Many patients with non–small cell lung cancer (NSCLC) have metastatic disease,¹ and for these patients, improved treatment modalities represent an ongoing unmet need. The good news is that clinical trials, as well as clinical experience, with nivolumab (Opdivo^R) in patients with NSCLC continue to yield important results.

Nivolumab is currently one of three immune checkpoint inhibitors (the others are pembrolizumab and atezolizumab) with a category 1 recommendation (preferred for all three) as second-line therapy in the NCCN Clinical Practice Guidelines in Oncology for NSCLC, after disease progression on first-line chemotherapy with or without bevacizumab.² Results announced at the 2019 World Conference on Lung Cancer indicate that patients treated with second-line nivolumab therapy realized a greater than fivefold increase in 5-year overall survival rate compared with those who received docetaxel.³ Second-line nivolumab monotherapy for patients with metastatic NSCLC was generally well tolerated, with promising antitumor activity and a manageable safety profile.

CheckMate 057 and 017: Second-Line Nivolumab

According to study investigator Scott Gettinger, MD, of Yale Comprehensive Cancer Center, New Haven, Connecticut, “CheckMate 057 and 017 are the first phase III trials to report 5-year outcomes for a PD-1 [programmed cell death protein 1] inhibitor in previously treated advanced NSCLC, showing a greater than fivefold increase in 5-year overall survival rates with nivolumab (13.4%) compared with docetaxel (2.6%). Nivolumab remained well tolerated with no new safety signals.”³

Both the CheckMate 057 and 017 trials compared 3 mg/kg of nivolumab every 2 weeks with 75 mg/m² of docetaxel every 3 weeks among patients with previously treated stage IIIB/stage IV NSCLC and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1; most patients had stage IV disease.^3-5 Treatment continued until disease progression or unacceptable toxicity. CheckMate 057 included 582 patients with nonsquamous NSCLC⁴; CheckMate 017 included 272 patients with squamous cell NSCLC.⁵

CheckMate 227: First-Line Nivolumab Plus Ipilimumab

Results from the phase III CheckMate 227 trial reported at the 2019 European Society for Medical Oncology (ESMO) Congress in Barcelona⁶ generated a good deal of interest. According to Solange Peters, MD, PhD, of the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, who presented the data, the combination of nivolumab and low-dose ipilimumab improved overall survival in some patients with untreated advanced NSCLC compared with chemotherapy. The report of this study was simultaneously published in The New England Journal of Medicine.⁷

Among patients with PD-L1 (programmed cell death ligand 1) expression of ≥ 1%, the median overall survival was 17.1 months (95% confidence interval [CI], = 15.0–20.1 months) in the nivolumab/ipilimumab group versus 14.9 months (95% CI = 12.7–16.7 months) in the chemotherapy group (hazard ratio [HR] = 0.79 [0.65–0.96]; P = .007). Among patients with PD-L1 expression < 1%, the median overall survival was 17.2 months (95% CI = 12.8–22.0 months) versus 12.2 months (95% CI = 9.2–14.3 months; HR = 0.62 [95% CI = 0.49–0.79]). Among all patients, the median overall survival was 17.1 months (95% CI = 15.2–19.9 months) versus 13.9 months (95% CI = 12.2–15.1 months; HR = 0.73 [95% CI = 0.64–0.84]).

Treatment-related grade 3 to 4 adverse events were observed in 32.8% of those who received nivolumab/ipilimumab compared with 36.0% of those given chemotherapy. Treatment-related serious adverse events of any grade were observed in 24.5% versus 13.9%, respectively, and treatment-related adverse events led to treatment discontinuation in 18.1% versus 9.1%. The most common treatment-related immune-related adverse events of any grade in the nivolumab/ipilimumab group were skin reactions (34.0%) and endocrine events (23.8%). Treatment-related death occurred in eight patients in the nivolumab/ipilimumab group and six patients in the chemotherapy group.

CheckMate 817

The results of the CheckMate 817 study likewise offered interesting news for patients with advanced NSCLC. The data were presented at the 2019 Hematology/Oncology Pharmacy Association Annual Conference in Dallas.⁸

According to Fabrice Barlesi, MD, PhD, of Aix-Marseille University, Assistance Publique Hôpitaux de Marseille, France, the lead presenter of Checkmate 817 at the 2019 World Conference on Lung Cancer, this special population of patients included those with a poor ECOG performance status, asymptomatic untreated brain metastases, hepatic or renal impairment, or HIV infection.⁹ “First-line flat-dose nivolumab plus weight-based ipilimumab showed a consistent safety profile in special populations with advanced NSCLC, including those with an ECOG performance status of 2,” noted Dr. Barlesi.⁹ “Patients with either high tumor mutational burden or higher tumor PD-L1 expression appeared to exhibit improved efficacy.”

NEOSTAR: Neoadjuvant Nivolumab or Nivolumab Plus Ipilimumab

The phase II NEOSTAR trial reported findings with neoadjuvant nivolumab or the combination of nivolumab and ipilimumab for patients with stage I to IIIA resectable NSCLC.¹⁰ Overall, a 24% major pathologic response rate with neoadjuvant immune checkpoint inhibitors was observed. Of interest, antitumor activity was associated with higher pretreatment PD-L1 levels.

Nivolumab and CIMAvax-EGF

In another study, the Cuban-developed immunotherapy CIMAvax-EGF, in combination with nivolumab, appeared to be safe as second-line therapy for patients with advanced NSCLC, according to results from the first portion of a phase I/II trial (ClinicalTrials.gov identifier NCT02955290).¹¹ The combination also showed better effectiveness than either agent alone. “Although this is a small study and we will need to verify that these conclusions hold true when we move on to our phase II study, these early hints of clinical activity encourage us to continue exploring this combination approach,” commented study investigator Grace Dy, MD, of Roswell Park Comprehensive Cancer Center, Buffalo, New York.¹¹

Talking With Patients About the Likelihood of Benefit

With all the news surrounding nivolumab, both as a single agent or in combination, clinicians should consider some caveats, particularly in regard to biomarker testing. The complexity of the immune response has thus far hindered efforts to identify which patients would be most likely to respond well to nivolumab.

Hossein Borghaei, DO, MS, of Fox Chase Cancer Center in Philadelphia, emphasized that how to frame those test results for patients represents an important challenge in communication. “When patients [with adenocarcinoma] are known to have no PD-L1 or very low levels, we need to explain that the chance of benefit with nivolumab is lower and that we will perform a CT scan in 6 to 8 weeks to make a preliminary assessment.”¹²

For clinicians, if there is a question about whether something on imaging represents pseudoprogression versus real disease progression, checking back to the PD-L1 levels at baseline will provide another clue about the likelihood of real response.¹² The phenomenon of pseudoprogression may be due to peritumoral lymphocyte infiltration or delayed immune activity.

“We try to paint as clear a picture as we can for patients with any new treatment. And we talk about what’s next if the therapy doesn’t work,” noted Dr. Borghaei. In addition to transparency and a candid assessment of the likelihood of benefit, Dr. Borghaei suggested that patients with little or no PD-L1 expression consider a clinical trial exploring a combination of agents.¹²

Managing Side Effects

Because nivolumab is an immune checkpoint inhibitor that works by enhancing the patient’s immune system, most adverse reactions associated with nivolumab are related to overactivity of the patient’s immune system (ie, immune-related adverse events). Nivolumab-related immune-related adverse events may occur at any time, including after treatment completion or discontinuation. Various organ systems (often more than one) or tissues may be affected, commented Sumit Subudhi, MD, PhD, of MD Anderson Cancer Center, Houston. “We don’t know for sure which patients are more likely to experience these side effects, but side effects don’t tend to be related to the cancer type,” Dr. Subudhi noted. “Instead, they’re more often tied to the type of immunotherapy the patient receives.”¹³

In the case of diarrhea, for example, Dr. Subudhi focuses on behavioral changes first. “An antidiarrheal medication can cause life-threatening complications, so we first try diet modifications, such as limiting dairy,” he emphasized. But if the side effect is severe, other medications may help. “We’ll pause the immunotherapy and prescribe an immunosuppressant, such as an oral steroid, to help ‘cool off’ the inflammation to a safer level. The ultimate goal is to cut down on these medications as quickly as possible, so the patient can resume immunotherapy.”¹³

Pneumonitis is another serious immune-related adverse event and is of major concern in patients with lung cancer who may already have poor lung reserve due to prior smoking or metastatic lung disease. Clinicians should be familiar with how to manage immune-related adverse events.¹⁴

The presence—or lack thereof—of a side effect does not indicate that the drug is working or not. “I want patients to know that it’s OK to feel well on these drugs,” Dr. Subudhi commented. “Patients are often so used to feeling sick while on treatment that if they feel OK, they sometimes think they’re taking a placebo or that it’s not working, but that’s not the case.”¹³

A report from researchers at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore has shown improvement in 5-year survival for people with several types of advanced cancer who are treated with multiple doses of nivolumab. Nivolumab treatment was associated with long-term survival in a subset of heavily pretreated patients with advanced melanoma, renal cell carcinoma, or NSCLC. Characterizing the factors associated with long-term survival may inform treatment approaches and strategies for future clinical trial development.¹⁵

“A particular and perhaps unexpected finding of the new study was that patients who experienced side effects from nivolumab treatment survived significantly longer than those who did not,” said study author Suzanne Topalian, MD, of the Bloomberg Kimmel Institute for Cancer Immunotherapy. “The real issue is whether we can devise treatments to manage these side effects that will not interfere at all with the antitumor immune response,” she added.¹⁵

The study by Dr. Topalian and colleagues was a secondary analysis of the CA209-003 trial (ClinicalTrials.gov identifier NCT00730639).¹⁵ The objective response rate (complete and partial responses) to nivolumab treatment was 31.8% for patients with melanoma (34 of 107 patients), 29.4% for those with renal cell carcinoma (10 of 34 patients), and 17.1% for patients with NSCLC (22 of 129 patients). The median overall survival was 20.3 months for patients with melanoma, 22.4 months for patients with renal cell carcinoma, and 9.9 months for patients with NSCLC. Among on-treatment measures, an association between objective tumor regression (complete and partial responses) and 5-year overall survival and between a greater percent reduction in total tumor burden and increased long-term survival was found. These findings favor the general assumption that objective tumor regression provides an early surrogate for long-term clinical benefit.

Notable Precautions

When nivolumab is administered in combination with ipilimumab, clinicians should refer to the Summary of Product Characteristics for ipilimumab before starting treatment. Immune-related adverse reactions have occurred at higher frequencies when nivolumab was administered in combination with ipilimumab compared with nivolumab as monotherapy.

It is important to note that ethnic/racial differences may affect risk/benefit profiles and dosing regimens of medications.¹⁶ Intrinsic factors, such as genetic and physiologic characteristics, and extrinsic factors, such as culture and environment, may ultimately contribute to differences in drug exposures and therefore the efficacy and/or safety in distinct ethnic/racial groups.¹⁶

Such differences must be considered when establishing prescribing information for patients in different geographic regions.

Another factor to consider in relationship to race is body weight. Although race largely relates to intrinsic factors, which can affect drug metabolism, lower body weight may lead to decreased clearance and, therefore, greater drug exposure.¹⁶ Body weight is particularly relevant for Asian patients, including Chinese patients, who may have a lower mean body weight than members of non‐Asian races, especially when using a fixed dose of a therapeutic agent.

References

1. Chen S, Hu B, Li H. A meta-analysis of nivolumab for the treatment of advanced non–small-cell lung cancer. Onco Targets Ther 2018;11:7691–7697.
2. Ettinger DA, Wood, DE, Aggarwal C, et al. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version 7.2019. Accessed October 7, 2019. To view the most recent version of these guidelines, visit https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.
3. Patients Taking Nivolumab Experience Five-Fold Increase in Overall Survival Compared to Chemotherapy. International Association for the Study of Lung Cancer press release. Available at https://www.iaslc.org/About-IASLC/News-Detail/patients-taking-nivolumab-experience-five-fold-increase-in-overall-survival-compared-to-chemotherapy. Accessed October 3, 2019.
4. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015;373:1627–1639.
5. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015;373:123–135.
6. Peters S, Ramalingam SS, Paz-Ares L, et al. Nivolumab + low-dose ipilimumab vs platinum-doublet chemotherapy as first-line treatment for advanced non-small cell lung cancer: CheckMate 227 part 1 final analysis. Ann Oncol 2019;30(suppl 5):LBA4_PR. Abstract.
7. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med. September 28, 2019. [Epub ahead of print]
8. Paz-Ares L. Flat-dose nivolumab dosing in first-line treatment of NSCLC. 2019 Hematology/Oncology Pharmacy Association Annual Conference. Poster CR004. Available at http://www.hoparx.org/conference-events/annual-conference/. Accessed October 3, 2019.
9. Barlesi F, Audigier-Valette C, Felip E, et al. CheckMate 817: first-line nivolumab + ipilimumab in patients with ECOG PS 2 and other special populations with advanced NSCLC. Abstract OA04.02. 2019 World Conference on Lung Cancer. Available at https://library.iaslc.org/virtual-library-search?product_id=15&author=&category=&date=&session_type=&session=&presentation=PL02.09&keyword=. Accessed October 3, 2019.
10. Cascone T, William WN, Weissferdt A, et al. Neoadjuvant nivolumab or nivolumab plus ipilimumab for resectable non-small cell lung cancer: clinical and correlative results from the NEOSTAR study. J Clin Oncol 2019;37(15 suppl):8504. Abstract.
11. CIMAvax-nivolumab combination appears safe, demonstrates ‘good signals’ in advanced lung cancer. Healio. Available at https://www.healio.com/hematology-oncology/lung-cancer/news/online/%7Be0a64b30-ae01-4c42-ad09-c3fee1485743%7D/cimavax-nivolumab-combination-appears-safe-demonstrates-good-signals-in-advanced-lung-cancer. Accessed October 3, 2019.
12. Borghaei H, Brahmer JR, Horn L, et al. Nivolumab vs docetaxel in patients with advanced NSCLC: CheckMate 017/057 2-year update and exploratory cytokine profile analyses. J Clin Oncol 2016;34(15 suppl):9025. Abstract.
13. Carter D. Immunotherapy side effects: what to know. MD Anderson Cancer Center. October 4, 2018. Available at https://www.mdanderson.org/publications/cancerwise/immunotherapy-side-effects--what-to-know.h00-159228090.html. Accessed October 3, 2019.
14. Thompson JA, Schneider BJ, Brahmer J, et al. NCCN Clinical Practice Guidelines in Oncology: Management of Immunotherapy-Related Toxicities. Version 2.2019. Accessed October 28, 2019. To view the most recent version, visit NCCN.org.
15. Topalian SL, Hodi FS, Brahmer JR, et al. Five-year survival and correlates among patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer treated with nivolumab. JAMA Oncol. July 25, 2019. [Epub ahead of print]
16. Zhang J, Cai J, Bello A, et al. Model‐based population pharmacokinetic analysis of nivolumab in Chinese patients with previously treated advanced solid tumors, including non-small cell lung cancer. J Clin Pharmacol 2019;59:1415–1424.

Commentary by NSCLC Site Editor for JNCCN 360

David S. Ettinger, MD

Alex Grass Professor of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore

The most important of the updates on nivolumab since the 2017 JNCCN 360 Spotlight is the report of Checkmate 227, presented at the ESMO meeting in Barcelona in September 2019. It demonstrated that the first-line combination of nivolumab and ipilimumab is superior to chemotherapy in the treatment of metastatic NSCLC, whether PD-L1 expression was < 1% or ≥ 1%. The primary endpoint was overall survival. At 2 years, the overall survival in those with tumor PD-L1 expression ≥ 1% was 40% for immunotherapy versus 33% for chemotherapy, with a median overall survival of 17.1 months versus 14.9 months. Surprisingly, the results were better if PD-L1 expression was < 1%. Serious grade 3 to 4 adverse events occurred in 32.8% of patients receiving nivolumab and ipilimumab versus 36.0% of patients receiving chemotherapy alone.

Solange Peters, MD, PhD, who presented the data, said these findings are “practice changing,” but more time is needed to determine whether the regimen offers long-term survival with a good quality of life. In addition, the increase in immunotherapy toxicities associated with the combination is of concern. It should also be noted that the overall response rate with immunotherapy was 35.9% (5.8% complete responses) in those with tumor PD-L1 expression ≥ 1%, whereas the response rate was 44.4% (8.8% complete responses) in a subgroup analysis of those with tumor PD-L1 expression ≥ 50%. This overall response rate is similar to what we see with pembrolizumab monotherapy in patients with PD-L1 expression scores of ≥ 50%.

When the nivolumab plus ipilimumab combination is approved, we will have two immunotherapy regimens available for the first-line treatment of metastatic NSCLC: pembrolizumab plus or minus chemotherapy, depending on the tumor PD-L1 expression score, and nivolumab plus ipilimumab without chemotherapy. If the patient has a PD-L1 expression score of ≥ 50%, for example, we might consider using pembrolizumab plus chemotherapy, which is associated with a higher overall response rate compared with nivolumab plus ipilimumab. In contrast, if a patient does not have many symptoms, we might consider using immunotherapy alone, either single-agent pembrolizumab or nivolumab plus ipilimumab. Other factors to be considered include the toxicity profile of the selected regimen and the costs.

Disclosures

Dr. Ettinger has received clinical research support/data safety monitoring board support from Golden Biotechnology and has served on a scientific advisory board or as a consultant or expert witness for AbbVie, BeyondSpring Pharmaceuticals, Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Genentech, Inc., and Guardant Health, Inc.