Over the past year, the combination of platinum-based chemotherapy and immunotherapy has become the standard of care for patients with metastatic non–small-cell lung cancer with any programmed death ligand 1 tumor proportion score. There is preclinical evidence demonstrating potential synergistic immunomodulation with combination therapy by enhancing immune-mediated tumor death and by disrupting the immunosuppressive tumor microenvironment that prevents immune detection. This potential synergy or complementary activity has been demonstrated in clinical trials showing improved and durable responses with chemo-immunotherapy.
Key points
- •
Adaptive immunity plays a major role in the prevention of tumor growth and development.
- •
Platinum-based chemotherapy augments antitumor immunity by inducing immunogenic cell death, increasing tumor neo-antigen expression, and disturbing the immunosuppressive tumor microenvironment that prevents immune detection.
- •
Antibodies targeting the PD-1 receptor-ligand interaction, which tumor cells exploit to evade immune detection, enhance the antitumor immune response.
- •
Based on preclinical studies, there is a strong rationale for combining platinum-based chemotherapy and immunotherapy and this potential synergistic effect has been verified with improved outcomes in the clinical setting.
Introduction: overview of advanced non–small cell lung cancer treatment
Lung cancer remains the leading cause of cancer-related deaths worldwide. In the United States, there were an estimated 234,030 new lung cancer cases and 154,050 lung cancer–related deaths in 2018, with higher incidence and mortality in men compared with women. Non–small cell lung cancer (NSCLC) is the most common histologic subtype, accounting for approximately 85% of all lung cancer cases. Unfortunately, most patients with lung cancer are deemed incurable, with advanced disease at diagnosis. Therefore, systemic therapy is the primary treatment option. Although pembrolizumab monotherapy has replaced cytotoxic chemotherapy as first-line treatment in patients whose tumor cell programmed death ligand 1 (PD-L1) staining (tumor proportion score) is ≥50%, this is only a fraction of patients with NSCLC. It is important to maximize the response to first-line treatment, as more than half of patients with NSCLC clinically decline before ever receiving second-line therapy. With many preclinical studies demonstrating immunomodulatory effects of cytotoxic chemotherapy, first-line clinical trials using combination therapy, with PD-1 receptor or ligand inhibitors and chemotherapy, were initiated to improve treatment response and prolong survival. Recently, combination therapy has become the standard of care for most patients with NSCLC.
Non–small cell lung cancer immunology and the use of checkpoint inhibition
Cancer is associated with a state of chronic inflammation, as well as severe systemic immune suppression. Cancer develops by accumulating genetic alterations and the loss of normal cellular regulation. These events lead to the expression of neo-antigens, a peptide bound to major histocompatibility class I (MHC-I) molecules, on the cancer cell surface, which differentiates them from normal cells. It is well established that evasion of immune surveillance is one of the hallmarks of cancer. Previously, development of new therapies had focused on direct tumor cytotoxicity and disturbing tumor microenvironment interactions, such as angiogenesis. However, ongoing research has determined that adaptive immunity plays a major role in the prevention of cancer growth.
The adaptive immune system can effectively kill cancer cells if a series of steps are able to occur. Initially, neo-antigens from the tumor cells are released and captured for processing by dendritic cells (DCs). Then the DCs present the tumor-specific antigens on MHC-I and MHC-II molecules to CD8+ and CD4+ T cells, respectively. This results in priming and activation of the effector T cells against the foreign antigen. At this stage, the ratio of T effector cells to regulatory T cells, which act by suppressing the immune response, determine the final outcome. The effector T cells will travel to the tumor and the T-cell receptor will recognize the tumor-specific antigen presented on the MHC-I complex on the tumor surface, resulting in destruction of the target cell. Subsequently, more tumor-associated antigens are released, thus enhancing tumor-specific immunity. However, this cycle does not function properly in patients with cancer for a variety of reasons; tumor antigens may not be detected and captured by DCs, the antigens may be recognized as self and thus create a T regulatory response leading to tumor tolerance, T cells may not travel to or are prevented from infiltrating the tumors, and, importantly, the tumor microenvironment may suppress the effector cells from functioning.
There are additional co-stimulatory receptors that regulate T-cell activation, also called immune-checkpoints. Under normal physiologic conditions, these molecules allow self-tolerance, but cancer cells exploit these molecules for immune evasion. The PD-1 receptor on T cells interacts with the PD-L1/PD2 ligand (PD-L2) on antigen-presenting cells and peripheral tissue acting as a co-inhibitory signal to maintain self-tolerance. Following T-cell activation, the PD-1 receptor is expressed on T cells; however, concurrent activation of the ligand on macrophages and in tumor tissue prevents immune destruction. This interaction is manipulated by tumor cells to evade immune eradication and has become an important therapeutic target. Antibodies targeting PD-1 and PDL-1 have been developed that prevent this receptor-ligand interaction and, therefore, enhance the antitumor immune response. ,
Platinum-based chemotherapy immunomodulation and synergy with immunotherapy
Platinum-based chemotherapy augments antitumor immunity by inducing immunogenic cell death (ICD), increasing tumor neo-antigen expression and also by disturbing the immunosuppressive tumor microenvironment that prevents immune detection. ICD involves changes on the cell membrane that signal DCs to remove the dying cell followed by release of factors, which stimulates DC activation and maturation. Subsequently, DCs present tumor antigens to T cells creating tumor-specific effector cells. Chemotherapy also alters the tumor microenvironment by promoting increased infiltration of CD8+ T cells, decreasing regulatory T cells and myeloid suppressor cells, and stimulating antigen-presenting cell maturation. , , Several preclinical studies have demonstrated how chemotherapy can augment effector T-cell function by a variety of mechanisms. A study in mice treated with oxaliplatin-cyclophosphamide demonstrated increased CD8+ T-cell infiltration resulting in an increased ratio of CD8+ T cells to regulatory T cells; therefore, sensitizing the tumor microenvironment for immune detection. It has also been shown that expression of PD-L2, a T-cell inhibitor, was downregulated in human tumor cells and dendritic cells after exposure to platinum agents, which led to enhanced antigen-specific proliferation and tumor identification by T cells. Platinum-based chemotherapy also improves tumor cell destruction by granzyme-B–mediated cytotoxic effects of T lymphocytes. Other mechanisms by which platinum agents stimulate the immune system include increasing human leukocyte 1 (HLA1) gene complex expression encoding MHC-I, which is associated with cytotoxic T-cell function. Therefore, based on preclinical studies, there is a strong rationale for combining platinum-based chemotherapy and immunotherapy, and this potential synergistic effect has been demonstrated with improved outcomes in the clinical setting.
Clinical data combining chemotherapy with immunotherapy in nonsquamous non–small cell lung cancer
In patients with metastatic nonsquamous NSCLC, 3 trials, KEYNOTE-189, IMpower150, and IMpower130, have demonstrated improved overall survival (OS) with the addition of an anti-PD-1/PD-L1 antibody to standard chemotherapy ( Table 1 ).
| Name | Description | ORR | mPFS, mo | mOS, mo | HR for OS |
|---|---|---|---|---|---|
| Nonsquamous cell | |||||
| KeyNote 189 , | Pembrolizumab + chemotherapy vs chemotherapy | 48% vs 19% | 8.8 vs 4.9 | 22 .0 vs 10.7 P <.00001 | 0.56 |
| IMPower 150 | Atezolizumab + chemotherapy/bevacizumab vs chemotherapy/bevacizumab | 64% vs 48% | 8.3 vs 6.8 | 19.2 vs 14.7 P = .02 | 0.78 |
| IMPower 130 | Atezolizumab + chemotherapy vs chemotherapy | 49% vs 32% | 7.0 vs 5.5 | 18.6 vs 13.9 P = .033 | 0.79 |
| Squamous cell | |||||
| KeyNote 407 | Pembrolizumab + chemotherapy vs chemotherapy | 58% vs 38% | 6.4 vs 4.8 | 15.9 vs 11.3 P <.001 | 0.64 |
| IMPower 131 | Atezolizumab + chemotherapy vs chemotherapy | 59% vs 51% | 6.3 vs 5.6 | 14.0 vs 13.9 P = .6931 | 0.96 |
KEYNOTE-189 was a phase III trial of treatment-naïve patients with nonsquamous NSCLC without sensitizing epidermal growth factor receptor (EGFR) or anaplastic large-cell lymphoma kinase (ALK) mutations, who were randomized to receive a platinum and pemetrexed doublet in addition to fixed dose pembrolizumab (200 mg) or placebo. , This 3-drug combination was administered every 3 weeks for 4 cycles followed by pemetrexed plus pembrolizumab or placebo as maintenance therapy. Outcomes were assessed by an independent central review committee, which demonstrated improved co-primary endpoints, progression-free survival (PFS), and OS. Median PFS was 8.8 months (95% confidence interval [CI] 7.6–9.2) in the pembrolizumab-combination group compared with 4.9 months (95% CI 4.7–5.5) in the placebo-combination group (hazard ratio [HR] for disease progression or death, 0.52; 95% CI 0.43–0.64; P <.001). In the updated 18.7-month follow-up analysis, the median OS was 22.0 months in the pembrolizumab arm compared with 10.7 months in the placebo arm (HR 0.56; 95% CI 0.45–0.70; P <.00001). Importantly, improvement in OS with immunotherapy and chemotherapy combination was seen across all PD-L1 categories evaluated by tumor proportion score (TPS), including those classified as PD-L1 negative (TPS <1%; HR 0.59; 95% CI 0.39–0.88). The response rate was 47.6% in the pembrolizumab-combination group compared with 18.9% in the placebo-combination group. On disease progression, 50% of the patients randomized to the placebo arm had crossed over to the pembrolizumab arm at the time of analysis. The safety profile was similar with a grade 3 or higher adverse event (AE) occurring in 67.2% of patients in the pembrolizumab arm versus 65.8% of those in the placebo arm. However, more patients discontinued treatment due to an AE in the pembrolizumab-combination group (28% vs 15%). The most common grade 3 or higher adverse events of any cause reported in at least 10% of the patients in the pembrolizumab-combination or the placebo-combination arm were anemia (16.3% vs 15.3%) and neutropenia (15.8% vs 11.9%), which can be attributed to platinum-based combination chemotherapy. As expected, immune-related AEs (irAEs) were more common in the pembrolizumab-combination arm compared with the placebo-combination arm (22.7% vs 11.9%). The most common irAEs of any grade in the pembrolizumab-combination arm compared with the placebo-combination arm were hypothyroidism (6.7% vs 2.5%) and pneumonitis (4.4% vs 2.5%). Grade 3 or higher irAEs occurred in 8.9% of patients in the pembrolizumab-combination arm compared with 4.5% of patients in the placebo-combination arm, the most common of which were pneumonitis (2.7% vs 2.0%) and severe skin reactions (2.0% vs 2.0%). Three patients in the pembrolizumab-combination arm died of pneumonitis. By cross-trial comparison, pembrolizumab combined with chemotherapy did not increase the rate of irAEs compared with pembrolizumab monotherapy given in KEYNOTE-024.
The IMpower130 and the IMpower150 trials both demonstrated OS benefit when atezolizumab was combined with chemotherapy in patients with metastatic nonsquamous NSCLC. Notably, patients with EGFR or ALK mutations who had been treated with 1 or more tyrosine kinase inhibitors (TKIs) were enrolled in both of these studies; however, they were excluded from the primary PFS and OS analysis (intention-to-treat population with wild-type genotype; ITT-WT) in the IMpower 130 study.
IMpower130 was a randomized phase III trial that studied a platinum doublet backbone of carboplatin and nab-paclitaxel with and without atezolizumab (ACnP vs CnP) in patients with metastatic nonsquamous NSCLC. Atezolizumab maintenance was given in the experimental arm and switch maintenance was allowed in the control arm. In the ITT-WT population, a median PFS (7.0 vs 5.5 months; HR 0.64; 95% CI 0.540–.00; P <.0001) and OS (18.6 vs 13.9 months; HR 0.79; 95% CI 0.64–0.98; P = .033) benefit was demonstrated in the atezolizumab arm. The PFS and OS benefit was seen, consistently, in all PD-L1 subgroups except in patients with liver metastases or EGFR/ALK alterations. The objective response rate (ORR) was 49.2% versus 31.9% in the ACnP versus CnP arms, respectively.
IMpower150 was a phase III trial with 3 treatment arms comparing atezolizumab plus bevacizumab, carboplatin and paclitaxel (ABCP) and atezolizumab plus carboplatin and paclitaxel (ACP) with bevacizumab, carboplatin and paclitaxel (BCP). Four to 6 cycles of carboplatin and paclitaxel were completed, followed by maintenance with atezolizumab, bevacizumab, or both. The median PFS was longer in the ABCP group than in the BCP group in the WT population (8.3 vs 6.8 months; HR 0.62; 95% CI 0.52–0.74; P <.001). The PFS benefit was also seen in the entire ITT population, including those with EGFR/ALK genetic alterations, low or negative PD-L1 expression, and those with liver metastases. The median OS in the WT population was also longer in the ABCP group compared with the BCP group (19.2 vs 14.7 months, HR 0.78; 95% CI 0.64–0.96; P = .02). Notably, the atezolizumab, carboplatin and paclitaxel (ACP) arm did not show a survival benefit compared with the BCP control arm. The WT population ORR was 63.5% in the ABCP group and 48% in the BCP group; 3.7% of patients in the ABCP group had a complete response compared with 1.2% of the patients in the BCP group.
The magnitude of PFS benefit with immunotherapy was similar in both the IMpower130 trial (7.0 vs 5.5 months with ACnP vs CnP) and IMpower 150 (8.3 vs 6.8 months with ABCP vs BCP). , The absolute median PFS was longer and ORR was greater with the bevacizumab-containing regimen in the IMpower150 trial. However, the median OS was similar between the IMpower130 (18.6 vs 13.9 months with ACnP vs CnP) and the IMpower 150 (19.2 vs 14.7 months with ABCP vs BCP) trials. The safety profiles of ABCP and ACnP were consistent with previously reported safety risks of the individual medications.
The rate of grade 3 or greater AEs was higher for the 4-drug combination of ABCP than with BCP (58.5% vs 50.0%, respectively) in the IMpower150 trial, but the rate of treatment-related death was similar (2.8% vs 2.3%). As expected, there were more irAEs in the ABCP arm; 77.4% were grade 1 or grade 2 and there were no irAE-associated deaths. The most common irAEs of any grade in the ABCP arm compared with the BCP arm were rash (28.8% vs 13.2%), hepatitis (12.0% vs 7.4%), and hypothyroidism (12.7% vs 3.8%) and grade 3 to 4 irAEs were hepatitis (4.1% vs 0.8%), rash (2.3% vs 0.5%), and pneumonitis (1.5% vs 0.5%).
Role of immunotherapy in epidermal growth factor receptor and anaplastic large-cell lymphoma kinase mutated non–small cell lung cancer tumors
Earlier randomized trials in patients with EGFR or ALK sensitizing alterations, previously treated with a TKI, indicated that immunotherapy was less effective in the second line compared with patients with WT tumors. In fact, in patients with tumors harboring EGFR or ALK alterations, inferior outcomes were observed in those treated with immunotherapy compared with chemotherapy, as first line or after progression on a TKI, regardless of their PD-L1 expression. , However, in the more recent IMpower 150 trial, PFS benefit was demonstrated in patients with these tumor alterations who had progressive disease after or unacceptable side effects with treatment with at least one approved TKI, who were included in the ITT population, with subsequent treatment including atezolizumab and bevacizumab in addition to a platinum doublet. These data suggest that vascular endothelial growth factor inhibition combined with chemotherapy has immune-modulatory effects, which enhance the efficacy of immunotherapy, resulting in improved survival not typically seen in this subset of patients.
Trial data combining chemotherapy with immunotherapy in squamous non–small cell lung cancer
In patients with metastatic squamous NSCLC, the KEYNOTE-407 trial demonstrated improved survival in patients treated with the combination of pembrolizumab and a standard platinum doublet (see Table 1 ). This was a phase III trial in treatment-naïve patients randomized to receive carboplatin and the physician’s choice of either paclitaxel or nab-paclitaxel in addition to pembrolizumab or placebo for 4 cycles, followed by pembrolizumab or placebo maintenance. There was improvement in the co-primary endpoints, median PFS (6.4 vs 4.8 months, HR 0.56; 95% CI 0.45–0.70; P <.001) and median OS (15.9 vs 11.3 months, HR 0.64; 95% CI 0.49–0.85; P <.001), in the pembrolizumab arm. The OS benefit was observed regardless of PDL-1 expression. There was also improvement in the ORR with the addition of pembrolizumab compared with placebo (57.9% vs 38.4%, respectively). The incidence of grade 3 or greater AEs was similar in both groups: 69% in the pembrolizumab arm and 68% in the placebo arm. Although there was a higher rate of treatment discontinuation due to AEs in the pembrolizumab arm (23.4%) compared with the placebo arm (11.8%), patients were treated for a longer duration in the pembrolizumab arm (median 6.3 months vs 4.7 months). There were more irAEs in the pembrolizumab arm compared with the placebo arm, as expected, with 28.8% versus 8.6% any grade and 10.8% versus 3.2% grade 3 to 5 irAEs, respectively. The most common irAEs of any grade in the pembrolizumab arm compared with the placebo arm were hypothyroidism (7.9% vs 1.8%), hyperthyroidism (7.2% vs 0.7%), and pneumonitis (6.5% vs 2.1%) and grade 3 to 4 irAEs were pneumonitis (2.5% vs 1.1%), hepatitis (1.8% vs 0%), and infusion reactions (1.4% vs 0.4%). One patient in each arm died of pneumonitis.
Another phase III study, IMpower 131, used the same chemotherapeutic agents combined with atezolizumab but separated into 3 arms: carboplatin with either paclitaxel (ACP) or nab-paclitaxel (ACnP) was compared with carboplatin plus nab-paclitaxel (CnP) alone (see Table 1 ). This study did demonstrate a median PFS benefit with ACnP versus CnP (6.3 vs 5.6 months, respectively; HR 0.71; 95% CI 0.60–0.85; P <.0001); however, there was no statistically significant difference in the co-primary endpoint, OS (14.0 vs 13.9 months; HR 0.96; 95% CI 0.78–1.18).
Outline of active treatment protocols
Currently, per National Comprehensive Cancer Network guidelines, platinum-based chemotherapy combined with immunotherapy is considered the preferred, category 1, treatment for most cases of advanced or metastatic NSCLC. Patients with metastatic adenocarcinoma, not harboring a driver mutation in EGFR, ALK, ROS1, or BRAF V600 E, and with PDL1 TPS <50%, should receive systemic triplet therapy with carboplatin or cisplatin and pemetrexed combined with pembrolizumab or quadruple therapy with carboplatin, paclitaxel, and bevacizumab combined with atezolizumab, a PD-L1 inhibitor ( Fig. 1 ). , If there is disease response or stable disease per Response Evaluation Criteria in Solid Tumors (RECIST) after 4 cycles of combination therapy, maintenance therapy is continued with pemetrexed and pembrolizumab after triplet therapy or bevacizumab and atezolizumab after quadruple therapy, respectively. First-line, category 1, preferred, systemic therapy options for patients with metastatic squamous cell carcinoma, not harboring the aforementioned driver mutations and with a PD-L1 TPS less than 50%, include pembrolizumab combined with carboplatin and either paclitaxel or nab-paclitaxel (see Fig. 1 ). , For any patient with metastatic NSCLC whose tumor does not have a driver mutation and has a PD-L1 TPS of ≥50%, the preferred, category 1 treatment is pembrolizumab monotherapy (see Fig. 1 ). There are no currently published trials directly comparing pembrolizumab monotherapy versus combination chemo-immunotherapy in the first-line setting. Therefore, based on clinician discretion, it may be necessary to give combination therapy even in circumstances when the PD-1 TPS is greater than 50%, such as a patient having severely symptomatic disease requiring a time-sensitive response to treatment, or pembrolizumab monotherapy when the PD-L1 TPS is less than 50% if it was felt that the patient would not tolerate chemotherapy.
