Lung cancer is the second-most common type of cancer in the United States, including approximately 235,000 new cases each year, 84% of which are non–small-cell lung cancer (NSCLC).1 Although lung cancer remains the leading cause of cancer mortality—outweighing prostate, breast, and colon cancer combined—advances in treatment are improving patient outcomes and decreasing mortality.1
The NSCLC treatment paradigm began to shift in the late 2000s when epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors were shown to be highly active in patients with lung cancers harboring EGFR-activating mutations.2 Since then, more than 15 targeted agents have been FDA-approved for an expanding range of driver alterations, enabling personalized therapy, and as a result, better outcomes, for an increasing number of patients.2 Despite these improvements, targeted therapies offer an incomplete approach to patients with NSCLC because more than half of patients lack actionable drivers that can be matched to approved drugs.2,3
Fortunately, for many of these patients, immunotherapy may offer an effective treatment approach.2 Beginning in 2015 with nivolumab, immunotherapies—alone or in combination with other agents—have been delivering promising results in patients with NSCLC, leading to a total of 6 FDA approvals.2 All of these agents are immune checkpoint inhibitors (ICIs) that act on 1 of 3 targets: programmed cell death protein 1 (PD-1; nivolumab, pembrolizumab, cemiplimab), programmed death-ligand 1 (PD-L1; atezolizumab, durvalumab), or cytotoxic T-lymphocyte–associated protein 4 (CTLA-4; ipilimumab).2
Long-term outcomes from phase 3 trials are becoming available for these agents, suggesting that immunotherapies are improving lung cancer survival at a population level, making it a treatable, chronic disease for many patients.4 Still, optimal treatment selection remains unclear, as head-to-head trials are lacking, and cross-study comparisons remain challenging because of different designs and population characteristics.5 Trial results are therefore best translated into clinical practice after considering both published evidence and real-world insights. This article reviews the most recent data for first-line immunotherapies in patients with advanced NSCLC alongside expert perspectives from Jonathan Wesley Riess, MD, MS, from the University of California Davis Comprehensive Cancer Center, Sacramento.
“Immune checkpoint inhibitors have brought about a paradigm shift in the treatment of non–small-cell lung cancer,” Dr Riess said, noting “dramatic overall survival benefit” that amounts to a revolution in this clinical setting.
After a brief look at immunotherapy mechanisms of action, trial highlights will be discussed, followed by safety considerations and recommendations for treatment planning. Deeper dives into related topics, including biomarker testing and patient selection, adverse event (AE) profiles and management, and patient/caregiver education, will be available in 3 subsequent installments in this 4-part series.
Mechanisms of Action
At the time of this writing, FDA-approved immunotherapies for NSCLC include 6 ICIs.2 Nivolumab, pembrolizumab, and cemiplimab are PD-1 inhibitors, binding directly to the PD-1 receptor, whereas atezolizumab and durvalumab bind to the associated ligand, PD-L1.2
“There was some thought initially that the PD-L1 inhibitors may have fewer immune-related adverse events since they are more specific for PD-L1, but that hasn’t been borne out,” Dr Riess said. “So, I don’t really see any practical differences between [targeting] PD-1 or PD-L1. I go by the trial results for the respective PD-1/PD-L1 antibodies to make treatment decisions.”
Both PD-1 and PD-L1 inhibitors enhance T-cell proliferation and cytokine production.6 In comparison, CTLA-4 inhibitors augment T-cell activity and proliferation of T-effector cells while reducing T-regulatory cell function.7 The only double-immunotherapy combination currently approved by the FDA involves dual checkpoint blockade with nivolumab (a PD-1 inhibitor) and ipilimumab (a CTLA-4 inhibitor), resulting in greater T-cell function than would result from use of either agent alone.8 Most other approved combinations pair checkpoint inhibition with chemotherapy, an approach that reduces immunosuppression in the tumor microenvironment while strengthening immune-driven tumor-cell recognition and destruction.9
“[With chemo-immunotherapy combinations] the thought is that chemotherapy may induce more antigens from cell death, which can lead to greater immune system activity via immunotherapy,” Dr Riess said, although he noted that “the mechanism of action isn’t entirely clear, as chemotherapy often generates subclonal, rather than clonal, antigens.”
Atezolizumab and platinum-based chemotherapy may also be supplemented with bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor that is thought to enhance immunotherapy-mediated destruction of cancer cells.10
“We now have a plethora of options in the first-line setting, regardless of PD-L1 expression,” Dr Riess said. “Combining dual immune checkpoint inhibition, chemo-immunotherapy, or the combination thereof in the 9LA regimen, has very good data behind it.”
Nivolumab + Ipilimumab ± Chemotherapy
Checkmate 227 and Checkmate 9LA
Reflecting on the Checkmate 227 and Checkmate 9LA trials, Dr Riess described the reasoning behind dual-checkpoint blockade with nivolumab, a PD-1 inhibitor, and ipilimumab, a CTLA-4 inhibitor.
“CTLA-4 acts in the periphery at the level of the antigen-presenting cell and at the inactive T-cell to activate it,” Dr Riess said. “PD-1 interaction involves the tumor immune microenvironment. So, there’s a strong rationale for combining a CTLA-4 inhibitor and a PD-1 inhibitor.”
The Checkmate 227 trial involved a 1:1:1 design that compared first-line nivolumab + ipilimumab versus nivolumab alone versus platinum-doublet chemotherapy in 1189 patients with PD-L1 ≥1%.11 At a 4-year follow-up, patients treated with nivolumab + ipilimumab demonstrated a median overall survival (OS) of 17.1 months, compared with 14.9 months for those treated with chemotherapy (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.65-0.90).11 This and other OS data from phase 3 trials are highlighted in Table 1.4,10-21 The benefits of dual immunotherapy were even more pronounced in the PD-L1 ≥50% subgroup, which had an OS of 21.2 months, compared with 14.0 months in the chemotherapy arm (HR, 0.66; 95% CI, 0.52-0.84).11 Nivolumab + ipilimumab was also associated with better duration of response (DOR). Across all responders, median DOR was 23.2 months in the immunotherapy combination group, compared with 6.7 months in the chemotherapy group.11 Echoing the association between PD-L1 expression and survival, responders with PD-L1 ≥50% had even longer median DOR, at 31.8 months, versus 5.8 months for chemotherapy.11 These findings highlight the importance of PD-L1 as a prognostic indicator and clinical decision-making tool, a theme demonstrated by multiple other immunotherapy trials.
The Checkmate 9LA trial built on the above findings by adding a limited regimen (2 cycles) of platinum-doublet chemotherapy to first-line nivolumab + ipilimumab.12 At a 2-year follow-up, among 719 patients with advanced NSCLC and any level of PD-L1 expression, those who received nivolumab + ipilimumab + 2 cycles of chemotherapy had a median OS of 15.8 months, compared with 11.0 months for patients who received 4 cycles of chemotherapy alone (HR, 0.72; 95% CI, 0.61-0.86).12
Of note, in a post-hoc analysis of 61 patients who discontinued nivolumab + ipilimumab + chemotherapy due to treatment-related adverse events (TRAEs), median OS was 27.5 months (95% CI, 15.8-not reached) and durable responses were maintained, suggesting that patients discontinuing treatment due to AEs are still likely to achieve significant benefit.12
Durvalumab + Tremelimumab + Chemotherapy
Tremelimumab, like ipilimumab, is a CTLA-4 inhibitor, although it is not yet FDA-approved.22 The POSEIDON trial involved 1013 patients with advanced NSCLC regardless of PD-L1 expression level who were randomized in a 1:1:1 ratio to receive first-line durvalumab + tremelimumab + chemotherapy or durvalumab + chemotherapy or chemotherapy alone.13 In contrast with the Checkmate 9LA trial, which involved a limited, 2-cycle chemotherapy regimen in the combination cohorts and a 4-cycle regimen in the chemotherapy control cohort, the POSEIDON trial used 4 cycles of chemotherapy in the combination groups and 6 cycles in the control group.12,13 The triplet combination led to significantly greater median OS, at 14.0 months, compared with 11.7 months in the chemotherapy group (HR, 0.77; 95% CI, 0.65-0.92).13
Pembrolizumab ± Chemotherapy
KEYNOTE-024 and KEYNOTE-042
The KEYNOTE-024 trial randomized 305 patients with advanced NSCLC and PD-L1 ≥50% in a 1:1 ratio to receive first-line pembrolizumab alone or platinum-based chemotherapy.4 At 5-year follow-up, the median OS in the pembrolizumab group was 26.3 months, compared with 13.4 months in the chemotherapy group (HR, 0.62; 95% CI, 0.48-0.81).4
The KEYNOTE-042 trial followed a similar protocol—first-line pembrolizumab monotherapy versus chemotherapy—albeit with 1274 patients expressing PD-L1 ≥1%.14 At 3-year follow-up, median OS in the pembrolizumab group was 16.4 months, compared with 12.1 months in the chemotherapy group (HR, 0.73; 95% CI, 0.65-0.82).14 Patients with PD-L1 expression ≥20% and ≥50% had respective HRs of 0.66 and 0.62.14
“Responses in KEYNOTE-042 were really driven by patients with PD-L1 of 50% or more, not as much by patients with PD-L1 expression between 1% and 49%,” Dr Riess noted.
Collectively, the results from these 2 KEYNOTE trials support the direct relationship between PD-L1 expression level and efficacy of ICI monotherapy, suggesting that combination therapies should be considered among patients with lower PD-L1 expression.
KEYNOTE-189 and KEYNOTE-407
The KEYNOTE-189 and KEYNOTE-407 trials evaluated first-line pembrolizumab + chemotherapy for patients with nonsquamous or squamous NSCLC, respectively, regardless of PD-L1 expression.15,16 In both trials, pembrolizumab + chemotherapy outperformed chemotherapy alone.15,16
After almost 2 years of follow-up in the KEYNOTE-189 trial, patients with nonsquamous NSCLC treated with pembrolizumab + chemotherapy had a median OS of 22.0 months, compared with 10.7 months for chemotherapy alone (HR, 0.56; 95% CI, 0.45-0.70).15
With approximately 1 year of follow-up in the KEYNOTE-407 trial, patients with squamous NSCLC treated with pembrolizumab + chemotherapy had a median OS of 17.1 months, versus 11.6 months in the chemotherapy group (HR, 0.71; 95% CI, 0.58-0.88).16
“KEYNOTE-189 and KEYNOTE-407 showed that you can improve survival in PD-L1–negative patients—not just PD-L1–positive patients—by adding chemo to immunotherapy, compared to chemotherapy alone,” Dr Riess said.
Cemiplimab ± Chemotherapy
EMPOWER-Lung 1 and EMPOWER-Lung 3
The EMPOWER-Lung 1 trial evaluated first-line cemiplimab monotherapy versus chemotherapy in 710 patients with NSCLC.18 The population consisted of 563 patients with PD-L1 ≥50%.18 After a median follow-up of approximately 11 months in this high-expression group, median OS was not reached with cemiplimab versus 14.2 months in the chemotherapy group (HR, 0.57; 95% CI, 0.42-0.77).18 In the overall population, after a median follow-up of approximately 13 months, cemiplimab monotherapy was associated with a median OS of 22.1 months, compared with 14.3 months in the chemotherapy group (HR, 0.68; 95% CI, 0.53-0.87).17
The EMPOWER-Lung 3 trial evaluated first-line cemiplimab + chemotherapy versus chemotherapy alone in 466 patients with advanced NSCLC irrespective of histology or PD-L1 status.19 Patients treated with cemiplimab combination therapy demonstrated a median OS of 21.9 months, compared with 13.0 months for those treated with chemotherapy alone (HR, 0.71; 95% CI, 0.53-0.93).19
Again, these findings demonstrate that ICI monotherapy is effective for patients with high PD-L1 expression, whereas combination therapy is effective for all patients. At the time of this writing, cemiplimab combination therapy is not yet FDA-approved for NSCLC.23
Atezolizumab ± Chemotherapy ± Bevacizumab
IMpower110, IMpower130, and IMpower150
The IMpower trials tested atezolizumab in 3 first-line regimens: as monotherapy, in combination with chemotherapy, and with both chemotherapy and bevacizumab. The findings follow general patterns demonstrated in previous trials; namely, that patients with high PD-L1 expression respond well to monotherapy with checkpoint blockade, whereas patients with lower PD-L1 expression derive greater benefit from a combination regimen.
The IMpower110 trial showed that atezolizumab monotherapy outperformed chemotherapy alone in 572 patients with advanced NSCLC, although this depended on PD-L1 expression level.20 Among 205 patients with PD-L1 ≥50%, median OS in the atezolizumab group was 20.2 months, compared with 13.1 months in the chemotherapy group (HR, 0.59; 95% CI, 0.40-0.89).20 This survival benefit decreased among patients with PD-L1 ≥5% (18.2 vs 14.9 months; HR, 0.72; 95% CI, 0.52-0.99) and was not statistically significant among patients with PD-L1 ≥1%.20
IMpower130 evaluated atezolizumab + chemotherapy versus chemotherapy alone in a 2:1 ratio among 679 patients with advanced NSCLC regardless of PD-L1 expression.21 The study showed that the atezolizumab combination regimen offered a significantly higher median OS than chemotherapy alone (18.6 vs 13.9 months; HR, 0.79; 95% CI, 0.64-0.98).21
IMpower150 added bevacizumab to the atezolizumab + chemotherapy protocol, creating a triplet regimen that outperformed bevacizumab + chemotherapy; median OS was 19.5 versus 14.7 months among 697 patients with wild-type disease and any level of PD-L1 expression (HR, 0.80; 95% CI, 0.67-0.95).10
Dr Riess noted that in the IMpower150 trial, patients with EGFR mutations who had previously received a tyrosine kinase inhibitor (TKI) responded well to atezolizumab + bevacizumab + chemotherapy.24
“After TKI, the addition of bevacizumab and atezolizumab may potentiate activity with chemotherapy in those patients that classically don’t respond to single-agent immunotherapy,” Dr Riess said. “The updated data are not quite as impressive, and it [atezolizumab + bevacizumab + chemotherapy] is not FDA-approved for that indication, but the response rate in the EGFR subgroup was about 70%.”24
Collectively, the IMpower trials affirm patterns demonstrated by other trials, including the association between PD-L1 expression and outcomes, and the benefit of an approach with immunotherapy plus chemotherapy.
Durvalumab Consolidation Therapy
Moving away from the stage IV frontline setting, the PACIFIC trial tested durvalumab consolidation therapy in 709 patients with stage III unresectable NSCLC and any PD-L1 status that had not progressed after platinum-based concurrent chemoradiotherapy.25 After a median follow-up of almost 3 years, patients treated with durvalumab demonstrated a median OS of 47.5 months, compared with 29.1 months for those administered a placebo (HR, 0.72; 95% CI, 0.45-0.68).25 These findings demonstrate that checkpoint blockade is also beneficial in a consolidation setting.
“PACIFIC is an important pivotal trial in the locally advanced setting,” Dr Riess said. “It showed a profound improvement in progression-free survival and overall survival, where 5-year overall survival was over 40%. This represents a major advance in this area.”
Understanding the relative safety of various immunotherapies is challenging due to the many differences in trial designs and patient populations. This makes it difficult to compare safety profiles of different immunotherapy agents across clinical trials.5 However, using Table 2 as a guide, some safety trends become apparent among first-line, FDA-approved therapies.4,10-12,15,16,18,20,21,26
Foremost, monotherapies are generally better tolerated than combination therapies. This is demonstrated by safety data from the KEYNOTE-024 and KEYNOTE-189 trials, which evaluated pembrolizumab monotherapy and pembrolizumab + chemotherapy, respectively, and reported AEs of any cause.4,15 In KEYNOTE-024, 30% of patients treated with pembrolizumab monotherapy experienced grade 3 or 4 AEs, compared with 65% of patients treated with pembrolizumab + chemotherapy in KEYNOTE-189, and rates of AEs leading to treatment discontinuation followed suit (14% vs 34%).4,15
Differences in safety between individual PD-1/PD-L1 inhibitors appear to be minimal. In KEYNOTE-042, 16% of patients treated with pembrolizumab monotherapy had grade 3 or 4 TRAEs, compared with 12% of patients treated with cemiplimab monotherapy in the EMPOWER-Lung 1 trial, with respective discontinuation rates of 8% and 6%.18,26 Any real difference in safety is likely negligible, as patients treated with chemotherapy in the EMPOWER-Lung 1 trial also had fewer TRAEs than the chemotherapy group in the KEYNOTE-042 trial, suggesting that the EMPOWER-Lung 1 population may have been more tolerant of treatment in general.18,26 The similarity of safety profiles between monotherapy agents is further supported by a comparison of KEYNOTE-024 and IMpower110 trials, which evaluated pembrolizumab and atezolizumab, respectively, and found that 30% of patients in each group experienced grade 3 or 4 TRAEs.4,20 Taken together, these 4 trials suggest that PD-1/PD-L1 inhibitors have similar safety profiles, a conclusion that is supported by results of recent meta-analysis.27
Similarities in safety appear to be maintained when chemotherapy is added to a PD-1/PD-L1 inhibitor, as demonstrated by the KEYNOTE-189, KEYNOTE-407, and IMpower130 trials, which had grade 3 or 4 AEs ranging from 65% to 73%, and rates of treatment discontinuation due to AEs ranging from 26% to 34%.15,16,21 Adding bevacizumab to such a protocol—specifically, atezolizumab + chemotherapy—appears to have a relatively minor impact on tolerability, considering that grade 3 or 4 TRAEs in the IMpower150 trial increased from 40.5% to 48.6% when patients also received the VEGF inhibitor.28
While some patients may need to discontinue ICIs due to TRAEs, Dr Riess noted that they can still achieve significant improvement. He offered some insights into the underlying mechanism behind such responses.
“When you give these immunotherapy drugs, there’s a reprogramming of the immune system that could lead to long-lasting effects, despite discontinuation of the drugs,” Dr Riess said. “They remain bound to the receptor for 3 months or so, but even beyond that, there could be a durable response, as the immune system is reprogrammed and continuing to surveil and attack the tumor. I have multiple patients who’ve come off immunotherapy for immune-related adverse events or other reasons who then have no evidence of disease years later. I think it’s very exciting to be able to get that benefit.”
What have we learned from these key clinical studies and how can we apply the learnings to clinical practice? Although biomarker testing is an important component in the optimal use of immunotherapy for the treatment of patients with NSCLC, this topic will be addressed in greater detail in the next installment in this series. For now, best practices and practical clinical guidance will be reviewed in treating patients with advanced NSCLC with immunotherapy.
Principles of Patient Selection
When considering immunotherapy for patients with NSCLC, eligibility should first be determined by testing for oncogenic driver variants, such as EGFR mutations and ALK fusions, as these generally limit the efficacy of immunotherapies; patients with actionable drivers such as EGFR and ALK that are typically not associated with smoking should therefore receive immunotherapy only after failing other treatment options, including targeted agents.29 If actionable drivers are not detected, immunotherapy selection should be guided by PD-L1 expression, histology, and performance status; in some cases, symptomatology and extent of disease/tumor volume may also play a role.30 Pembrolizumab monotherapy for patients with PD-L1 ≥50% can spare chemotherapy-related toxicities.30
Still, some patients with high PD-L1 expression may elect combination immunotherapy such as nivolumab + ipilimumab with or without chemotherapy, especially if treatment is expected to preserve or improve the patient’s quality of life, and the benefit-to-risk ratio is acceptable.30,31
“In patients with PD-L1 of 50% or more, I usually will start with pembrolizumab alone to spare them chemo toxicity, unless I really feel they need a response,” Dr Riess said. “For example, with patients who are increasingly symptomatic or have bulky disease, I do chemotherapy and immunotherapy.”
Such combinations may be suitable even in the context of suboptimal performance status, considering that Eastern Cooperative Oncology Group (ECOG) score is not always an accurate predictor of tolerability. In a recent meta-analysis involving >26,000 NSCLC patients treated with immunotherapy, AEs were no more common in patients with an ECOG performance status ≥2 than in patients who had a performance status ≤1.32
“We always take into account performance status,” Dr Riess said, “and we also go by physiologic age rather than numerical age because I’ve had plenty of older patients that have done very well with immunotherapy, very well.”
For patients with PD-L1 levels <50%, or those with an unknown PD-L1 status, combination regimens are typically recommended, especially for patients with large-volume visceral tumors or high symptom burden.30
“The 9LA regimen with limited chemotherapy, ipilimumab, and nivolumab is a reasonable option [in this setting],” Dr Riess said.
A variety of other combinations are appropriate, most involving checkpoint blockade and chemotherapy, with the latter determined by tumor subtype.31
“For PD-L1 zero patients who don’t have any actionable molecular driver with an FDA-approved agent, my practice in that setting has been to give chemotherapy with immunotherapy,” Dr Riess said. “I select a chemotherapy regimen mainly by histology.”
When using nivolumab + ipilimumab + chemotherapy for nonsquamous histology, for instance, pemetrexed should be combined with carboplatin or cisplatin, whereas patients with squamous disease are more likely to benefit from carboplatin and paclitaxel.31 Dosing schema for FDA-approved immunotherapy regimens, including chemotherapy selection based on histology, are shown in Table 3.4,10-12,15,18,20,21,25
Unique Patient Subgroups
Although brain metastases occur in approximately 40% of patients with NSCLC, such patients have historically been excluded from clinical trials.33 Retrospective data, however, suggest that brain metastases are not associated with diminished response and survival in patients treated with ICIs, suggesting that checkpoint blockade is appropriate for otherwise eligible individuals.33
Dr Riess modifies his approach based on severity of intracranial disease. “Generally, with brain metastases in patients with planned systemic treatment with immunotherapy, I refer to a radiation oncologist to discuss stereotactic radiosurgery,” Dr Riess said, “unless they’re small brain metastases that are asymptomatic. Then I feel like I can wait several weeks to follow with serial exams to see if there’s a response.”
Immunotherapy Response Patterns
Unlike chemotherapy, which works rapidly through a direct cytotoxic effect, immunotherapy depends on immune system activity, so disease improvements in some patients may be delayed for weeks or months after starting immunotherapy.34
“I’ve seen a variation of responses to immunotherapy,” Dr Riess said. “Sometimes responses could be as early as a few weeks, although it’s classically thought that it may take a bit more time than that to prime the immune system.”
Delayed responses to immunotherapy may lead to some challenging clinical scenarios, including the decision to continue therapy in the presence of apparent disease progression. This choice is made in the context of 2 possibilities: (1) pseudoprogression, a temporary increase in tumor size that resolves in time, or (2) hyperprogression, an extremely rapid increase in tumor size that is indicative of true acceleration of disease activity.35
In <10% of patients, immunotherapy may induce pseudoprogression, which is defined as progression based on RECIST criteria, followed by a response to therapy.35 Pseudoprogression may be due to early recruitment of T-cells to the tumor, leading to an apparent increase in tumor size that precedes T-cell–dependent anticancer activity.35 Unfortunately, pseudoprogression can only be identified retrospectively, so it remains a challenging judgment call; for now, experts recommend continuing immunotherapy only if patients have improving or stable clinical signs despite a rapid increase in tumor size, and severe toxicities are absent.35
“Pseudoprogression happens infrequently,” Dr Riess said. “Usually, clinically, these are patients who start immunotherapy, and their scans show some potential progression, but you talk to them, and they say, ‘I feel great. I feel so much better.’ What I do practically is if patients are feeling well and there’s some slight growth, I just get a scan several weeks later to see. Usually, their scan improves and they get better. Alternatively, if there’s some slight growth and they’re only on immunotherapy, I may add chemo instead of bailing on immunotherapy altogether. And sometimes, since there’s an association with clearance of circulating tumor DNA and efficacy of the PD-1 [inhibitor], I’ll even look at a circulating tumor DNA to see if it’s detectable or not, although that’s still done more on a research basis.”
Hyperprogression—in which immunotherapy accelerates tumor growth at a very high rate—is a more controversial phenomenon, as controlled data have yet to demonstrate a link with ICIs.35 Hyperprogression has been defined in at least 3 ways, although it generally refers to a 2-fold increase in tumor growth rate during immunotherapy.35
From a practical perspective, hyperprogression warrants immediate discontinuation of immunotherapy because disease worsening is likely real; however, Dr Riess noted that it is a rare occurrence.35
“Hyperprogression has been more often described in EGFR-mutant lung cancer,” Dr Riess said. “We don’t really use single-agent immunotherapy anymore in those patients, so it’s become less of an issue.”
Over the past 6 years, immunotherapy has become the standard of care for patients with NSCLC and has filled the unmet need of first-line chemotherapy, clearly extending survival for patients without oncogenic driver alterations. Although ICI monotherapy may be suitable for patients with high PD-L1 expression, broader efficacy has been observed with immunotherapy combinations, now including a regimen with dual ICIs and a limited, 2-cycle chemotherapy protocol. In addition, increasing amounts of retrospective data suggest that unique patient populations, such as those with autoimmune disease, may also be safely treated with immunotherapy.
Still, some treatment gaps remain. According to Dr Riess, more work is needed to overcome resistance and refine treatment planning.
“That involves finding new biomarkers in addition to PD-L1 to better decide which patients will benefit from immunotherapy and who might not,” he said. “For the patients that don’t benefit, what can we add to make them benefit?”
To this end, Dr Riess highlighted emerging screening strategies and regimens, including earlier use of circulating tumor DNA, as well as immunotherapies that address novel targets, and cancer vaccines.
For now, best outcomes rely on careful treatment selection based on known predictive and prognostic clinical variables. These extend beyond PD-L1 expression to encompass histology, performance status, symptoms, extent of disease/tumor volume, and other factors. For more information about treatment selection, AE management, and patient/caregiver education, continue reading the remaining 3 installments in this 4-part series.
- American Cancer Society. Key Statistics for Lung Cancer. Updated January 12, 2021. www.cancer.org/content/dam/CRC/PDF/Public/8703.00.pdf. Accessed January 15, 2022.
- Rodak O, Peris-Diaz MD, Olbromski M, et al. Current landscape of non-small cell lung cancer: epidemiology, histological classification, targeted therapies, and immunotherapy. Cancers (Basel). 2021;13:4705.
- Lee T, Clarke JM, Jain D, et al. Precision treatment for metastatic non-small cell lung cancer: a conceptual overview. Cleve Clin J Med. 2021;88:117-127.
- Reck M, Rodriguez-Abreu D, Robinson AG, et al. Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score ≥50%. J Clin Oncol. 2021;39:2339-2349.
- Kim H, Gurrin L, Ademi Z, Liew D. Overview of methods for comparing the efficacies of drugs in the absence of head-to-head clinical trial data. Br J Clin Pharmacol. 2014;77:116-121.
- Keytruda (pembrolizumab) [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; December 2021.
- Yervoy (ipilimumab) [package insert]. Princeton, NJ: Bristol Myers Squibb Company; May 2021.
- Opdivo (nivolumab) [package insert]. Princeton, NJ: Bristol Myers Squibb Company; September 2021.
- Leonetti A, Wever B, Mazzaschi G, et al. Molecular basis and rationale for combining immune checkpoint inhibitors with chemotherapy in non-small cell lung cancer. Drug Resist Updat. 2019;46:100644.
- Socinski MA, Nishio M, Jotte RM, et al. IMpower150 final overall survival analyses for atezolizumab plus bevacizumab and chemotherapy in first-line metastatic nonsquamous NSCLC. J Thorac Oncol. 2021;16:1909-1924.
- Paz-Ares LG, Ramalingam SS, Ciuleanu TE, et al. First-line nivolumab plus ipilimumab in advanced NSCLC: 4-year outcomes from the randomized, open-label, phase 3 CheckMate 227 part 1 trial. J Thorac Oncol. 2022;17:289-308.
- Reck M, Ciuleanu TE, Cobo M, et al. First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small-cell lung cancer: CheckMate 9LA 2-year update. ESMO Open. 2021;6:100273.
- Johnson M, Cho B, Luft A, et al. Durvalumab ± tremelimumab + chemotherapy as first-line treatment for mNSCLC: results from the phase 3 POSEIDON study. Presented at: 2021 IASLC World Conference on Lung Cancer; September 8-14, 2021; Virtual.
- Cho BC, Wu Y, Lopes G, et al. FP13.04 KEYNOTE-042 3-year survival update: 1L pembrolizumab vs platinum-based chemotherapy for PD-L1+ locally advanced/metastatic NSCLC. J Thorac Oncol. 2021;16:S225-S226.
- Gadgeel S, Rodriguez-Abreu D, Speranza G, et al. Updated analysis from KEYNOTE-189: pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non-small-cell lung cancer. J Clin Oncol. 2020;38:1505-1517.
- Paz-Ares L, Vicente D, Tafreshi A, et al. A randomized, placebo-controlled trial of pembrolizumab plus chemotherapy in patients with metastatic squamous NSCLC: protocol-specified final analysis of KEYNOTE-407. J Thorac Oncol. 2020;15:1657-1669.
- Libtayo (cemiplimab-rwlc) [package insert]. Tarrytown, NY: Regeneron Pharmaceuticals; February 2021.
- Sezer A, Kilickap S, Gümüş M, et al. Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial. Lancet. 2021;397:592-604.
- Gogishvili M, Melkadze T, Makharadze T, et al. LBA51 - EMPOWER-Lung 3: cemiplimab in combination with platinum doublet chemotherapy for first-line (1L) treatment of advanced non-small cell lung cancer (NSCLC). Ann Oncol. 2021;32:S1283-S1346.
- Herbst RS, Giaccone G, de Marinis F, et al. Atezolizumab for first-line treatment of PD-L1-selected patients with NSCLC. N Engl J Med. 2020;383:1328-1339.
- West H, McCleod M, Hussein M, et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20:924-937.
- Selby K. Tremelimumab. Asbestos.com. Updated March 17, 2022. www.asbestos.com/treatment/immunotherapy/tremelimumab. Accessed March 23, 2022.
- Sanofi. Phase 3 trial of Libtayo (cemiplimab) combined with chemotherapy stopped early due to significant improvement in overall survival in patients with first-line advanced nonsmall cell lung cancer [press release]. August 5, 2021. www.sanofi.com/en/media-room/press-releases/2021/2021-08-05-12-00-00-2275303. Accessed January 4, 2022.
- Reck M, Mok TSK, Nishio M, et al. Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial. Lancet Respir Med. 2019;7:387-401.
- Spigel DR, Faivre-Finn C, Gray JE, et al. Five-year survival outcomes with durvalumab after chemoradiotherapy in unresectable stage III NSCLC: an update from the PACIFIC trial. J Clin Oncol. 2021;39(15_suppl):8511-8511.
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