1021 advanced squamous lung cancer patients. Patients were randomized to one of three treatment arms: atezolizumab plus carboplatin and paclitaxel, atezolizumab plus carboplatin and nab-paclitaxel, or carboplatin and nab-paclitaxel. In this study, the addition of atezolizumab to carboplatin/nab-paclitaxel demonstrated longer PFS, with a doubling of the 1-year PFS rate from 12.0% to 24.7%. There was a trend to better OS in the atezolizumab/carboplatin/nab-paclitaxel group compared with chemotherapy, but this did not meet statistical significance. In patients with high PD-L1 tumor cell expression, median OS was 23.4 months compared with 10.2 months. Finally, the combination of atezolizumab plus carboplatin/nab-paclitaxel appeared to have a manageable toxicity profile with no new safety signals emerging in the trial.

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