Advances in Immunotherapy in Metastatic Non–Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) is the most common histologic subtype of the disease, accounting for approximately 85% of cases. The recognition of targetable gene alterations and immune response has resulted in rapid changes to the therapeutic spectrum for NSCLC in recent years. As drug developments continue in the area of metastatic NSCLC, there is promise for prolonged survival for these patients.¹

On October 27, 2020, OncLive^® brought together a group of medical oncologists who specialize in the treatment of lung cancer to participate in the workshop “Advances in Immunotherapy in Non–Small Cell Lung Cancer.” This article summarizes key data regarding the current and emerging therapeutic agents for NSCLC shared at the meeting, as well as insights from stakeholder discussions regarding the findings.

Current Standards of Care

Clinical trials over the past few years have established a new standard of care in treating metastatic NSCLC, including single-agent immunotherapies and combination regimens. Several key trials were highlighted.

Single-agent Immunotherapy

Pembrolizumab was the first FDA-approved checkpoint inhibitor for
the frontline treatment of lung cancer. The results of the KEYNOTE-024 study (NCT02142738) played a major part in its approval indicated for patients with meta- static NSCLC with PD-L1 tumor expression determined by an FDA-approved test.² In patients with previously untreated stage IV NSCLC, a PD-L1 tumor proportion score (TPS) of at least 50%, and no activating EGFR mutation or ALK translocation, the KEYNOTE-024 trial showed that pembrolizumab was a more effective therapy compared with chemotherapy. Patients were randomly assigned (n = 305) to pembrolizumab (n = 154) or investigator’s choice of platinum doublet chemotherapy with optional pemetrexed (n = 151). Crossover was allowed upon disease progression.³

The 5-year safety and efficacy update showed that pembrolizumab continues to improve overall survival vs chemotherapy as a first-line therapy in this patient group. At a median data cutoff of 59.9 months, 55% of patients crossed over from chemotherapy to pembrolizumab, and 7 patients had died from disease progression. Median overall survival (OS) was 26.3 months in the pembrolizumab group vs 13.4 months in the chemotherapy group. The Kaplan-Meier estimates for 5-year OS were 31.9 months vs 16.3 months. Treatment-related adverse events (TRAEs) grades 3 to 5 were 31.2% with pembrolizumab compared with 53.3% with chemotherapy.⁴

Stakeholder Insights: The 5-year survival data look impressive for patients with metastatic NSCLC using a single agent vs a platinum-based doublet chemotherapy. It is a notable accomplishment in the management of these patients.

The KEYNOTE-042 trial (NCT02220894) also evaluated pembrolizumab as a first- line monotherapy vs chemotherapy in patients without EGFR mutations or ALK translocations.⁵ The results of this study expanded pembrolizumab’s indication for first-line NSCLC with PD-L1 TPS of at least 1%.⁶ Patients with locally advanced or metastatic NSCLC with PD-L1 TPS of at least 1% were given either pembrolizumab (n = 637) or chemotherapy (n = 637). Forty-seven percent of patients had TPS of 50% or more, and 64% had TPS of 20% or more. At a median follow-up of 12.8 months, the pembrolizumab group had shown a considerably longer OS in all TPS groups: in PD-L1 ≥ 50%, HR, 0.69; 95% CI, 0.56-0.85; P = .0003; in PD-L1 ≥ 20%, HR, 0.77; 95% CI, 0.64-0.92; P = .0020; in PD- L1 ≥ 1%, HR, 0.81; 95% CI, 0.71-0.93; P = .0018. Grade 3 or higher TRAEs were experienced in 18% of the pembrolizumab group and 41% of the chemotherapy group, with death occurring in 2% of patients in both groups. Results of the study suggest that pembrolizumab monotherapy can be a first-line option for this patient population.⁵

Furthering the therapeutic spectrum for first-line treatments for patients with metastatic NSCLC, atezolizumab was studied in the randomized, open-label, phase 3 IMpower110 trial (NCT02409342), looking at the safety and efficacy of the anti–PD-L1 monoclonal antibody vs platinum-based chemotherapy of nonsequential cisplatin/carboplatin/pemetrexed and sequential cisplatin/carboplatin/gemcitabine. Enrolled patients (n = 572) were assigned 1:1 to either atezolizumab or chemotherapy.⁷

The primary end point was OS. In a subgroup analysis of patients with EGFR and ALK wild-type tumors and highest expression of PD-L1 (n = 205), the median OS was 20.2 months in the atezolizumab group and 13.1 months in the chemotherapy group (HR for death, 0.59; P = .01). In the patient subgroups who had a high blood-based tumor mutational burden, OS and progression-free survival (PFS) both favored atezolizumab. Approximately 90.2% of patients in the atezolizumab group and 94.7% in the chemotherapy group experienced adverse events (AEs). Regardless of histologic subtype, atezolizumab achieved significantly longer OS compared with platinum-based chemotherapy in patients with NSCLC and high PD-L1 expression.⁷ The results of the IMpower110 trial prompted FDA approval for atezolizumab as a first-line treatment of adults with metastatic NSCLC whose tumors have PD-L1 expression and no EGFR or ALK genomic tumor aberrations.⁸

Stakeholder Insights: For single-agent immunotherapy, patient-level decisions, extent of disease, symptom burden, and tumor mutation burden are factors to consider in treatment selection. Those with lesser symptoms and disease may be better candidates for monotherapy, and other patients may be better suited for chemotherapy plus immunotherapy.

Combination Therapy

Immunotherapy has greatly changed the therapeutic landscape for advanced NSCLC. Clinical trials from recent years have shown the benefits of immunotherapy combinations and immunotherapy in combination with chemotherapy having an impact on clinical practice guidelines and decision-making in the space.

Pembrolizumab was approved as a first-line therapy in combination with pemetrexed and platinum in patients with metastatic nonsquamous NSCLC and no EGFR or ALK genomic tumor aberrations. This approval was based on results from the KEYNOTE-189 trial (NCT02578680).⁹

The double-blind, phase 3 KEYNOTE-189 trial investigated first-line pembrolizumab as a combination therapy with chemotherapy in patients with metastatic NSCLC. Patients with no sensitizing EGFR or ALK mutations and no prior metastatic cancer treatment (n = 616) were randomly assigned 2:1 to pemetrexed and a platinum-based therapy plus pembrolizumab (n = 410) or placebo (n = 206) every 3 weeks for 4 cycles, with pembrolizumab or placebo given subsequently for up to 35 cycles along with pemetrexed maintenance therapy. Crossover to pembrolizumab monotherapy was allowed for those who progressed in the placebo combination group. The approximate OS at 12 months was 69.2% in the pembrolizumab arm compared with 49.4% in the placebo arm. Median follow-up was 10.5 months; median PFS was 8.8 months vs 4.9 months, respectively. In the PD-L1 groups that were evaluated, all patients saw an improvement in OS. Grade 3 or higher AEs were more frequent in the pembrolizumab group (67.2%) than in the placebo group (65.8%). Nausea, anemia, and fatigue were the most common AEs in both groups.¹⁰

The final updated results from the trial showed that median OS and PFS were both longer in the pembrolizumab combination group, with overall response rates (ORRs) of 48.3% vs 19.9%, respectively. Toxicities were reported to be manageable. It was concluded that the combination of pembrolizumab plus chemotherapy showed continuous improvements in OS, PFS, and ORR, supporting this first-line option for metastatic NSCLC.¹¹

Stakeholder Insights: These data suggest that the pembrolizumab-plus-pemetrexed combination evaluated in the KEYNOTE-189 study has an important role to play in patients with EGFR and ALK tumor aberrations. For patients struggling with chemotherapy, it is suitable to continue the pembrolizumab alone.

The phase 3, open-label IMpower150 trial (NCT02366143) also showed improved survival with a combination therapy of atezolizumab and bevacizumab
plus chemotherapy in patients with metastatic nonsquamous NSCLC irrespective of EGFR, PD-L1, and ALK status. Patients were randomly assigned to either atezolizumab/ carboplatin/paclitaxel, bevacizumab/carboplatin/paclitaxel (BCP), or atezolizumab/bevacizumab/carboplatin/ paclitaxel (ABCP). The wild-type genotype intention-to-treat (ITT) population had 356 in the ABCP group and 336 in the BCP group. The ABCP group achieved significantly greater median PFS compared with the BCP group (8.3 months vs 6.8 months; stratified HR for disease progression or death, 0.62; 95% CI, 0.52-0.74; P < .001). The ITT ABCP population also achieved greater median OS (19.2 months vs 14.7 months; HR for death, 0.78; 95% CI, 0.64-0.96; P = .02). No surprising toxicity findings were reported for ABCP compared with prior data for the individual therapies.¹²

Stakeholder Insights: The inclusion of patients with EGFR mutations made this trial interesting. There may be a role for bevacizumab in select patients; however, some do not prefer the quadruple regimen because of its toxicity.

The combination of nivolumab plus ipilimumab was approved by the FDA based on the CheckMate 227 (NCT02477826) and CheckMate 9LA (NCT03215706) trials. The combination is approved for first-line use in metastatic NSCLC with PD-L1 expression of at least 1%, as determined by an FDA-approved test, and no EGFR or ALK genomic tumor mutations or for first-line therapy in those with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor mutations who have received 2 cycles of platinum-based doublet chemotherapy.¹³

CheckMate 227 evaluated the long-term benefit of nivolumab plus ipilimumab in patients with NSCLC who had no prior chemotherapy treatment. Patients were randomized 1:1:1 to nivolumab plus ipilimumab, nivolumab monotherapy, or chemotherapy; those who had less than 1% PD-L1 expression were randomized 1:1:1 to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy.¹⁴ Updated 3-year data show that at a median follow-up of 43.1 months, patients with PD-L1 expression of at least 1% who were given ipilimumab plus nivolumab continued to achieve an OS benefit, with 3-year OS rates of 33% in the nivolumab plus ipilimumab arm, 29% in the nivolumab arm, and 22% in the chemotherapy arm. No new safety signals were observed. At 3-year minimum follow-up, nivolumab plus ipilimumab as a first-line therapy showed continued durable and long-term response.¹⁵

CheckMate 9LA also found OS benefit, meeting its primary end point, with nivolumab plus ipilimumab plus 2 cycles of chemotherapy vs 4 cycles of chemotherapy in first-line treatment of stage IV recurrent NSCLC. Patients were stratified by PD-L1 status, sex, and squamous or nonsquamous histology, and they were randomized 1:1 to nivolumab plus ipilimumab plus chemotherapy (2 cycles; n = 361) or chemotherapy alone (4 cycles; n = 358). The median follow-up was 12.7 months. The median OS was 5.6 months with ipilimumab/nivolumab/ chemotherapy compared with 10.9 months with chemotherapy alone (HR, 0.66; 95% CI, 0.55-0.80), with 1-year OS rates of 63% and 47%, respectively; grade 3 to 4 TRAEs were observed in 47% vs 38%, respectively.¹⁶

Stakeholder Insights: Concern surrounded the use of ipilimumab plus nivolumab due to potential toxicity. This may be an option in patients who refuse a chemotherapy-containing regimen or in those with a good performance status. Efficacy in the PD-L1-zero population may be of consideration and interest.

Emerging Approaches

Cemiplimab is another immunotherapy option on the horizon that may soon receive FDA approval for patients with advanced NSCLC with PD-L1 expression in more than 50% of tumor cells. The PD-L1 monoclonal antibody is currently approved for the treatment of metastatic cutaneous squamous cell carcinoma in patients who are ineligible for surgery or radiation.¹⁷ In the EMPOWER-Lung 1 trial (NCT03088540), investigators evaluated cemiplimab monotherapy vs platinum-based doublet chemotherapy.¹⁸ The results, which were presented at the 2020 European Society for Medical Oncology (ESMO) Virtual Congress, offered a glimpse of how cemiplimab may fit into the treatment spectrum for first-line locally advanced or metastatic NSCLC.

Investigators randomized patients 1:1 to either cemiplimab 350 mg every 3 weeks or investigator’s-choice chemotherapy. After progression, crossover from chemotherapy to cemiplimab was permitted. The primary end points were OS and PFS per independent review committee. Secondary end points included overall response rate, duration of response, and quality of life. At a median follow-up of 13.1 months in the ITT population, median OS was 22.1 months (95% CI, 17.7-not evaluable [NE]) in the cemiplimab group (n = 356) compared with 14.3 months (95% CI, 11.7-19.2) in the chemotherapy group (n = 354; HR, 0.68; 95% CI, 0.53-0.87; P = .002); median PFS was 6.2 months (95% CI, 4.5-8.3) with cemiplimab compared with 5.6 months (95% CI, 4.5-6.1) in the chemotherapy group (HR, 0.59; 95% CI, 0.49-0.72; P < .0001).¹⁸

The ITT population with PD-L1 greater than or equal to 50% had a median follow-up of 10.8 months.¹⁸ Risk of death decreased 43% (HR, 0.57; 95% CI, 0.42-0.77; P = .0002). The cemiplimab group (n = 283) did not reach median OS (95% CI, 17.9-NE) compared with 14.2 months (95% CI, 11.2-17.5) in the chemotherapy group (n = 280; HR, 0.57; 95% CI, 0.42-0.77; P = .0002); median PFS was 8.2 months (95% CI, 6.1-8.8) in the cemiplimab group compared with 5.7 months (95% CI, 4.5-6.2) in the chemotherapy group (HR, 0.54; 95% CI, 0.43-0.68; P < .0001). There was a 73.9% crossover rate to cemiplimab. Despite the high crossover rate, first-line cemiplimab monotherapy considerably improved OS and PFS compared with chemotherapy in this patient population.¹⁸ The ITT population achieved a greater response rate (36.5% vs 20.6%, respectively), longer median duration of response (21.0 months vs 6.0 months), and fewer grade 3 or higher AEs (37.2% vs 48.5%) compared with those in the chemotherapy group.¹⁸

Immune-mediated AEs occurred in 17% of those treated with cemiplimab, with the most frequent being hypothyroidism (6%), hyperthyroidism (4%), pneumonitis (2%), hepatitis (2%), skin adverse reaction (2%), and arthritis, increased blood thyroid stimulating hormone, thyroiditis, colitis, nephritis, and peripheral neuropathy (each 1%).¹⁸ At the time of this publication, the FDA has accepted cemiplimab for priority review as a first-line therapy to treat patients with locally advanced or metastatic NSCLC with at least 50% PD-L1 expression. The FDA is expected to reach a decision about approval by late February.¹⁹

New Combinations

New combination therapies are also under investigation, with pivotal data presented at the 2020 American Society of Clinical Oncology Virtual Scientific Program and the 2020 ESMO Virtual Congress. Because research has indicated that cytotoxic chemotherapy and angiogenesis inhibitors may enrich therapeutic advantage of immune checkpoint inhibitors, the randomized, double-blind, phase 3 TASUKI-52 trial (NCT03117049) was the first study to evaluate first-line nivolumab plus platinum chemotherapy with bevacizumab for patients with nonsquamous NSCLC.²⁰

Patients were given 1 or more doses of nivolumab (n = 273) or placebo (n = 275). The median follow-up was 13.7 months at the interim analysis in July 2020. PFS was considerably longer in the nivolumab arm vs the placebo arm, with a median PFS of 12.12 vs 8.11 months, respectively (HR, 0.56; 96.37% CI, 0.43-0.71; P < .0001); the 12-month PFS rate was 50.1% vs 30.2%, respectively. Objective response rates per independent radiology review committee were 61.5% in the nivolumab arm and 50.5% in the placebo arm. The OS was not mature at the time of the presentation, but the OS for the nivolumab group was noted to be longer (HR, 0.85; 95% CI, 0.63-1.14). Grade 3 and 4 TRAEs that led to discontinuation of therapy were 73.6% and 16.5% in the nivolumab group and 72.0% and 4.4% in the placebo group, respectively. The most commonly observed TRAEs were alopecia, peripheral sensory neuropathy, and decreased neutrophil count. The study met its primary end point of a significantly prolonged PFS in the nivolumab group with no uncontrollable toxicities.²⁰

The single-arm, phase 2, WJOG @BeStudy trial evaluated the clinical advantages of the addition of bevacizumab to atezolizumab as a frontline therapy in patients with nonsquamous NSCLC and high PD-L1 expression. The primary end point of the study was ORR. Of the 40 patients enrolled from 14 institutions, 1 patient was ineligible. As of March 31, 2020, there was an ORR of 64.1% (95% CI, 47.2%-78.8%). The 1-year PFS was 54.9%, and the median number of treatment cycles was 12. Investigators concluded that this could be a potential treatment option for patients with nonsquamous NSCLC with high PD-L1 expression.²¹

In a phase 1 study of the anti-TIGIT antibody tiragolumab plus atezolizumab in chemotherapy-naive patients with NSCLC and PD-L1–positive disease, ORR was found to be improved with this regimen. The prospective, randomized, double-blind, placebo-controlled CITYSCAPE trial (NCT03563716) looked at tiragolumab plus atezolizumab vs placebo in PD-L1–selected disease as first-line therapy in chemotherapy-naive patients with locally advanced or metastatic NSCLC without EGFR or ALK alterations. Patients were randomized 1:1 to receive tiragolumab plus atezolizumab (n = 67) or placebo (n = 68). The coprimary end points were investigator-assessed ORR and PFS. The ORR was 16.2% in the placebo group vs 31.3% in the tiragolumab-atezolizumab group; median PFS was 3.6 months vs 5.4 months, respectively. The toxicity profiles were similar between the groups, with TRAEs occurring in 72% of the placebo group and 80.6% in the tiragolumab-atezolizumab group. Tiragolumab added to atezolizumab showed clinically significant improvements in both ORR and PFS.²²

Stakeholder Insights: Tiragolumab is the next generation of therapy. Results from phase 3 trials, especially in high expressors of PD-L1, are highly anticipated.

Conclusions

With the approval of new agents and combination regimens in recent years, much progress has been made in the treatment of NSCLC. However, more advancements are still needed, especially in resistant patients who progress on immunotherapy. An emphasis on PD-L1 expressors is also needed for future research and development efforts.

The stakeholders noted that they are excited to delve more into the personalized immuno-oncology space through the recognition of both biomarkers and neoantigens. Although a wider variety of standard options is available, trials are still needed to understand how these agents compare against one another, as well as for novel combinations in the first-line space. Currently, treatment decisions should be based on patient preference and disease characteristics. Looking ahead, there is a need for agents that benefit patients who are not responding to therapies already in the space and to push toward the curative setting for NSCLC.

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