Are all PD-1 Monoclonal Antibodies Equally Efficacious in Advanced NSCLC? A Summary of the Debate between Dr. Penelope Bradbury and Dr. Paul Wheatley-Price at CLCCO 2018

At the 2018 Canadian Lung Cancer Conference (CLCCO), Dr. Penelope Bradbury, Medical Oncologist at the Princess Margaret Cancer Centre and Mount Sinai Hospital in Toronto, and Dr. Paul Wheatley-Price, Medical Oncologist at the Ottawa Hospital Cancer Centre in Ottawa, debated whether the efficacy of all monoclonal antibodies targeting the programmed death-1 (PD-1) receptor are equally efficacious for the treatment of advanced non-small cell lung cancer (NSCLC). Dr. Bradbury defended that they are indeed equally efficacious, while Dr. Wheatley-Price argued that they were not. Audience voting determined the winner of this light-hearted discussion. This article summarizes the two arguments and concludes with the results of the audience vote.

Are all PD-1 Monoclonal Antibodies Equally Efficacious in Advanced NSCLC? Yes!

Dr. Penelope Bradbury

Dr. Penelope Bradbury began the debate by emphasizing that the question at hand was not regarding programmed death-ligand 1 (PD-L1) testing, clinical trial design, or drug approvals, but rather, a question of comparing the efficacy of PD-1 monoclonal antibodies, such as nivolumab and pembrolizumab, and making sure that we are comparing ‘apples to apples’ when looking at the data.

In the first-line setting, the phase III KEYNOTE-024 study investigated the efficacy of single-agent pembrolizumab versus platinum-doublet chemotherapy in patients with stage IV NSCLC who had a PD-L1 tumour proportion score (TPS) of at least 50%.1 Although this was an excellent trial showing improved overall survival (OS) for pembrolizumab over chemotherapy (median OS: 30.0 months vs. 14.2 months), Dr. Bradbury argued that the lack of an appropriate comparator in this trial indicates that we are not comparing ‘apples to apples’ and suggests that this trial is not relevant to the question being asked. The phase III CheckMate 026 trial, a more inclusive trial enrolling patients with untreated stage IV or recurrent NSCLC who had a PD-L1 TPS of at least 1%, did not show a progression-free survival (PFS) advantage for nivolumab over investigator’s choice of chemotherapy.2 However, similar to KEYNOTE-024, lack of an appropriate comparator in CheckMate 026 dismisses this trial from the discussion. Likewise, the phase III KEYNOTE-021 trial assessing pemetrexed carboplatin with or without the addition of pembrolizumab in patients with non-squamous stage IIIb/IV NSCLC would also not be relevant.3

Dr. Bradbury chose to focus on a paper written by faculty at Cambridge University, which compared the structural properties of both nivolumab and pembrolizumab.4 This paper highlighted the similarity between the two anti–PD-1 monoclonal antibodies in terms of total buried surface of epitopes, antibody affinity, and glucose modifications. (Table 1) The authors concluded that given the available molecular, preclinical, and early clinical data on nivolumab and pembrolizumab, these drugs may be interchangeable, and that disparity in clinical trial results is likely to be explained by drug-independent factors, such as trial design and patient selection. Based on the findings of this paper and the inability to compare results from first-line trials in advanced NSCLC, Dr. Bradbury concluded that there were no data to support that anti–PD-1 monocloncal antibodies were not equally efficacious in this setting.

Beyond first-line therapy, an opportunity to compare ‘apples to apples’ is available through the CheckMate 017 and 057 trials comparing nivolumab to docetaxel in the second-line setting for advanced NSCLC5,6 and the KEYNOTE-010 trial comparing pembrolizumab to docetaxel in patients with advanced NSCLC who progressed following at least one line of chemotherapy.7 Upon comparison of these three trials, Dr. Bradbury highlighted the similarity between response rates (range: 18%–20%) and OS results, with the median OS for nivolumab or pembrolizumab ranging 9–12.7 months, and hazard ratios between 0.59 and 0.73 favouring treatment with these anti–PD-1 antibodies over docetaxel. (Table 2) Taking into consideration the selection for patients with ≥1% PD-L1 expression in the KEYNOTE-010 trial, an evaluation of patients with ≥1% PD-L1 expression from the CheckMate 057 trial (supplementary data) still showed similar OS results (median OS: 17.7 months, HR = 0.58). (Table 2)

The notion that both nivolumab and pembrolizumab are equally efficacious in advanced NSCLC is supported by both the European Medicines Agency and the American Society of Clinical Oncology, which declare an equally strong recommendation for both pembrolizumab and nivolumab treatment in this setting.8,9 To conclude the “yes” side of the debate, Dr. Bradbury cheekily exposed her opponent, Dr. Paul Wheatley-Price, by highlighting a manuscript he had authored which equally recommended both pembrolizumab and nivolumab as second-line therapy options for patients with advanced NSCLC progressing after first-line platinum doublet therapy.10

Table 1. Comparison of the structural properties of nivolumab and pembrolizumab

Table 2. Comparison of phase III clinical trial results of nivolumab and pembrolizumab in second-line therapy for advanced NSCLC

 

Are all PD-1 Monoclonal Antibodies Equally Efficacious in Advanced NSCLC? No!

Dr. Paul Wheatley-Price

dr-wheatleyAfter sharing the commonalities between himself and Dr. Bradbury with a series of jokes he hoped would sway the audience, Dr. Wheatley-Price opened his side of the debate by telling a cautionary tale of comparing drugs, using breast cancer treatment as an example. He explained that trying to find minute differences in the efficacy of the aromatase inhibitors letrazole, anastrazole, and exemestane was time consuming and frustrating for both the pharmaceutical industry and physicians. Rather than following down that same path with anti–PD-1 monoclonal antibodies, it would be more helpful to concentrate on the big picture instead of the data.

The focus of Dr. Wheatley-Price’s argument was that a patient can only benefit from a drug if they can receive the drug, and from an access perspective, there are huge differences between the anti–PD-1 monoclonal antibodies. In terms of regulatory approval in Canada, nivolumab and pembrolizumab are currently the only PD-1 monoclonal antibodies that have been approved by Health Canada for NSCLC.11,12 They have both completed the entire process of gaining a positive recommendation by the pan-Canadian Oncology Drug Review (pCODR), as well as price negotiations with the pan-Canadian Pharmaceutical Alliance. (Table 3)

In terms of access, pembrolizumab is available in the first line for patients with NSCLC with PD-L1 expression ≥50% based on positive results from the KEYNOTE-024 study.1 Although there may be many explanations for the negative results reported in the CheckMate 026 study,2 Dr. Wheatley-Price emphasized that because of these negative results, nivolumab is not available for first-line treatment in NSCLC which impacts benefit to the patients.

There are several other ongoing phase III trials investigating PD-1 monoclonal antibodies in the first-line setting for advanced NSCLC. (Table 4) Of these studies, recent press releases have been published for the IMPower 150 (atezolizumab plus bevacizumab and chemotherapy versus bevacizumab and chemotherapy), KEYNOTE-189 (pembrolizumab plus pemetrexed and platinum chemotherapy versus pemetrexed and platinum chemotherapy alone), CheckMate 227 (nivolumab and ipilimumab versus chemotherapy), and MYSTIC (durvalumab versus durvalumab and tremelimumab versus platinum-based standard of care) trials.1316 Dr. Wheatley-Price stressed that the differences in terms of patients benefitting from these PD-1 monoclonal antibodies will not only come from the results of these trials, but where pharmaceutical companies choose to position their product and get through the regulatory minefield. It will also be important how physicians engage with regulatory authorities and ask for more data, so they can make clearer decisions.

In the second line, nivolumab and pembrolizumab are currently available to Canadians with advanced NSCLC11,12 and selection of these drugs is influenced by PD-L1 testing. Nivolumab is the only PD-1 monoclonal antibody with an indication in the PD-L1 negative or untested population, which may favour the administration of this drug over pembrolizumab in the second-line setting.

Upcoming in second-line therapy, atezolizumab is seeking an indication in this setting with a more favourable administration schedule than nivolumab (intravenous infusion every three weeks vs. every two weeks), which Dr. Wheatley-Price believes will be better for busy chemotherapy units. In the future, intravenous infusion of nivolumab (or even durvalumab) may be available on a dosing schedule of every four weeks which may be even more preferable.

Dr. Wheatley-Price also chose to highlight the results from the PACIFIC trial in patients with stage III NSCLC, where durvalumab was shown to triple PFS compared to placebo following concurrent chemoradiation therapy.17 Although there are several other trials ongoing in this setting, he believes the results from this trial will have a greater impact on patient benefit as patients will likely gain access to durvalumab in this setting based on these positive results.

To conclude his side of the debate, Dr. Wheatley-Price spoke of the explosion of safe and effective drugs for patients with NSCLC in the last 2 to 3 years, which ultimately makes patients the winners, regardless of the differences or similarities of the drugs. Having 15%–20% of stage IV lung cancer patients living five years due to the benefit of immunotherapy and being able to avoid chemotherapy in the first-line setting (despite some of the caveats to this approach) shows remarkable progress in the field, and he believes it is the most important take-away from this debate.

Table 3. Canadian regulatory approval status of anti–PD-1 monoclonal antibodies in NSCLC

Table 4. Future trials investigating anti–PD-1 monoclonal antibodies in NSCLC

Conclusion

Based on the audience vote, the winner of this debate was Dr. Penelope Bradbury with 71% of the vote.

References: 1. Brahmer J, Rodríguez-Abreu D, Robinson A, et al. Updated analysis of KEYNOTE-024: Pembrolizumab vs platinum-based chemotherapy for advanced NSCLC with PD-L1 TPS ≥50%. WCLC 2017 Abstracts:OA 17.06. 2. Carbone DP, Reck M, Paz-Ares L, et al. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med 2017;376(25):2415–26. 3. Borghaei H, Langer C, Gadgeel S, et al. Pemetrexed-carboplatin plus pembrolizumab as first-line therapy for advanced nonsquamous NSCLC: KEYNOTE-021 cohort G update. WCLC 2017 Abstracts:OA 17.01. 4. Fessas P, Lee H, Ikemizu S, et al. A molecular and preclinical comparison of the PD-1–targeted T-cell checkpoint inhibitors nivolumab and pembrolizumab. Semin Oncol 2017;44(2):136–40.  5. Spigel DR, Reckamp KL, Rizvi NA, et al. A phase III study (CheckMate 017) of nivolumab (anti-programmed death-1) vs docetaxel in previously treated advanced or metastatic squamous cell (SQ) non-small cell lung cancer (NSCLC). J Clin Oncol 2015;33(Suppl): abstr 8009. 6. Paz-Ares L, Horn L, Borghaei H, et al. Phase III, randomized trial (CHECKMATE 057) of nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous (non-SQ) cell non-small cell lung cancer (NSCLC). J Clin Oncol 2015;33(Suppl): abstr LBA109. 7. Herbst RS, Kim D-W, Felip E, et al. KEYNOTE-010: Phase 2/3 study of pembrolizumab (MK-3475) vs docetaxel for PD-L1–positive NSCLC after platinum-based therapy. ESMO Asia 2015 Congress Abstracts:LBA3 PR. 8. Remon J, Besse B, Soria J-C. Successes and failures: what did we learn from recent first-line treatment immunotherapy in trials in non-small cell lung cancer? BMC Med 2017;15(1):55. 9. Hanna N, Johnson D, Temin S, et al. Systematic therapy for stage IV non-small-cell lung cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2017;35(30):3484–515. 10. Brulé S, Wheatley-Price P. Second line and maintenance therapy for advanced non-small cell lung cancer without driver mutation: An evolving paradigm. Int J Cancer Clin Res 2016;3(4):055. 11. Bristol-Myers Squibb Company. OPDIVO® (nivolumab) Prescribing Information. January 2018. 12. Merck & Co., Inc. KEYTRUDA® (pembrolizumab) Prescribing Information. November 2017. 13. Hoffmann-La Roche Ltd. Tecentriq® Press Release. https://www.roche.com/investors/updates/inv-update-2017-11-20.htm. Accessed February 28, 2018. 14. Merck & Co., Inc. Keytruda® Press Release. http://investors.merck.com/news/press-release-details/2018/Mercks-KEYTRUDAR-pembrolizumab-Significantly-Improved-Overall-Survival-and-Progression-Free-Survival-as-First-Line-Treatment-in-Combination-with-Pemetrexed-and-Platinum-Chemotherapy-for-Patients-with-Metastatic-Nonsquamous-Non-Small-Cell-Lung-Cancer-/default.aspx. Accessed February 28, 2018. 15. Bristol-Myers Squibb. Opdivo® Press Release. https://news.bms.com/press-release/bms/pivotal-phase-3-checkmate-227-study-demonstrates-superior-progression-free-surviva. Accessed February 28, 2018. 16. AstraZeneca. Imfinzi® Press Release. https://www.astrazeneca.com/media-centre/press-releases/2017/astrazeneca-reports-initial-results-from-the-ongoing-mystic-trial-in-stage-iv-lung-cancer-27072017.html. Accessed February 28, 2018. 17. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in Stage III non–small-cell lung cancer. N Engl J Med 2017;377(20):1919–29.