INTRODUCTION — Lung cancer is the leading cause of cancer-related mortality in the United States and worldwide. More than 80 percent of lung cancers are classified as non-small cell lung cancer (NSCLC). Although targeted therapies have redefined treatment options for patients with molecularly defined NSCLC (eg, epidermal growth factor receptor [EGFR]-mutant, anaplastic lymphoma kinase [ALK]-rearranged NSCLC), these therapies are ineffective in those whose tumors lack such genetic alterations, who comprise the majority of NSCLC patients. However, immunotherapy has become integrated into the treatment of such patients, which has led to improvements in survival and quality of life.
This topic reviews the initial approach to management of patients with nondriver-mutated NSCLC. An overview of the approach to advanced NSCLC, discussions of management of driver-mutated NSCLC, management of brain metastases in NSCLC, and further details regarding chemotherapy selection in NSCLC are all found separately.
●(See "Overview of the initial treatment of advanced non-small cell lung cancer".)
●(See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)
●(See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer".)
●(See "Brain metastases in non-small cell lung cancer".)
●(See "Systemic chemotherapy for advanced non-small cell lung cancer".)
FACTORS IN CHOOSING INITIAL THERAPY — Treatments for patients with advanced NSCLC are palliative, and thus intended to prolong survival and preserve quality of life for as long as possible, while minimizing the side effects due to treatment. Immune checkpoint inhibitors targeting either programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1) have become routinely part of the clinical approach for management of NSCLC. Rationale for use and mechanism of action of checkpoint inhibitors in cancer is discussed elsewhere. (See "Principles of cancer immunotherapy".)
Factors that affect choice of treatment in NSCLC that lacks a driver mutation include the level of PD-L1 expression, the extent of disease, and histology. Our approach is consistent with expert guidelines from The American Society of Clinical Oncology and Ontario Health (Cancer Care Ontario) [1]. Specifically, patients with PD-L1 expression ≥50 percent are typically offered monotherapy with the anti-PD-1 antibody pembrolizumab, although some with rapidly progressing or very extensive disease may be treated with a platinum doublet chemotherapy plus pembrolizumab. For patients with PD-L1 expression <50 percent, the combination of a platinum-doublet chemotherapy and pembrolizumab is standard. Choice of chemotherapy, for those receiving it, is influenced by histology. (See "Systemic chemotherapy for advanced non-small cell lung cancer", section on 'Effect of histology'.)
Although immunotherapy is entering treatment paradigms for those with driver mutations, we typically do not integrate it into treatment strategies until progression has occurred on available next-generation targeted agents. We also advocate for particular caution when using PD-1 or PD-L1 blockade prior to or concurrent with osimertinib in patients with epidermal growth factor receptor (EGFR) mutations because increased risk of pulmonary toxicity has been reported when these medications are used together [2]. The approach to advanced NSCLC with driver mutations is discussed in more detail elsewhere. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor", section on 'Resistance to osimertinib' and "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer", section on 'Treatment after progression on second-generation ALK TKIs'.)
Further details on the rationale and choice of chemotherapy, for those in whom it is warranted, are discussed elsewhere. (See "Principles of cancer immunotherapy".)
CHEMOTHERAPY-NAIVE
PD-L1 low (<50 percent) or unselected tumors — Pembrolizumab has received US Food and Drug Administration (FDA) approval for the frontline treatment of metastatic nonsquamous NSCLC in combination with pemetrexed and carboplatin, irrespective of programmed cell death ligand 1 (PD-L1) expression. This combination is our preferred treatment option for those with PD-L1 expression <50 percent or unknown advanced adenocarcinomas. However, the combination of platinum-based doublet chemotherapy, bevacizumab, and atezolizumab is a potential alternative in patients with nonsquamous NSCLC, and it has received FDA approval for this indication [3]. Nivolumab-based combinations are an alternative, discussed below. (See 'Nivolumab, with or without chemotherapy' below.)
We favor pembrolizumab in combination with a carboplatin/taxane doublet in patients with advanced squamous cell cancers with low or absent PD-L1 expression, based on results discussed below. (See 'Squamous' below.)
Rationale for choice of chemotherapy is found elsewhere. (See "Systemic chemotherapy for advanced non-small cell lung cancer", section on 'Effect of histology'.)
Irrespective of histology, nivolumab plus ipilimumab is an appropriate alternative to these regimens, particularly if a chemotherapy-free option is desired. (See 'Nivolumab plus ipilimumab, with or without chemotherapy' below.)
Nonsquamous
Pembrolizumab plus chemotherapy — The frontline addition of pembrolizumab (200 mg intravenous [IV] every three weeks) to platinum-doublet chemotherapy (platinum agent and pemetrexed) has improved outcomes relative to chemotherapy alone in two randomized trials enrolling patients with advanced, nonsquamous NSCLC.
In the phase III KEYNOTE-189 trial, 616 patients with advanced, PD-L1-unselected, nonsquamous NSCLC were randomized in a 2:1 ratio to chemotherapy (cisplatin or carboplatin with pemetrexed) with or without pembrolizumab [4]. Those receiving chemotherapy alone could receive pembrolizumab upon progression. At a median follow-up of 10.5 months, the addition of pembrolizumab to chemotherapy improved 12-month overall survival (OS) rates relative to chemotherapy alone (69 versus 49 percent; hazard ratio [HR] for death 0.49, 95% CI 0.38-0.64). Twelve-month OS improvements were observed in all PD-L1 categories, with the greatest numerical differences observed in PD-L1-expressing tumors:
●<1 percent – 62 versus 52 percent (HR 0.59, 95% CI 0.38-0.92)
●1 to 49 percent – 72 versus 51 percent (HR 0.55, 95% CI 0.34-0.90)
●≥50 percent – 73 versus 48 percent (HR 0.42, 95% CI 0.26-0.68)
Similar observations were made at longer follow-up [5,6]; at a median follow-up of 31 months, the two-year OS rate in those receiving chemotherapy with or without pembrolizumab was 46 versus 27 percent [5].
Median progression-free survival (PFS), the other primary endpoint, was also improved with the addition of pembrolizumab (8.8 versus 4.9 months; HR for disease progression or death 0.52, 95% CI 0.43-0.64). The HR for PFS was less than 1.0 across all subgroups of PD-L1 expression (HR, 0.36 for PD-L1 ≥50 percent; HR, 0.55 for PD-L1 1 to 49 percent; and HR, 0.75 for PD-L1 <1 percent), but the differences were not statistically significant in the group with PD-L1 <1 percent.
Among all patients in the trial, objective response rate (ORR) was improved with the addition of pembrolizumab (48 versus 19 percent). Severe adverse events (≥grade 3) occurred in 67 percent of the patients in the pembrolizumab-combination group and in 66 percent of those in the placebo-combination group, with improved patient-reported quality of life [7].
These results confirmed findings of the earlier phase II KEYNOTE-021 trial, in which 123 patients were randomized in a 1:1 ratio to chemotherapy with or without pembrolizumab. ORR, the primary endpoint, was higher with the addition of pembrolizumab (55 versus 29 percent; 95% CI 8-42), as was PFS (13 versus 6 months; HR for disease progression or death 0.53, 95% CI 0.31-0.91) [8]. Results from this study led to initial accelerated approval of combination therapy with carboplatin, pemetrexed, and pembrolizumab for patients with advanced, untreated, nonsquamous NSCLC without activating epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) alterations.
Atezolizumab plus chemotherapy — Atezolizumab is an anti-PD-L1 antibody engineered to avoid antibody-dependent, cell-mediated cytotoxicity of activated T cells that may express PD-L1. The combination of platinum-based doublet chemotherapy, bevacizumab, and atezolizumab is a potential alternative to pembrolizumab and chemotherapy in patients with nonsquamous NSCLC (table 1), and this regimen now has regulatory approval for patients without an EGFR mutation or ALK translocation.
The IMpower 150 trial randomly assigned 1202 patients with PD-L1-unselected, advanced, nonsquamous NSCLC to first-line chemotherapy (carboplatin and paclitaxel) combined with either atezolizumab (ACP), atezolizumab plus bevacizumab (ABCP), or bevacizumab (BCP) [9]. Crossover on progression was not allowed. Among 692 EGFR/ALK wild-type patients, those receiving ABCP experienced improved PFS (8.3 versus 6.8 months; HR for disease progression or death 0.62, 95% CI 0.52-0.74) and OS (19.2 versus 14.7 months; HR for death 0.78, 95% CI 0.64-0.96) relative to those receiving BCP. The PFS benefit of ABCP over BCP was also observed among patients with baseline liver metastases [10]. Patients across arms rated common symptoms with chemotherapy and immunotherapy similarly [11]. In KEYNOTE-189, this subgroup also experienced improvements with the combination of pembrolizumab and chemotherapy [4], suggesting that immunotherapy plus chemotherapy is a viable treatment option for this subset.
The most common grade 3 or 4 treatment-related adverse events were neutropenia, febrile neutropenia, and hypertension. Rash, stomatitis, febrile neutropenia, and hemoptysis were higher among those receiving ABCP than among those in the BCP group by <10 percentage points. This regimen has now been FDA approved as a treatment alternative for driver mutation-negative patients with advanced, nonsquamous NSCLC.
In IMpower 150, improvements with ABCP over BCP were also observed in the 14 percent of enrolled patients who had EGFR- or ALK-positive NSCLC, all of whom had received at least one line of targeted therapy, though the FDA approval for this regimen excludes the subset of patients with an EGFR mutation or ALK rearrangement. No differences were observed with the addition of atezolizumab in this subset of patients in the IMpower 130 trial. These results are discussed in more detail elsewhere. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer" and "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor".)
Other trials have also shown benefits with the addition of atezolizumab to chemotherapy.
●In IMpower 130, adding atezolizumab to carboplatin plus nabpaclitaxel in the frontline setting for advanced nonsquamous NSCLC improved both PFS (7.0 versus 5.5 months; HR 0.64) and OS (18.6 versus 13.9 months; HR 0.79), differences that were statistically significant [12]. Although an atypical chemotherapy backbone in the nonsquamous NSCLC setting, nabpaclitaxel was chosen because, unlike paclitaxel, it does not require steroid premedication, which may affect the response to an immune checkpoint inhibitor. This regimen is approved by the FDA.
●Additionally, in IMpower 132, in nonsquamous cancers, atezolizumab plus pemetrexed-based chemotherapy improved median PFS (7.6 months versus 5.2 months; HR 0.60, 95% CI 0.49-0.72) relative to chemotherapy alone, with a nonsignificant trend toward improved OS (18.1 versus 13.5 months; HR 0.46, 95% CI 0.64-1.03) [13].
Squamous
Pembrolizumab plus chemotherapy — The addition of frontline pembrolizumab to platinum-based doublet chemotherapy has also improved outcomes in squamous cell cancers, without adding substantial toxicity. Atezolizumab plus chemotherapy is investigational for squamous NSCLCs. (See 'Atezolizumab in squamous NSCLC' below.)
In the phase III KEYNOTE-407 559 patients with PD-L1-unselected, treatment-naïve, advanced squamous NSCLC were randomized in a 1:1 ratio to chemotherapy (carboplatin with either paclitaxel or nabpaclitaxel) with either pembrolizumab or placebo [14]. At a median follow-up of 7.8 months, the addition of pembrolizumab to chemotherapy improved coprimary endpoints of OS (15.9 versus 11.3 months; HR for death 0.64, 95% CI 0.49-0.85) and PFS (median, 6.4 versus 4.8 months; HR for disease progression or death 0.56, 95% CI 0.45-0.70).
The median OS with and without pembrolizumab, by tumor PD-L1 expression was:
●<1 percent – 15.9 versus 10.2 months (HR 0.61, 95% CI 0.38-0.98)
●1 to 49 percent – 14 versus 11.6 months (HR 0.57, 95% CI 0.36-0.9)
●≥50 percent – Not reached (NR) versus NR; (HR 0.64, 95% CI 0.37-1.10)
Although the OS benefit did not achieve statistical significance among those with the highest level of PD-L1 expression (≥50 percent), analysis was limited by the small number of patients in this subgroup (n = 146).
The median PFS with and without pembrolizumab, by tumor PD-L1 expression was:
●<1 percent – 6.3 versus 5.3 months (HR 0.68, 95% CI 0.47-0.98)
●1 to 49 percent – 7.2 versus 5.2 months (HR 0.56, 95% CI 0.39-0.8)
●>50 percent – 8 versus 4.2 months (HR 0.37, 95% CI 0.24-0.58)
In the overall group, the ORR was 58 percent (95% CI 51.9-63.8) in the pembrolizumab-combination group and 38 percent (95% CI 32.7-44.4) in the placebo-combination group. Severe adverse events (≥grade 3) occurred in 70 percent of the patients in the pembrolizumab-combination group and in 68 percent of those in the placebo-combination group.
Alternatives, irrespective of histology
Nivolumab plus ipilimumab, with or without chemotherapy — Although we typically use the pembrolizumab-or atezolizumab-based strategies discussed above, given cross-trial comparisons of toxicity and efficacy, nivolumab plus ipilimumab is another US Food and Drug Administration-approved option for adult patients with metastatic NSCLC without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor alterations with programmed cell death ligand 1 (PD-L1) expression ≥1 percent; nivolumab and ipilimumab is also approved with two cycles of platinum-based chemotherapy in tumors lacking EGFR and ALK alterations, irrespective of PD-L1 expression [15].
Nivolumab plus ipilimumab has demonstrated a superior survival compared with chemotherapy in the CheckMate-227 trial, irrespective of PD-L1 expression [16].
●Among 1739 patients with chemotherapy-naïve NSCLC across the spectrum of tumor PD-L1 expression, the median duration of overall survival (OS) was 17.1 months with nivolumab plus ipilimumab versus 13.9 months with chemotherapy (hazard ratio [HR] 0.73, 95% CI 0.64-0.84) [16].
●In the subset of 793 patients with PD-L1 expression ≥1 percent, the median duration of OS was 17.1 months with nivolumab plus ipilimumab versus 14.9 months with chemotherapy (HR 0.79, 95% CI 0.65-0.96). The four-year OS rate with nivolumab plus ipilimumab versus chemotherapy was 29 versus 18 percent in the subset with PD-L1 ≥1 percent [17]. The shape of the OS curves suggests an initial short-term benefit with chemotherapy, followed by long-term improvements with nivolumab plus ipilimumab.
•In the subset of patients with PD-L1 expression of 1 to 49 percent, OS results of nivolumab plus ipilimumab versus chemotherapy were similar (median, 15.1 months in each arm).
•Among 397 patients with PD-L1 expression ≥50 percent, nivolumab plus ipilimumab showed an OS advantage over chemotherapy (median, 21 versus 14 months; HR 0.70, 95% CI 0.55-0.90) [16]. Additionally, there were numerical improvements in efficacy with nivolumab plus ipilimumab compared with nivolumab monotherapy, based on OS, progression-free survival (PFS), overall response rate, complete response rate, and duration of response.
●Among 373 patients with tumor PD-L1 expression <1 percent, the median OS with nivolumab plus ipilimumab was 17.2 months, versus 12.2 months with chemotherapy (HR 0.62, 95% CI 0.48-0.78). The four-year OS rate with nivolumab plus ipilimumab versus chemotherapy was 24 versus 10 percent in this subset [17].
Additionally, in those with tumor PD-L1 expression <1 percent, OS was greater with nivolumab plus ipilimumab versus nivolumab plus chemotherapy, which was also evaluated in this study (HR 0.77, 95% CI 0.60-0.98).
The percentage of patients with grade 3 or 4 treatment-related adverse events in the overall population (which included patients with PD-L1-expressing as well as PD-L1-negative tumors) was 33 percent with nivolumab plus ipilimumab and 36 percent with chemotherapy. Treatment-related adverse events leading to discontinuation were more frequent with nivolumab plus ipilimumab versus chemotherapy (18 versus 9 percent, respectively). The most common immunologic adverse events of any grade among those receiving nivolumab plus ipilimumab were skin reactions (34 percent) and endocrine events (24 percent). Treatment-related deaths occurred in eight patients who received nivolumab plus ipilimumab and in six patients who received chemotherapy.
Nivolumab in combination with ipilimumab and platinum-doublet chemotherapy was evaluated in the CheckMate-9LA trial, in which 719 patients were randomly assigned to either two cycles of platinum-doublet chemotherapy plus nivolumab and ipilimumab (until progression), or four cycles of platinum doublet chemotherapy without immunotherapy [15,18]. Patients receiving nivolumab/ipilimumab/chemotherapy experienced improved median OS (15.6 versus 10.9 months; HR 0.66, 95% CI 0.55-0.80), PFS (6.8 versus 5.0 months; HR 0.70, 95% CI 0.57-0.86) and overall response rate (38 versus 25 percent), relative to those receiving chemotherapy alone.
Serious adverse reactions occurred in 57 percent of patients receiving nivolumab, ipilimumab, and chemotherapy, with the most frequent (>2 percent) being pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Fatal adverse reactions occurred in 7 patients (2 percent) and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea, and hemoptysis in the setting of thrombocytopenia.
Cemiplimab plus chemotherapy — Cemiplimab has US FDA approval for use in combination with platinum-based chemotherapy for patients with NSCLC lacking an EGFR, ALK, or ROS1 alteration [19], based on preliminary results from a clinical trial demonstrating improved survival relative to chemotherapy alone. It likely has similar outcomes relative to pembrolizumab and other checkpoint inhibitors, when used in combination with chemotherapy, although there have been no direct comparisons.
In preliminary results of the randomized trial Study 16113, among 466 patients assigned to chemotherapy with or without cemiplimab, the cemiplimab group experienced improvements in median OS (22 versus 13 months, HR 0.71, 95% CI 0.53-0.93), PFS (8.2 versus 5.0, HR 0.56, 95% CI 0.44-0.70), and objective response rate (43 versus 23 percent) [20]. Serious adverse events occurred in 25 percent of patients in the cemiplimab group, with the most frequent being pneumonia, anemia, and neutropenia, and 6 percent were fatal.
Tremelimumab and durvalumab plus chemotherapy — Tremelimumab and durvalumab have regulatory approval in combination with platinum-based chemotherapy in patients with metastatic NSCLC with no sensitizing EGFR or ALK genetic alteration [21,22].
In the open-label POSEIDON trial, 1013 patients with EGFR/ALK wild-type tumors were randomly assigned to tremelimumab plus durvalumab plus chemotherapy, durvalumab plus chemotherapy, or chemotherapy alone [23]. The three drug combination performed better than chemotherapy alone, both in regards to OS (median 14.0 versus 11.7 months, HR 0.77, 95% CI 0.65-0.92) and PFS (median, 6.2 versus 4.8 months, HR 0.72, 95% CI 0.60-0.86), with grade 3 to 4 adverse effects occurring in 52 and 44 percent of patients, respectively. Although durvalumab plus chemotherapy (without tremelimumab) improved PFS compared with chemotherapy (HR 0.74), differences in OS were not statistically significant.
Given these results, we consider tremelimumab and durvalumab plus chemotherapy an acceptable frontline option in metastatic NSCLC lacking an EGFR or ALK mutation.
Less favored options — Although we prefer pembrolizumab and chemotherapy for most patients with PD-L1-low tumors (1 to 49 percent), there is also evidence to consider using pembrolizumab monotherapy as an alternative in patients with low PD-L1 expression (but not in PD-L1-negative tumors).
In the ongoing phase III KEYNOTE-042 trial of patients with treatment-naïve, advanced, EGFR/ALK wild-type NSCLC and at least 1 percent tumor PD-L1 expression, pembrolizumab monotherapy is being compared with platinum-doublet chemotherapy, chosen according to histology. Of note, this trial did not permit crossover. At a median follow-up of 12.8 months, results are as follows [24]. OS, the primary endpoint, was prolonged among patients receiving pembrolizumab compared with those receiving chemotherapy as follows, according to PD-L1 expression:
●≥50 percent (599 patients), 20 versus 12 months (HR 0.69, 95% CI 0.56-0.85)
●≥20 percent (818 patients), 18 versus 13 months (HR 0.77, 95% CI 0.64-0.92)
●≥1 percent (1274 patients), 17 versus 12 months (HR 0.81, 95% CI 0.71-0.93)
●In exploratory analysis of survival among patients with PD-L1 expression between 1 and 49 percent, OS was 13.4 versus 12.1 months (HR 0.92, 95% 0.77-1.11)
There was no statistically significant PFS benefit among patients receiving pembrolizumab compared with those receiving chemotherapy, except for those with the highest level of PD-L1 expression (≥50 percent; median PFS, 7.1 versus 6.4 months [HR 0.81, 95% CI 0.67-0.99]). As in KEYNOTE-024, pembrolizumab was better tolerated than chemotherapy, with grade 3 to 5 adverse events occurring in 18 percent of those receiving pembrolizumab and 41 percent of those receiving chemotherapy.
Overall, the survival benefit with pembrolizumab seen amongst all patients with >1 percent PD-L1 expression seems to be largely driven by the subgroup of patients with high (≥50 percent) PD-L1 expression. Among those with intermediate PD-L1 expression (1 to 49 percent), chemotherapy resulted in similar OS as pembrolizumab despite the fact that most of the patients assigned to chemotherapy did not receive immunotherapy upon progression, which is considered standard of care. Meanwhile, chemotherapy plus pembrolizumab was superior to chemotherapy in those with intermediate PD-L1 expression in KEYNOTE-189, while pembrolizumab monotherapy was only equivalent to chemotherapy in this subgroup in KEYNOTE-042. We therefore typically favor the combination of pembrolizumab and chemotherapy over pembrolizumab monotherapy for those with PD-L1 expression 1 to 49 percent. Still, for patients with intermediate PD-L1 expression who decline chemotherapy, pembrolizumab monotherapy is an acceptable, but likely inferior, option compared with pembrolizumab and chemotherapy.
PD-L1-high tumors (at least 50 percent) — Randomized trials have demonstrated that a high level of programmed cell death ligand 1 (PD-L1) expression predicts response to pembrolizumab and atezolizumab. This level of PD-L1 expression may be seen in approximately 30 percent of advanced NSCLCs [25].
Checkpoint inhibitor monotherapy versus chemoimmunotherapy — For patients with PD-L1-high rapidly progressive disease, or such a high tumor burden that early progression might lead to functional decline precluding chemotherapy in the second-line setting, we suggest concurrent use of a checkpoint inhibitor with chemotherapy. This approach has been associated with higher response rates than checkpoint inhibitor monotherapy. The choice of agents is analogous to those with PD-L1-unselected or low tumors. (See 'PD-L1 low (<50 percent) or unselected tumors' above.)
For those without rapidly progressive disease whose tumors have ≥50 percent PD-L1 expression, either checkpoint inhibitor monotherapy or chemoimmunotherapy are appropriate, and shared decision making is appropriate. In the absence of an overall survival benefit, those who value fewer burdens of treatment may choose immunotherapy monotherapy; patients who value delayed time to progression may opt for chemoimmunotherapy, as discussed above. (See 'PD-L1 low (<50 percent) or unselected tumors' above.)
Treatment with a checkpoint inhibitor plus chemotherapy has not been directly compared with checkpoint inhibitor monotherapy in those with PD-L1-high NSCLCs in a randomized trial. However, the following data are available:
●A meta-analysis of five randomized trials suggested, through indirect comparisons, that pembrolizumab plus chemotherapy was superior to pembrolizumab alone in regards to ORRs (relative risk 1.6, 95% CI 1.2-2.2) and PFS (HR 0.55, 95% CI 0.32-0.97) [26]. No statistically significant differences in OS were observed (HR 0.76, 0.51-1.14).
●In a presented abstract of an analysis of 12 trials in patients with tumor PD-L1 ≥50 percent, half of them evaluating chemoimmunotherapy and the other half evaluating immunotherapy alone, median PFS was longer with chemoimmunotherapy than with immunotherapy (9.6 versus 7.1 months, HR 0.69, 95% CI 0.55-0.87) [27]. ORR was also better with chemoimmunotherapy (61 versus 43 percent). Although there was a trend towards improved OS with chemoimmunotherapy in the overall group (HR 0.82), improvements did not meet statistical significance, and among patients ≥75 years there was a nonsignificant trend towards worsened survival with chemoimmunotherapy (HR 1.7). Although some find these modest PFS benefits with incorporation of chemotherapy compelling, others see the lack of OS benefit a reason to favor immunotherapy alone.
Data regarding checkpoint inhibitor monotherapy — If checkpoint inhibitor monotherapy is chosen, either pembrolizumab or atezolizumab as single agents are appropriate [1]. Pembrolizumab has the practical advantage of regulatory approval for an every-six-week schedule based on data from the metastatic melanoma setting, as well as longer-term follow-up (discussed below). (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Dosing considerations'.)
Nivolumab-plus-ipilimumab-based treatments are a reasonable alternative. (See 'Nivolumab plus ipilimumab, with or without chemotherapy' above and 'PD-L1 low (<50 percent) or unselected tumors' above.)
●Pembrolizumab – Pembrolizumab is approved by the FDA for the front-line treatment of patients with advanced EGFR/ALK wild-type NSCLC whose tumors have ≥50 percent PD-L1 expression based on the 22C3 pharmDx test [28]. Use of pembrolizumab for patients with PD-L1 expression ≥50 percent is supported by the phase III KEYNOTE-024 trial, in which 305 treatment-naïve patients with advanced NSCLC having at least 50 percent tumor cell PD-L1 staining were randomly assigned to pembrolizumab monotherapy (200 mg intravenous [IV] every three weeks) versus standard platinum-doublet chemotherapy [25]. At a median follow-up of 11.2 months, PFS, the primary endpoint, was prolonged with pembrolizumab compared with platinum-doublet chemotherapy (median PFS, 10.3 versus 6 months; HR 0.50, 95% CI 0.37-0.68), and ORRs were improved (45 versus 28 percent). The median duration of response was not reached in the pembrolizumab group and was 6.3 months in the chemotherapy group. Severe (≥grade 3) treatment-related adverse effects were lower among patients receiving pembrolizumab (27 versus 53 percent). Any-grade pneumonitis was reported in 5.8 percent of patients treated with pembrolizumab, with severe pneumonitis in 2.6 percent.
Results at five-year follow-up demonstrate improved median OS with pembrolizumab (26.3 versus 13.4 months with chemotherapy; HR 0.62, 95% CI 0.48-0.81) [29].
Although randomized trial data have demonstrated improved outcomes with chemotherapy plus pembrolizumab versus chemotherapy alone, no trial has evaluated chemotherapy plus pembrolizumab versus pembrolizumab alone. Therefore, the question remains regarding whether patients with high PD-L1 expression would benefit from the addition of chemotherapy to pembrolizumab. Cross-trial comparisons between KEYNOTE-024 and the PD-L1-high subgroup of KEYNOTE-189 suggest comparable outcomes between pembrolizumab and chemotherapy and pembrolizumab alone among those with PD-L1-high tumors (eg, 12-month OS rate of approximately 70 percent in each trial) [4,30]. However, head-to-head comparisons alone can validate this hypothesis, particularly given that the corresponding chemotherapy control arms experienced somewhat different 12-month survival rates (55 and 48 percent in KEYNOTE-024 and 189 [PD-L1-high subgroup], respectively). In the absence of direct comparative data, we generally suggest pembrolizumab monotherapy over pembrolizumab plus chemotherapy for most patients with PD-L1-high tumors, given better tolerability, thus allowing for the option of using a platinum-based doublet in the second-line setting.
Adding ipilimumab to pembrolizumab did not show improved efficacy relative to pembrolizumab monotherapy in a randomized trial in patients with high-PD-L1 NSCLC, but did increase toxicity [31]. As such, we do not use pembrolizumab in combination with ipilimumab; the combination of nivolumab plus ipilimumab is discussed below. (See 'Nivolumab plus ipilimumab, with or without chemotherapy' above.)
●Atezolizumab – Atezolizumab is FDA approved for the front-line treatment of those with PD-L1-stained ≥50 percent of tumor cells or PD-L1-stained tumor-infiltrating immune cells covering ≥10 percent of the tumor area, as determined by an FDA-approved test, with no EGFR or ALK genomic alterations [3].
This approval is based on results of IMpower 110 [3,32], which enrolled 572 treatment-naϊve patients with stage IV NSCLC expressing PD-L1 (PD-L1 stained ≥1 percent of tumor cells [TC] or tumor-infiltrating immune cells [IC] covering ≥1 percent of the tumor area). Among the subset of 205 patients with high PD-L1 (TC ≥50 percent or IC ≥10 percent), atezolizumab demonstrated improved OS relative to platinum-based chemotherapy (20 versus 13 months; HR 0.59, 95% CI 0.40-0.89). There were no statistically significant differences in OS for the other two PD-L1 subgroups evaluated (TC ≥5 percent or IC ≥5 percent; and TC ≥1 percent or IC ≥1 percent).
In the PD-L1-high subgroup, median PFS was 8.1 months with atezolizumab, versus 5 months with chemotherapy (HR 0.63, 95% CI 0.45-0.88); the confirmed ORR was 38 versus 29 percent, respectively.
Fatal adverse reactions occurred in 3.8 percent of the overall group of patients receiving atezolizumab, from causes including pulmonary embolism, acute myocardial infarction, and sepsis [32]. Grade ≥3 adverse events occurred in approximately 30 percent assigned to atezolizumab and 53 percent assigned to chemotherapy, with the most frequent in the atezolizumab group including pneumonia (2.4 percent), chronic obstructive pulmonary disease (1.7 percent), and pneumonitis (0.7 percent).
●Cemiplimab – Cemiplimab, a programmed cell death protein 1 (PD-1) inhibitor, improved OS and PFS compared with chemotherapy in patients with advanced NSCLC with PD-L1 of ≥50 percent without an EGFR, ROS1, or ALK genetic aberration [33], and has FDA approval for this indication [34].
In EMPOWER-Lung 1, among 563 patients with advanced NSCLC with PD-L1 of ≥50 percent, cemiplimab 350 mg every three weeks improved OS relative to platinum-doublet chemotherapy (median, not reached versus 14.2 months, respectively; HR 0.57, 95% CI 0·42-0·77), as well as PFS (8.2 versus 5.7 months; HR 0.54, 95% CI 0.43-0.68) [33]. OS and PFS were also improved in the intention-to-treat population of 710 patients (which additionally included patients with PD-L1 expression that had not been confirmed or had been established as <50 percent), despite 74 percent crossover. Grade ≥3 toxicities were 28 percent with cemiplimab and 39 percent with chemotherapy.
INVESTIGATIONAL OPTIONS — These strategies do not have regulatory approval in the United States, and we do not use them outside of a clinical trial.
Nivolumab, with or without chemotherapy — Nivolumab is an immunoglobulin G4 (IgG4) monoclonal antagonist antibody to programmed cell death protein 1 (PD-1). It is not approved by the US Food and Drug Administration (FDA) for use in the first-line setting for NSCLC, but is being investigated both as monotherapy and in combinations with chemotherapy. Nivolumab does have approval for use in those with progression after chemotherapy. (See 'Following platinum-based chemotherapy' below.)
●Nivolumab with chemotherapy – In a trial in 550 treatment-naïve patients with stage IIIB to IV nonsquamous NSCLC, the addition of nivolumab to bevacizumab, carboplatin, and paclitaxel increased progression-free survival (PFS; 12.1 versus 8.1 months; hazard ratio [HR] 0.56, 96.4% CI 0.43-0.71) [35]. The PFS benefit was observed, irrespective of programmed cell death ligand 1 (PD-L1) expression. Objective response rates (ORRs) were 62 and 51 percent in the nivolumab and placebo arms, respectively. Grade ≥3 treatment-related adverse events occurred at comparable rates between the two arms. We await further data or regulatory approval prior to routine use of this regimen.
●Nivolumab monotherapy – Available data do not support nivolumab monotherapy for treatment-naïve NSCLC. The CheckMate 026 trial randomized 541 patients with advanced, untreated, PD-L1-positive NSCLC to nivolumab or standard first-line, histology-based, platinum-doublet chemotherapy. Neither PFS, the primary endpoint of the study, nor overall survival (OS) were prolonged with nivolumab (HR for disease progression or death in patients with >5 percent tumor PD-L1 staining 1.15, 95% CI 0.91-1.45; HR for death 1.02, 95% CI 0.80-1.30) [36]. Grade ≥3 treatment-related adverse events occurred in 18 percent of the patients who received nivolumab and in 51 percent of those who received chemotherapy.
Atezolizumab in squamous NSCLC — Although atezolizumab is an acceptable alternative to pembrolizumab when either is used in combination with chemotherapy for those with PD-L1-unselected or low nonsquamous tumors, we do not suggest this combination in PD-L1-unselected or low squamous tumors.
The IMpower 131 trial randomized 683 patients with PD-L1-unselected, advanced, squamous NSCLC to front-line chemotherapy (carboplatin and albumin-bound paclitaxel) alone or combined with atezolizumab (1200 mg intravenous [IV] every three weeks) [12,37]. At a median follow-up of approximately 17 months, those assigned to atezolizumab and chemotherapy experienced an improved PFS (6.3 versus 5.6 months; HR 0.7, 95% CI 0.60-0.85) relative to those receiving chemotherapy alone, with greatest benefits for those with high PD-L1 expression and no statistically significant benefit for those with PD-L1-negative tumors.
In the overall population, OS results at a median follow-up of approximately 25 months were not significantly different between those receiving atezolizumab and chemotherapy versus chemotherapy alone (14.2 versus 13.5 months), but an OS benefit with the addition of atezolizumab was seen among those with PD-L1-high tumors (23.4 versus 10.2 months; HR 0.48, 95% CI 0.29-0.81) [37]. Treatment-related grade 3 to 4 events occurred in 68 versus 57 percent, with and without atezolizumab, respectively.
Given the lack of OS benefit with the addition of atezolizumab to chemotherapy in patients with squamous NSCLC, we continue to prefer pembrolizumab as the checkpoint inhibitor to pair with chemotherapy, per KEYNOTE-407. (See 'PD-L1 low (<50 percent) or unselected tumors' above.)
Others — Durvalumab and tremelimumab have preliminarily shown efficacy over chemotherapy among those with high tumor mutational burden (TMB), though we await further data prior to routine clinical use of this combination or of TMB as a biomarker.
●In a randomized trial conducted in China, the addition of the anti-PD-1 inhibitor tislelizumab to chemotherapy improved median PFS in squamous cell NSCLC (7.6 versus 5.5 months with chemotherapy alone), as well as ORRs (approximately 70 to 75 versus 50 percent, respectively) [38]. There was no observed association between PD-L1 expression and outcomes with tislelizumab. Although this agent is not available in the United States, it has regulatory approval in China for use with chemotherapy in squamous cell NSCLC.
●Sintilimab, another anti-PD-1 antibody, has improved PFS when added to chemotherapy both in squamous and nonsquamous carcinoma [39,40], and is under review by the FDA.
MYSTIC was a phase III trial that evaluated durvalumab and durvalumab plus tremelimumab versus chemotherapy in patients with NSCLC. Neither durvalumab nor durvalumab plus tremelimumab improved outcomes compared with chemotherapy, either in the overall population, or among those with ≥25 percent of tumor cells expressing PD-L1 [41]. Nevertheless, additional post-hoc exploratory analysis has demonstrated that patients with high TMB (defined by blood-based testing of circulating tumor DNA) derive benefit from durvalumab plus tremelimumab. Among 211 patients with blood TMB ≥20 mutations/megabase, durvalumab plus tremelimumab improved OS relative to chemotherapy (22 versus 10 months; HR 0.49, 95% CI 0.32-0.74), with a nonsignificant trend toward improved survival with durvalumab over chemotherapy (13 versus 10 months; HR 0.72, 95% CI 0.50-1.05). Among the 187 patients with tissue TMB ≥10 mutations/megabase, trends towards improved OS were observed in both durvalumab groups relative to chemotherapy, but these did not achieve statistical significance (median OS, durvalumab and tremelimumab, 17 months; durvalumab, 19 months; chemotherapy, 12 months).
For patients with unresectable, stage III NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy, durvalumab is approved by the FDA. This is discussed in detail elsewhere. (See "Management of stage III non-small cell lung cancer", section on 'Incorporation of immunotherapy'.)
Similarly, in an open-label phase II trial, the combination of ipilimumab and nivolumab showed activity, with higher response rates among those with tissue TMB ≥10 mutations/megabase (approaching 50 percent, regardless of whether PD-L1 was expressed) compared with <10 mutations/megabase (18 percent for PD-L1-expressing and 5 percent for PD-L1-negative tumors) [42]. In the overall group (including PD-L1-positive and negative tumors), the response rate was 30 percent, and among those with PD-L1-expressing tumors, it was 41 percent. Nevertheless, at the present time, TMB testing has not been demonstrated to lead to any improvements in OS and is not involved in routine clinical decision-making.
FOLLOWING PLATINUM-BASED CHEMOTHERAPY — Although our preferred approach is incorporation of immunotherapy into the initial treatment strategy for most patients, many patients will have been treated with frontline chemotherapy, given previous treatment paradigms. For such patients, we suggest either an anti-programmed cell death protein 1 (PD-1) or anti-programmed cell death ligand 1 (PD-L1) antibody in the second-line setting, rather than single-agent chemotherapy. Nivolumab or atezolizumab are appropriate options (regardless of tumor PD-L1 expression). If tumor PD-L1 has been identified on at least 1 percent of tumor cells (using the Dako 22C3 PD-L1 assay), pembrolizumab is also an option. A choice among these agents depends on provider familiarity and local practice patterns, given a lack of data directly comparing these agents.
Nivolumab — Nivolumab is US Food and Drug Administration (FDA) approved for the treatment of patients with advanced squamous NSCLC and nonsquamous NSCLC who experience progression of disease on or after standard platinum-based chemotherapy (regardless of tumor PD-L1 expression). Although studies below describe results of nivolumab used at a 3 mg/kg intravenous (IV) dose, the FDA-approved dose regimen is 240 mg IV every two weeks, which is similar to the 3 mg/kg IV dose based on population pharmacokinetics analyses and dose/exposure-response analyses [15]. An alternative dosing schedule of 480 mg intravenously every four weeks was also subsequently FDA approved.
●Squamous NSCLC – In the phase III CheckMate 017 trial, among 272 patients with advanced, squamous NSCLC with progression after platinum-based doublet chemotherapy, those assigned to nivolumab versus docetaxel experienced improved overall survival (OS; median OS, 9.2 versus 6.0 months), objective response rate (ORR; 20 versus 9 percent), and duration of response (25 versus 8 months) [43-45]. Approximately half of patients had tumors with PD-L1 tumor expression of at least 1 percent, but this did not appear to influence survival outcomes. Grade ≥3 toxicities were less frequent with nivolumab compared with docetaxel (7 versus 54 percent), with any-grade pneumonitis observed in 5 versus 0 percent of those receiving docetaxel, although there was one treatment-related death from interstitial lung disease.
●Nonsquamous NSCLC – In the phase III CheckMate 057 trial, among 582 patients with advanced, nonsquamous NSCLC with progression after platinum-based chemotherapy, those assigned to nivolumab versus docetaxel experienced improved OS (12.2 versus 9.4 months), ORR (19 versus 12 percent), and duration of response (18 versus 6 months) [44-47]. Among the 55 percent of evaluable tumors with any degree of PD-L1 expression, survival was improved with nivolumab, but survival was similar between nivolumab and docetaxel for those with PD-L1-negative tumors. Grade ≥3 toxicities were less frequent with nivolumab (10 versus 54 percent), with any-grade pneumonitis in 1 percent of patients. In subsequent reporting, nivolumab provided improvements in health-related quality of life relative to docetaxel [48].
In a combined analysis of these two trials, with a median follow-up of 70 months, the five-year pooled OS rates were 13.4 versus 2.6 percent for those assigned to nivolumab versus docetaxel, respectively, and the five-year progression-free survival (PFS) rates were 8 versus 0 percent [49].
Atezolizumab — Atezolizumab is approved by the FDA for the treatment of patients with metastatic NSCLC whose disease progressed during or following platinum-containing chemotherapy.
In the phase III OAK trial enrolling 1225 patients with PD-L1-unselected, pretreated, advanced NSCLC, atezolizumab versus docetaxel improved OS (13.8 versus 9.6 months; hazard ratio [HR] 0.73, 95% CI 0.62-0.87) and duration of response (16.3 versus 6.2 months), but not PFS (2.8 versus 4 months) or ORR (14 versus 13 percent) [50,51]. In the 55 percent of patients having tumors with at least 1 percent PD-L1 staining, atezolizumab improved survival relative to docetaxel (median OS, 15.7 versus 10.3 months; HR 0.74, 95% CI 0.58-0.93), with greater improvements observed among those with PD-L1-high tumors (20.5 versus 8.9 months; HR 0.41, 95% CI 0.27-0.64). Grade ≥3 toxicities were less frequent with atezolizumab compared with docetaxel (15 versus 43 percent), with any-grade pneumonitis occurring in 1 percent of patients receiving atezolizumab, and severe pneumonitis (grade 3 to 4) in 0.7 percent.
OS was prolonged with atezolizumab versus docetaxel regardless of NSCLC histology (median OS, 15.6 versus 11.2 months in nonsquamous NSCLC; HR 0.73, 95% CI 0.60-0.89; median OS, 8.9 versus 7.1 months in squamous NSCLC; HR 0.73, 95% CI 0.54-0.98).
Pembrolizumab — In pretreated, advanced NSCLC, pembrolizumab is approved for tumors that express PD-L1 (at least 1 percent of tumor cells with membranous PD-L1 staining), as determined by the 22C3 pharmDx test [28]. Although various dosing strategies are examined below, pembrolizumab is approved at 200 mg every three weeks.
The phase II/III KEYNOTE-010 study randomly assigned 1034 patients with previously treated advanced NSCLC and at least 1 percent tumor cell PD-L1 expression to pembrolizumab 2 mg/kg (low dose), pembrolizumab 10 mg/kg (high dose), or docetaxel [52]. At a median follow-up of 13 months, pembrolizumab was associated with improvement in median OS compared with docetaxel (10.4 and 12.7 months for pembrolizumab low and high dose, respectively, versus 8.5 months for the docetaxel-treated group [HR 0.71, 95% CI 0.58-0.88 and 0.61, 95% CI 0.49-0.75, respectively]). Median PFS was similar across all the groups (approximately four months). ORRs were better in the pembrolizumab groups versus the docetaxel group (approximately 18 percent for both doses versus 9 percent with docetaxel), particularly among patients with at least 50 percent of tumor cells expressing PD-L1 (approximately 30 percent for both doses versus 8 percent with docetaxel). These results were confirmed with longer follow-up [53,54]. At approximately 3.5 years, pooled OS among those with tumor PD-L1 ≥1 percent for both pembrolizumab groups was 11.8 months versus 8.4 months with chemotherapy (HR 0.69) [53]. The differences were more pronounced among those with PD-L1 >50 percent, in whom median OS was 16.9 versus 8.2 months for the pembrolizumab groups versus chemotherapy, respectively.
Patients with PD-L1-high (≥50 percent) tumors experienced the greatest survival benefits with pembrolizumab (median OS of 14.9 months and 17.3 months for low- and high-dose pembrolizumab, respectively, versus 8.2 months for the docetaxel-treated group [HR 0.54, 95% CI 0.38-0.77 and 0.50, 95% CI 0.36-0.70, respectively]; median PFS of 5.0 and 5.2 months versus 4.1 months for the docetaxel-treated group [HR 0.59, 95% CI 0.44-0.78 and 0.59, 0.45-0.78, respectively]).
Pembrolizumab was better tolerated than docetaxel (13 to 16 percent in the pembrolizumab-treated groups had ≥grade 3 toxicities versus 35 percent for the docetaxel-treated group). Any-grade pneumonitis was reported in approximately 5 percent of patients receiving pembrolizumab, with grade 5 pneumonitis in 2 percent; any-grade pneumonitis was reported in 2 percent of patients receiving docetaxel, with grade 3 to 5 pneumonitis in 1 percent.
These results are consistent with the earlier phase I KEYNOTE-001 trial in patients with previously treated, advanced NSCLC and at least 1 percent tumor cell PD-L1 expression [55,56], which led to its approval in this setting [28].
TOXICITY OF IMMUNE CHECKPOINT INHIBITORS — Immune-related toxicities associated with programmed cell death protein 1 (PD-1), programmed cell death ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibodies are discussed in more detail separately. (See "Toxicities associated with checkpoint inhibitor immunotherapy" and "Ocular side effects of systemically administered chemotherapy", section on 'Immune checkpoint inhibitors'.)
DURATION OF TREATMENT — In general, we continue treatment with a programmed cell death protein 1 (PD-1) axis inhibitor until progression or unacceptable toxicity occurs, although discontinuation after two years of treatment may be a reasonable alternative. For patients whose initial regimen includes platinum-based chemotherapy, we continue chemotherapy typically for four to six cycles.
This approach is based upon the randomized clinical trials leading to US Food and Drug Administration approval of PD-1 axis inhibitors in which respective agents were continued until progression. Additional clinical trials evaluating alternatives to indefinite continuous dosing are needed, based upon the potential for durable responses to PD-1 axis inhibitors, continuous risk of toxicity, and the high cost of indefinite therapy.
Available data are limited, but suggest that continuing checkpoint inhibitor therapy beyond one year is beneficial. The CheckMate 153 safety trial evaluated duration of nivolumab monotherapy, but only as an exploratory endpoint [57]. In this trial, patients with pretreated, advanced, PD-1 axis inhibitor-naïve NSCLC received nivolumab. Among 174 patients who completed a year of treatment without progression, those randomly assigned to continue nivolumab treatment versus observation experienced an improvement in progression-free survival (median, 25 versus 9.4 months; hazard ratio [HR] 0.56, 95% CI 0.37-0.84), and overall survival (OS; not reached versus 32.5 months; HR 0.61, 95% CI 0.37-0.99).
However, other preliminary data suggest that discontinuation of pembrolizumab after two years may be an appropriate strategy [58]. In preliminary reporting of long-term follow-up of KEYNOTE-010, most patients who completed two years of pembrolizumab had a durable response (median three-year OS rate, 99 percent), with 64 percent of these patients demonstrating an ongoing response even after discontinuation of pembrolizumab. Nearly one-half (43 percent) of patients who underwent "rechallenge" with pembrolizumab after discontinuation of therapy had a second response upon retreatment with pembrolizumab. Similarly, in preliminary reporting of five-year follow-up of KEYNOTE-024, in which patients were randomly assigned to chemotherapy or two years of pembrolizumab, five-year OS was doubled in those receiving pembrolizumab (32 versus 16 percent) [59]. A second course of pembrolizumab was allowed in this trial, for patients who completed two years of pembrolizumab or who stopped pembrolizumab after achieving a complete response and then had progression.
MANAGING RESISTANCE TO PD-1 AXIS INHIBITORS — Data are evolving in regards to management of resistance to programmed cell death protein 1 (PD-1) axis inhibitors. Our approach is as follows:
●Typical approach – In general, patients who have progressed on a checkpoint inhibitor may be offered chemotherapy upon progression, either with a platinum-based doublet, if they are chemotherapy naïve, or with single-agent chemotherapy, if they are not. (See "Systemic chemotherapy for advanced non-small cell lung cancer".)
●Special circumstances
•Long interval between progression and immunotherapy – However, if progression occurs several months or years after the last dose of PD-1 or programmed cell death ligand 1 (PD-L1) blockade, rechallenge may be attempted, as some responses have been reported [60]. A reasonable time period might be at least six months since last immune checkpoint inhibitors (ICI) therapy, although data are limited to support any specific timeframe.
In a retrospective study in 59 patients with advanced NSCLC who had achieved complete response, partial response, or stable disease for ≥6 months with ICI therapy and experienced subsequent progression, nivolumab retreatment demonstrated an objective response rate of 8.5 percent (5 patients) [61]. Although median progression-free survival (PFS) was 2.6 months overall, the median PFS among the five responders was 11.1 months. On multivariate analysis, ICI-free interval was a predictive factor of PFS (HR 2), while prior efficacy was not.
•Oligometastatic disease – Additionally, if progression on a PD-1 axis inhibitor after initial response is limited to one or two sites ("oligoprogression"), local therapy to the site(s) of progression (ie, radiation, thermal ablation, or surgery) with continuation of systemic therapy with the PD-1 axis inhibitor may represent an alternative to salvage systemic therapy, recognizing that data supporting this approach are limited. In a retrospective analysis of 26 patients with acquired resistance to PD-1 axis inhibitor therapy, 88 percent had recurrence limited to one or two sites [62]. Fifteen patients (58 percent) received local therapy to site(s) of oligoprogression without initiation of salvage systemic therapy; 11 continued their respective PD-1 axis inhibitor after local therapy. The two-year survival rate among these 15 patients was 92 percent.
●Investigational approaches – In a randomized phase II trial, among 136 patients with NSCLC previously treated with ICI and platinum-based chemotherapy and progressive disease at least 12 weeks after initiation of ICI, those assigned to ramucirumab plus pembrolizumab experienced an improved overall survival relative to investigator's choice standard treatment (14.5 versus 11.6 months, HR 0.80, 95% CI 0.51-0.92) [63]. Progression-free survival and response rates were similar between arms. Grade ≥3 treatment related adverse events occurred in 42 percent of patients receiving ramucirumab plus pembrolizumab and 60 percent in the standard treatment arm. Preliminary data also suggest activity of cabozantinib, with or without atezolizumab, in patients with advanced NSCLC previously treated with ICI [64]. Further data are needed prior to routine clinical use of these approaches, and phase III trials evaluating them are ongoing.
SPECIAL CONSIDERATIONS
Limitations in biomarkers — Although trials have demonstrated that tumor programmed cell death ligand 1 (PD-L1) expression associates with increased likelihood of response to checkpoint inhibitors, it neither guarantees response in those with high tumor PD-L1 expression nor eliminates the possibility of response in those tumors that lack PD-L1 expression. There may be PD-L1 heterogeneity within tumors and between tumor sites and tumor PD-L1 expression can change over time in response to therapy. Nevertheless, based on the data from KEYNOTE-024 above, we recommend routine PD-L1 testing in all patients with newly diagnosed NSCLC to inform use of pembrolizumab monotherapy in the frontline setting.
Tumor mutational burden (TMB) is another marker being evaluated in trials of checkpoint inhibitors, though its clinical utility has yet to be established. (See 'Nivolumab, with or without chemotherapy' above and 'Others' above.)
Impact of steroids on efficacy of immunotherapy — Available data, largely from studies of immunotherapy in melanoma, suggest that corticosteroids for treatment of immune-related adverse events do not affect efficacy [65,66]. However, some evidence suggests that baseline corticosteroid use of ≥10 mg prednisone equivalent is associated with poorer outcomes with immunotherapy [67]. It remains unclear if the less favorable outcomes in these patients are directly related to the immunosuppressive effect of chronic corticosteroid use versus possibly a reflection of the unfavorable factors that necessitated use of steroids (eg, symptomatic brain metastases, weight loss, profound fatigue, or other factors) [68-70]. Although larger confirmatory studies are needed, we advise that corticosteroids be used sparingly and judiciously at the time of initiation of immunotherapy unless necessary for medical treatment (such as brain metastases).
In a retrospective review including 640 patients treated with single-agent programmed cell death protein 1 (PD-1)/PD-L1 blockade for advanced NSCLC, multivariate analysis suggested worsened overall survival (OS; hazard ratio [HR] 1.3, 95% CI 1.03-1.57) and progression-free survival (PFS; HR 1.66, 95% CI 1.3-2.2) among the 14 percent of patients who received corticosteroids of ≥10 mg of prednisone equivalent daily [67]. Similarly, in a separate retrospective review, both median PFS and OS were shorter among patients receiving ≥10 mg of prednisone at the time of immunotherapy initiation relative to those receiving lesser amounts or no steroids [68]. However, when analyzed according to the reason for steroid administration, the worsened survival outcomes were shorter only for patients receiving ≥10 mg of prednisone for palliative indications rather than for cancer-unrelated reasons.
Overall, these data suggest that the worsened outcomes observed in patients receiving steroids with immunotherapy may not be secondary to the steroids themselves, but rather are driven by other poor prognostic factors. Further data are needed.
Patterns of response and progression — The patterns of response to treatment with immunotherapy agents can differ from those with molecularly targeted agents or cytotoxic chemotherapy. For example, patients may have a transient worsening of radiologic lesions prior to disease stabilization or regression, though this is an uncommon presentation, and any evidence of clinical worsening makes this unlikely to be the case. This is discussed in more detail elsewhere. (See "Principles of cancer immunotherapy", section on 'Patterns of response'.)
Additionally, hyperprogressive disease, in which an acceleration of tumor growth occurs upon initiation of a given therapy, may occur among patients treated with immunotherapy, though this concept remains the subject of some debate even among experts in immunotherapy. If hyperprogressive disease is suspected, for example if tumor burden doubles or more at the first restaging scan, prompt recognition and transition to chemotherapy is warranted. In a retrospective study of over 400 previously treated patients with advanced NSCLC, hyperprogressive disease, defined as tumor growth rate exceeding 50 percent per month, occurred in 14 percent of those treated with PD-1/PD-L1 inhibitors and 5 percent of those treated with single-agent chemotherapy [71].
Considerations during the COVID-19 pandemic — The COVID-19 pandemic has increased the complexity of cancer care. Important issues in areas where viral transmission rates are high include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These and recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and management of lung cancer".)
SUMMARY AND RECOMMENDATIONS
●Factors in choosing initial therapy – Lung cancer is the leading cause of cancer-related mortality in the United States and worldwide. More than 80 percent of lung cancers are classified as non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors targeting either programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1) have become integrated into the clinical approach for management of NSCLC. (See 'Factors in choosing initial therapy' above.)
●Molecular assessment – For patients who have not received systemic therapy for advanced NSCLC, we assess tumor PD-L1 as well as evaluate for targetable driver mutations. The management of NSCLCs associated with targetable driver mutations is discussed elsewhere. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer" and "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor" and "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)
●Initial treatment for PD-L1 unselected tumors, or with PD-L1 <50 percent expression – For those without a targetable driver alteration and either less than 50 percent of tumor cells staining for PD-L1 or unknown PD-L1 expression, we recommend platinum-based chemotherapy combined with an immune checkpoint inhibitor, rather than chemotherapy alone (Grade 1B). For choice of immune checkpoint inhibitor, we typically suggest pembrolizumab (table 2) (Grade 2C), given that it has regulatory approval for an every-six-week schedule, as well as longer-term follow-up; however we note that other ICIs with chemotherapy that have supporting randomized trial data are also reasonable options.
•Pemetrexed-platinum combinations may be used in nonsquamous carcinoma (table 3), while paclitaxel or nabpaclitaxel, combined with a platinum in either case, are favored in squamous carcinoma (table 4 and table 5). Rationale for choice of chemotherapy is found elsewhere. (See "Systemic chemotherapy for advanced non-small cell lung cancer", section on 'Effect of histology'.)
•The combination of platinum-based doublet chemotherapy, bevacizumab, and atezolizumab is a potential alternative in patients with nonsquamous NSCLC (table 1). (See 'Nonsquamous' above.)
•Nivolumab plus ipilimumab is an acceptable alternative for both squamous and nonsquamous tumors. Use of nivolumab plus ipilimumab without chemotherapy preserves the possibility of platinum-doublet chemotherapy upon progression, provided the patient remains fit enough to tolerate it. (See 'Nivolumab plus ipilimumab, with or without chemotherapy' above.)
●Initial treatment for PD-L1 ≥50 percent expression – For patients without a targetable driver alteration in whom at least 50 percent of tumor cells stain for PD-L1, we recommend a checkpoint inhibitor, with or without chemotherapy, rather than chemotherapy alone (Grade 1A). For choice of immune checkpoint inhibitor, we typically suggest pembrolizumab (table 2) (Grade 2C), given that it has regulatory approval for an every-six-week schedule, as well as longer-term follow-up; however we note that other ICIs with supporting randomized trial data are also reasonable options.
•The decision regarding when to add chemotherapy to PD-1/PD-L1 blockade for those with PD-L1-high tumors depends upon the burden of disease and pace of progression. For those with rapidly progressive disease, or such a high tumor burden that early progression might lead to functional decline precluding second-line chemotherapy, we suggest the addition of concurrent chemotherapy to an immune checkpoint inhibitor (Grade 2C). For those without rapidly progressive disease, either checkpoint inhibitor monotherapy or chemoimmunotherapy are appropriate. (See 'PD-L1-high tumors (at least 50 percent)' above.)
●Treatment for disease that has progressed on prior chemotherapy – For patients without a targetable driver alteration who have progressed on prior chemotherapy for advanced NSCLC and who have not yet been treated with immunotherapy, we suggest either an anti-PD-1 or anti-PD-L1 antibody rather than single-agent chemotherapy (Grade 2B).
•For patients who have progressed on platinum-doublet chemotherapy and will receive immunotherapy, nivolumab or atezolizumab are appropriate options (regardless of tumor PD-L1 expression). If tumor PD-L1 has been identified on at least 1 percent of tumor cells (using the Dako 22C3 PD-L1 assay), pembrolizumab is also an option. A choice among these agents depends on provider familiarity and local practice patterns, given a lack of data directly comparing these agents.
●Duration of treatment – For patients treated with a PD-1 axis inhibitor, we suggest continued treatment until progression or unacceptable toxicity occurs (Grade 2C). Alternatively, one may reasonably discontinue after two years, although this has not been prospectively examined.
●Treatment for disease that has progressed on a PD-1 axis inhibitor – For most patients who develop progression on a PD-1 axis inhibitor and continue to be candidates for systemic therapy, we suggest chemotherapy (Grade 2C). However, for those with acquired resistance to PD-1 axis inhibitors limited to one or two sites, local therapy with continuation of the PD-1 axis inhibitor represents an acceptable alternative, recognizing that supporting data are limited. Additionally, for those in whom progression occurs several months or years after the last dose of PD-L1 blockade, immunotherapy rechallenge may be attempted, as some responses have been reported. (See 'Managing resistance to PD-1 axis inhibitors' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Scott Gettinger, MD, and Matthew Hellmann, MD, who contributed to earlier versions of this topic review.
