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Recent Reflections on Immuno-Oncology: Non-Small Cell Lung Cancer
The management of non-small cell lung cancer (NSCLC) evolved dramatically over the past decade, due to improvements in disease characterization and personalized therapy. In particular, immunotherapy has been a transformative innovation in lung cancer treatment, taking the form of antibodies designed to block immune checkpoints like the programmed cell death protein-1 (PD-1) and one of its ligands (PD-L1). At first, these antibodies were approved in the setting of relapsed, metastatic NSCLC after progression on or after platinum-based chemotherapy. Recently, long-term follow-up of studies like KEYNOTE-010 and CA209-003 continued to affirm the efficacy of single-agent checkpoint inhibitors in previously treated advanced disease.1,2 For example, the 3-year overall survival (OS) rate in KEYNOTE-010 was 23% in all patients with a PD-L1 tumor proportion score (TPS) ≥1%, and it was 35% in those patients with a PD-L1 TPS ≥50%.1 In patients who completed the full 35 cycles of pembrolizumab over 2 years, 95% achieved at least a partial response, and 64% of these responses persisted despite discontinuation of pembrolizumab.1 These findings demonstrate the potential to achieve long-term disease control in select patients with metastatic disease.
Highlights in single-agent immunotherapy for first-line metastatic nonsquamous NSCLC
To date, three PD-1 axis inhibitors have been approved in second-line metastatic NSCLC: nivolumab, pembrolizumab, and atezolizumab. Since then, a large portion of research has been devoted to exploring these agents in the first-line setting, either alone or in combination with chemotherapy-based regimens. In 2018, the field saw a surge of data for immunotherapy-based strategies, leading to new approvals and changes to standard practice across the treatment continuum for NSCLC.
Pembrolizumab remains the only PD-1 axis inhibitor to be approved as a monotherapy in the first-line metastatic disease setting, although this is restricted to patients who have a PD-L1 TPS ≥50%. This approval was based on findings from KEYNOTE-024, which demonstrated a significant improvement in median progression-free survival (PFS) over chemotherapy (pembrolizumab vs chemotherapy, 10.3 months vs 6.0 months, HR 0.50, P<.001).3 An updated analysis showed significant OS benefit for pembrolizumab as well (pembrolizumab vs chemotherapy, 30.0 months vs 14.2 months, HR 0.63, P = .002).4 These findings were confirmed in KEYNOTE-042, which allowed enrollment of a wider population of patients, including those with PD-L1 TPS ≥1%.5 Pembrolizumab was superior to chemotherapy in the entire TPS ≥1% population, but an exploratory analysis showed that the benefit was largely limited to patients whose PD-L1 expression exceeded 50% (overall survival, pembrolizumab vs chemotherapy, 20.0 months vs 12.2 months, HR 0.69, P = .0003), as opposed to those in the 1%-49% subgroup (pembrolizumab vs chemotherapy, 13.4 months vs 12.1 months, HR 0.92).5 These findings support the efficacy of first-line pembrolizumab in untreated, metastatic NSCLC, as well as the use of PD-L1 expression as a tool for patient selection.
MYSTIC was a randomized, phase III trial investigating the PD-L1 inhibitor durvalumab in patients with untreated, PD-L1–positive (≥25%) advanced NSCLC, either alone or in combination with the CTLA-4 antibody tremelimumab, compared with platinum-based chemotherapy.6 Findings from this study showed that durvalumab monotherapy improved OS compared with chemotherapy, but this improvement did not reach statistical significance (durvalumab vs chemotherapy, 16.3 months vs 12.9 months, HR 0.76, P = .036).6
Combinations continue to expand the reach of immune checkpoint inhibitors in first-line NSCLC
Conventional chemotherapy can elicit rapid tumor regression and release of antigens, potentially encouraging an immune response through several putative mechanisms.7 This observation has made the exploration of immunotherapy-chemotherapy combinations a high research priority. Data in 2018 offered critical insight into the role of these combinations for first-line treatment of metastatic NSCLC, both in nonsquamous and squamous cell histologies.
KEYNOTE-189 was a randomized, phase III study designed to confirm the findings from cohort G of KEYOTE-021, which demonstrated activity for the combination of pembrolizumab and platinum-based chemotherapy in previously untreated, advanced NSCLC, and led to an accelerated approval for this combination.8 Addition of pembrolizumab to platinum-based chemotherapy yielded a significant improvement in median OS compared with chemotherapy alone (not reached vs 11.3 months, HR 0.49, P<.00001).9 This benefit also extended to the patients with <1% PD-L1 staining.9 A follow-up analysis demonstrated that this OS benefit was present regardless of the specific platinum agent used in the chemotherapy backbone.10 Findings from KEYNOTE-189 led the United States Food and Drug Administration (US FDA) to convert the accelerated approval to a regular approval in August 2018.
The PD-L1 inhibitor atezolizumab has also been assessed as part of front-line therapy for advanced NSCLC in the IMpower150, 130, and 132 studies.11-14 IMpower150 examined carboplatin-paclitaxel, with or without atezolizumab and/or bevacizumab, in first-line metastatic NSCLC.11 The primary analysis presented at ASCO 2018 showed significant improvement in OS for atezolizumab-bevacizumab-carboplatin-paclitaxel compared with bevacizumab-carboplatin-paclitaxel (19.2 months vs 14.7 months, HR 0.78, P = .016), but not for atezolizumab-carboplatin-paclitaxel versus bevacizumab-carboplatin-paclitaxel (HR 0.88, P = .204).11 Interestingly, this quadruplet combination also appeared to improve survival in patients with EGFR/ALK mutations or liver metastases (HR 0.54 for each).11 These findings led to the approval of atezolizumab-bevacizumab-carboplatin-paclitaxel in the first-line treatment of metastatic, nonsquamous NSCLC in December 2018.
IMpower130 and 132 were both positive studies assessing combinations of atezolizumab and chemotherapy, without the addition of bevacizumab. In IMpower130, adding atezolizumab to albumin-bound paclitaxel (nab-paclitaxel) and carboplatin significantly improved PFS (median PFS, atezolizumab vs chemotherapy alone, 7.0 months vs 5.5 months, HR 0.64, P<.0001).12 A similar benefit was shown in IMpower132, which examined atezolizumab plus platinum-pemetrexed (median PFS, atezolizumab-chemotherapy vs chemotherapy, 7.6 months vs 5.2 months, HR 0.60, P<.0001), and interim analysis showed a trend toward improved median OS in the atezolizumab arm (atezolizumab-chemotherapy vs chemotherapy, 18.1 months vs 13.6 months, HR 0.81, P = .0797).13 A follow-up analysis of IMpower132 showed that the PFS benefit was observed regardless of smoking history, age (≥65 years vs <65 years), and Asian vs non-Asian race.14 However, the benefit of atezolizumab was not significant in patients with liver metastases (HR 0.77).14
The phase III CheckMate 227 study enrolled patients with either PD-L1–positive (TPS ≥1%) or PD-L1–negative stage IV or recurrent NSCLC. The first publication of results from this study focused on patients with a high tumor mutational burden (≥10 mutations/Mb), comparing nivolumab-ipilimumab to platinum-based chemotherapy.15 In this group, nivolumab-ipilimumab yielded a significant improvement in median PFS (7.2 months vs 5.5 months, HR 0.58, P<.001),15 even in the subgroup of patients with PD-L1 expression <1% (7.7 months vs 5.3 months, HR 0.48).16 This marked the first population of patients to achieve benefit with a chemotherapy-free immunotherapy regimen without PD-L1 selection.
Insights into immune-based combinations for squamous cell NSCLC
Squamous cell NSCLC has long been a challenging disease subgroup with few treatment options and poor outcomes. Several key phase III trials were presented in 2018 elucidating the role of chemotherapy-immunotherapy combinations in the first-line setting. KEYNOTE-407 assessed the addition of pembrolizumab to chemotherapy (carboplatin plus paclitaxel or nab-paclitaxel) in untreated, metastatic, squamous NSCLC.17 Adding pembrolizumab in this setting improved both median PFS (pembrolizumab-chemotherapy vs chemotherapy, 6.4 months vs 4.8 months, HR 0.56, P<.001) and OS (pembrolizumab-chemotherapy vs chemotherapy, 15.9 months vs 11.3 months, HR 0.64, P = .0008).17 This combination was approved for first-line squamous NSCLC in the US (October 2018) and European Union (EU, March 2019).
In IMpower131, patients were randomized to receive atezolizumab-chemotherapy (carboplatin plus nab-paclitaxel) or chemotherapy, and atezolizumab improved median PFS (atezolizumab-chemotherapy vs chemotherapy, 6.3 months vs 5.6 months, HR 0.71, P = .001).18 The first analysis did not show a difference in median OS (atezolizumab-chemotherapy vs chemotherapy, 14.0 months vs 13.9 months, HR 0.96, P = .69), but these data were not yet mature.18
Immunotherapy continues to move into earlier disease settings
The phase III PACIFIC trial was a landmark for the field of immunotherapy, as it was the first randomized study to demonstrate a benefit for immune checkpoint inhibition after definitive chemoradiation therapy in stage III NSCLC.19 This led to the approval of the PD-L1 antibody durvalumab after definitive chemoradiation therapy in this setting, and an update in 2018 established an OS benefit for consolidation durvalumab (durvalumab vs placebo, not reached vs 28.7 months, HR 0.68, P = .00251).20 An exploratory analysis of PACIFIC showed that the benefit from durvalumab was present regardless of PD-L1 status, although sample sizes were notably small in the PD-L1–negative cohort of patients.21 Pembrolizumab is also being tested in the consolidation therapy setting. Updated findings from the open-label, phase II LUN 14-179 at the 2018 World Congress on Lung Cancer continued to show impressive activity, with an 18-month PFS rate of 46.9%.22 Median OS was still not reached after a median follow-up of 23.9 months, and the 24-month OS rate was 61.5%.22
Reported findings from a pilot study have also spurred substantial interest in the use of checkpoint inhibitors in earlier stages of NSCLC.23 In this study, 22 patients with stage I, II, or IIIA NSCLC underwent neoadjuvant treatment with nivolumab, followed by resection.23 Of the 20 tumors with evaluable samples, 9 (45%) demonstrated a major pathologic response, defined as a postoperative sample with no more than 10% viable tumor cells.23 Consistent with these data, preliminary results from the phase II NEOSTAR study showed major pathologic response rate of 31% in patients receiving neoadjuvant nivolumab or nivolumab-ipilimumab.24 Another study assessing neoadjuvant atezolizumab demonstrated a 22% major pathologic response rate.25 Now, a variety of later-stage clinical studies are systematically evaluating immune checkpoint inhibitors in these earlier treatment settings, including moving PD-1/PD-L1 antibodies into neoadjuvant/adjuvant therapy for resectable NSCLC.26-32
2018 was an eventful year for NSCLC research. In particular, these findings demonstrated the feasibility and benefit of combining immunotherapy with chemotherapy regimens. It is now clear that using combination chemotherapy-immunotherapy can extend benefit to a wider range of patients with metastatic NSCLC, including those who do not express high levels of PD-L1. Important questions relating to overcoming resistance, optimal length of therapy, and patient selection continue to be explored, and upcoming data readouts should be enlightening.
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- Herbst RS, Garon EB, Kim D-W, et al. Long-term follow-up in the KEYNOTE-010 study of pembrolizumab for advanced NSCLC, including in patients who completed 2 years of pembrolizumab. Ann Oncol. 2018;29(suppl_10): Abstract LBA4.
- Gettinger S, Horn L, Jackman D, et al. Five-year follow-up of nivolumab in previously treated advanced non–small-cell lung cancer: Results from the CA209-003 study. J Clin Oncol. 2018;36(17):1675-1684.
- Reck M, Rodríguez-Abreu D, Robinson AG, et al; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823-1833.
- Reck M, Rodríguez-Abreu D, Robinson AG, et al. Updated analysis of KEYNOTE-024: Pembrolizumab versus platinum-based chemotherapy for advanced non–small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019;37(7):537-546.
- Lopes G, Wu Y-L, Kudaba I, et al. Pembrolizumab versus platinum-based chemotherapy as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: Open-label, phase 3 KEYNOTE-042 study. J Clin Oncol. 2018;36(suppl): Abstract LBA4.
- Rizvi NA, Cho B-C, Reinmuth N, et al. Durvalumab with or without tremelimumab vs platinum-based chemotherapy as first-line treatment for metastatic non-small cell lung cancer: MYSTIC. Ann Oncol. 2018;29(suppl_10): Abstract LBA6.
- Melero I, Berman DM, Aznar MA, Korman AJ, Pérez Gracia JL, Haanen J. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat Rev Cancer. 2015;15(8):457-472.
- Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: A randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17(11):1497-1508.
- Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092.
- Rodriguez-Abreu D, Garassino MC, Esteban E, et al. KEYNOTE-189 study of pembrolizumab (Pembro) plus pemetrexed (Pem) and platinum vs placebo plus pem and platinum for untreated, metastatic, nonsquamous NSCLC: Does choice of platinum affect outcomes? Ann Oncol. 2018;29(suppl_8): Abstract 1464P.
- Socinski MA, Jotte RM, Cappuzzo F, et al. Overall survival (OS) analysis of IMpower150, a randomized Ph 3 study of atezolizumab (atezo) + chemotherapy (chemo) ± bevacizumab (bev) vs chemo + bev in 1L nonsquamous (NSQ) NSCLC. J Clin Oncol. 2018;36(suppl): Abstract 9002.
- Cappuzzo F, McCleod MJ, Hussein MA, et al. IMpower130: Progression-free survival and safety analysis from a randomised phase III Study of carboplatin + nab-paclitaxel with or without atezolizumab as first-line (1L) therapy in advanced non-squamous NSCLC. Ann Oncol. 2018;29(suppl_8): Abstract LBA53.
- Papadimitrakopoulou V, Cobo M, Bordoni RE, et al. IMpower132: PFS and safety results with 1L atezolizumab + carboplatin/cisplatin + pemetrexed in stage IV non-squamous NSCLC. J Thorac Oncol. 2018;13(10_suppl): Abstract OA05.07.
- Barlesi F, Nishio M, Cobo M, et al. IMpower132: Efficacy of atezolizumab (atezo) + carboplatin (carbo)/cisplatin (cis) + pemetrexed (pem) as 1L treatment in key subgroups with stage IV non-squamous non-small cell lung cancer (NSCLC). Ann Oncol. 2018;29(suppl_8): Abstract LBA54.
- Hellmann MD, Ciuleanu T-E, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J 2018;378(22):2093-2104.
- Borghaei H, Hellman MD, Paz-Ares LG, et al. Nivolumab (Nivo) + platinum-doublet chemotherapy (Chemo) vs chemo as first-line (1L) treatment (Tx) for advanced non-small cell lung cancer (NSCLC) with <1% tumor PD-L1 expression: Results from CheckMate 227. J Clin Oncol. 2018;36(suppl): Abstract 9001.
- Paz-Ares L, Luft A, Vicente D, et al; KEYNOTE-407 Investigators. Pembrolizumab plus chemotherapy for squamous non–small-cell lung cancer. N Engl J Med. 2018;379(21):2040-2051.
- Jotte RM, Cappuzzo F, Vynnychenko I, et al. IMpower131: Primary PFS and safety analysis of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC. J Clin Oncol. 2018;36(suppl): Abstract LBA9000.
- Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377(20):1919-1929.
- Antonia SJ, Villegas AE, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379(24):2342-2350.
- Faivre-Finn C, Spigel DR, Senan S, et al. Efficacy and safety evaluation based on time from completion of radiotherapy to randomization with durvalumab or placebo in patients from PACIFIC. Ann Oncol. 2018;29(suppl_10): Abstract 1363O.
- Durm G, Althouse S, Sadiq A, et al. Updated results of a phase II trial of concurrent chemoradiation with consolidation pembrolizumab in patients with unresectable stage III NSCLC. J Thorac Oncol. 2018;13(10_suppl): Abstract OA01.07.
- Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med. 2018;378(21):1976-1986.
- Cascone T, William W, Weissferdt A, et al. Neoadjuvant nivolumab (N) or nivolumab plus ipilimumab (NI) for resectable non-small cell lung cancer. Ann Oncol. 2018;29(suppl_8): Abstract LBA49.
- Rusch VW, Chaft JE, Johnson B, et al. Neoadjuvant atezolizumab in resectable non-small cell lung cancer (NSCLC): Initial results from a multicenter study (LCMC3). J Clin Oncol. 2018;36(suppl): Abstract 8541.
- National Institutes of Health. A randomized, phase 3 trial with anti-PD-1 monoclonal antibody pembrolizumab (MK-3475) versus placebo for patients with early stage NSCLC after resection and completion of standard adjuvant therapy (PEARLS). https://clinicaltrials.gov/ct2/show/NCT02504372. Accessed March 18, 2019.
- National Institutes of Health. A phase III, open-label, randomized study to investigate the efficacy and safety of atezolizumab (anti-PD-L1 antibody) compared with best supportive care following adjuvant cisplatin-based chemotherapy in patients with completely resected stage IB-IIIA non-small cell lung cancer. https://clinicaltrials.gov/ct2/show/NCT02486718. Accessed on March 18, 2019.
- National Institutes of Health. A phase III, double-blinded, multicenter, randomized study evaluating the efficacy and safety of neoadjuvant treatment with atezolizumab or placebo in combination with platinum-based chemotherapy in patients with resectable stage II, IIIA, or select IIIB non−small cell lung cancer. https://clinicaltrials.gov/ct2/show/NCT03456063. Accessed March 18, 2019.
- National Institutes of Health. Randomized, openlabel, phase 3 trial of nivolumab plus ipilimumab or nivolumab plus platinum doublet chemotherapy versus platinum doublet chemotherapy in early stage NSCLC. https://clinicaltrials.gov/ct2/show/NCT02998528. Accessed March 18, 2019.
- National Institutes of Health. A phase III, randomized, double-blind trial of platinum doublet chemotherapy +/-pembrolizumab (MK-3475) as neoadjuvant/adjuvant therapy for participants with resectable stage IIB or IIIA non-small cell lung cancer (NSCLC) (KEYNOTE-671). https://clinicaltrials.gov/ct2/show/NCT03425643. Accessed March 18, 2019.
- National Institutes of Health. Adjuvant nivolumab in resected lung cancers (ANVIL) – A randomized phase III study of nivolumab after surgical resection and adjuvant chemotherapy in non-small cell lung cancers. https://clinicaltrials.gov/ct2/show/NCT02595944. Accessed March 18, 2019.
- National Institutes of Health. A phase III prospective double blind placebo controlled randomized study of adjuvant MEDI4736 in completely resected non-small cell lung cancer. https://clinicaltrials.gov/ct2/show/NCT02273375. Accessed March 18, 2019.
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Recent Reflections on Immuno-Oncology: Non-Small Cell Lung Cancer
This educational activity is designed to meet the needs of medical oncologists and other healthcare professionals involved in the treatment of patients with lung cancer, bladder cancer, and melanoma.
After successful completion of this educational activity, participants should be able to:
- Evaluate clinical trial data assessing the efficacy and safety of immune checkpoint inhibitors for the management of patients with solid tumors
- Develop optimal treatment plans utilizing immune checkpoint inhibitors for the treatment of solid tumors
- Assess the rationale for using immune checkpoint inhibitors, alone, and in combination with chemotherapy or other novel agents, for the treatment of solid tumors
- Formulate treatment plans to manage immune-related adverse events associated with the treatment with immune checkpoint inhibitors
This educational activity is supported by a grant from Merck Sharp and Dohme Corp.
In support of improving patient care, this activity has been planned and implemented by the Postgraduate Institute for Medicine and prIME Oncology. Postgraduate Institute for Medicine is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
The Postgraduate Institute for Medicine designates this enduring material for a maximum of 1.75 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Lung newsletter: 0.5
Bladder newsletter: 0.75
Melanoma newsletter: 0.5
This activity is jointly provided by Postgraduate Institute for Medicine and prIME Oncology.
Method of Participation
Estimated time to complete activity: 1.75 hours
To contact Postgraduate Institute for Medicine please visit www.pimed.com.
Disclosure of Relevant Financial Relationships
Postgraduate Institute for Medicine (PIM) and prIME Oncology require instructors, planners, managers, and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to PIM policy. PIM is committed to providing its learners with high quality activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest.
Postgraduate Institute for Medicine Planners and Managers have disclosed no relevant financial relationships.
The employees of prIME Oncology have disclosed:
- Briana Betz, PhD (scientific content reviewer/planner) –(scientific content reviewer/planner) – worked on non–CME certified projects in the last 12 months supported by Helsinn Healthcare, ImmunoGen, Karyopharm Therapeutics, Novartis, Pfizer, and TG Therapeutics
- Zach Hartman, PhD (author) – no relevant financial relationships
- Heather Tomlinson, ELS (editorial content reviewer) – worked on non–CME certified projects in the last 12 months supported by AstraZeneca, Clovis Oncology; F. Hoffmann-La Roche Ltd; ImmunoGen; Merck KGaA, Darmstadt, Germany; Pfizer; Novartis Oncology; Puma Biotechnology; and Tesaro
Disclosure Regarding Unlabeled Use
This activity may contain discussion of published and/or investigational uses of agents that are not indicated by the US Food and Drug Administration or European Medicines Agency. Please refer to the official prescribing information for each product discussed for discussions of approved indications, contraindications, and warnings.
Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.