Conference Update

Immunotherapy combinations herald new hopes for lung cancer patients

Oncology
5 months ago, OP Editor

Lung cancer is regarded as one of the deadliest cancers worldwide, leading to approximately 1.69 million deaths in 2015.1 When the majority of patients are diagnosed at the advanced or metastatic stage,2 identifying effective therapies for these patients is of paramount importance. In light of the data presented at the 17th World Conference on Lung Cancer (WCLC) and the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, combining immunotherapies either with each other or with chemotherapy may lead to higher response rates, more durable response, and broader benefits in patients with advanced or metastatic lung cancer.3

Lung cancer can be categorized into small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), of which the latter constitutes around 85% of the cases.4 In the past, platinum-based chemotherapies and epidermal growth factor receptor (EGFR)-targeting agents were the mainstay of the treatments for advanced NSCLC, as immunotherapies had limited success in lung cancer.5

However, a growing role of immunotherapies in lung cancer can be observed, as novel immunotherapies embodied with new checkpoint inhibitors such as programmed cell death protein 1 (PD-1) inhibitors and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors have shown durable clinical responses with manageable toxicity in numerous trials recently.5

To further unveil the therapeutic potential of these new agents, recent investigations have been conducted to assess whether it is useful to combine immunotherapies of different mechanisms of action either with each other or with chemotherapy, and the results are so far encouraging.3

Pembrolizumab + chemotherapy in nonsquamous NSCLC

KEYNOTE-021, which is one of the KEYNOTE trials investigating the use of pembrolizumab in different types of cancer, demonstrated promising results for the combination use of pembrolizumab and chemotherapy in NSCLC patients.

In this open-label, phase II study, 123 US and Taiwan patients with advanced, nonsquamous NSCLC without targetable EGFR or ALK genetic aberrations were randomized to receive carboplatin and pemetrexed chemotherapy, with (n=60) or without (n=63) pembrolizumab. An optional and indefinite pemetrexed maintenance therapy was allowed in both arms.6

After a median follow-up of 14.5 months, the overall response rate (ORR) in patients, which is the primary endpoint of the study, was significantly higher in the combination treatment arm (55% vs. 29%, p=0.0016). In addition, the ORR was analyzed based on various cut-offs of the programmed cell death ligand 1 (PD-L1) expressions (Table 1). Surprisingly, the ORRs for the combination arm were similar for patients with PD-L1 expression <1% or ≥1%, and were remarkably higher when the PD-L1 expression reached 50%, the threshold for the clinical use of pembrolizumab.6,7

CU-1-chart-2

“We know that concomitant chemotherapy with [immune] checkpoint blockade can lead to release of tumor antigen and potential stimulation of the immune system,” explained the lead investigator Corey J. Langer, Director of Thoracic Oncology and Professor of Medicine at the Hospital of the University of Pennsylvania in Philadelphia.3

The 12-month progression-free survival (PFS) rate was 56% in the pembrolizumab arm compared with 34% with chemotherapy alone (HR: 0.50, 95% CI: 0.29-0.84, p=0.0038; Figure 1) However, no difference was noted in the overall survival after 2 years of treatment. The underlying causes for the insignificant difference may be attributed to the lack of power of the study for a survival analysis and the crossover from chemotherapy arm to PD-1 or PD-L1 inhibitors after radiological disease progression (n=20).6

CU-1-chart-1

Regardless of more ≥ grade 3 adverse events in the combination arm (39% vs. 29%), the discontinuation rate due to adverse events was somehow similar for the combination arm and the chemotherapy arm (14% vs. 13%).6

In light of the outstanding ORR and PFS, an accelerated approval has been granted by the US Food and Drug Administration (FDA) to the combination use of pembrolizumab, pemetrexed, plus carboplatin as a first-line treatment for patients with metastatic or advanced NSCLC, regardless of the expression of PD-L1.7

“This combination could conceivably be an effective treatment option for chemotherapy-naive advanced nonsquamous NSCLC. And there is in fact an ongoing phase III trial that is about two-thirds accrued looking at chemotherapy alone or chemotherapy plus pembrolizumab,” Dr. Langer pinpointed, referring to the confirmatory KEYNOTE-189 trial that has an estimated completion date of March 2019.3

Pembrolizumab + necitumumab in nonsquamous NSCLC

Another ongoing, phase 1b, KEYNOTE-099 trial aims at testing the efficacy of combining pembrolizumab with necitumumab, an EGFR inhibitor, in patients with metastatic NSCLC who received at least one line of therapy. The interim results of this trial showed some positive signs for the combination approach.3

Of the 34 patients recruited, the ORR was 29.4%. In particular, the ORR for current or former smokers was higher (37%), although half of them had negative PD-L1 expression and received more than two lines of chemotherapy.3

The median progression-free survival was 6.9 months with a median follow-up of 6 month, and the 6-month survival rate was 55.1%. “This combination seems to be active whatever the expression of PD-L1 by the tumor,” emphasized Professor Benjamin Besse, Head of the Thoracic Pathology Committee and medical oncologist at the Gustave Roussy Cancer Campus in Villejuif, France.8

The side effects led by the combination treatment recapitulated those of both pembrolizumab and necitumumab, as most common grade 3 or 4 treatment-related adverse events included hypomagnesemia, rash, and venous thromboembolism (all 9%). “There were no particular additive toxicities,” Prof. Besse believed.3

Data in another patient population (squamous NSCLC) treated with pembrolizumab and necitumumab in this phase 1b trial will be presented later, according to Prof. Besse.3

Nivolumab + ipilimumab in SCLC

The phase I/II CheckMate-032 trial evaluated the use of nivolumab, another PD-1 inhibitor, with or without ipilimumab, a CTLA-4 inhibitor, in patients with recurrent SCLC.3

Results of 159 patients treated with nivolumab monotherapy or combination therapy (nivolumab 1mg/kg + ipilimumab 3mg/kg every 3 weeks for 4 cycles, followed by nivolumab 3mg/kg every 2 weeks) were reported by Dr. Matthew D. Hellmann, medical oncologist at the Memorial Sloan Kettering Cancer Center in New York.9

With the median follow-up of 15.7 and 21.0 months, the ORR was 25% and 11% in patients with the combination treatment or monotherapy respectively. Of note, the ORR in the combination arm slightly surged from 23% at the last update of the trial,10 and the response rates were similar in those with platinum-sensitive and -resistant disease, and by lines of therapy.3

When the 2-year overall survival rate has rarely exceeded 10% in previously trials of other resembling treatments in this patient population,3 the survival rate was 17% with nivolumab alone and 30% with nivolumab/ipilimumab combination.9

Interestingly, the expression of PD-L1 showed no association with the efficacy of both treatment arms, which echoes the observations in the aforementioned trials for NSCLC. Even though most of the patients (83%) with SCLC had tumor PD-L1 expression below 1%, the overall survival was similar whether patients had the expression <1% or ≥1%.3 “In many, but not all, diseases, PD-L1 expression is associated with an increased likelihood of benefit from anti-PD-1 therapies. However, that does not appear to be the case in small cell cancer,” Dr. Hellmann noted.3

Rate of treatment-related toxicity was higher with the combination arm, but the rate of treatment discontinuation due to adverse events was low overall (5% with monotherapy and 11% with the combination therapy).9

Dr. Naiyer Rizvi, director of Thoracic Oncology and Immunotherapy at Columbia University Medical Center, agreed with the potential benefit shown in the Checkmate-032 trial. “Those data are very important. We haven’t had any advances in small cell since forever, and there’s nothing other than standard chemotherapy, which has been around for a long time. Small cell does seem biologically different than NSCLC in that the response to single-agent PD-1 therapy is lower than that of NSCLC. The combination data looked very encouraging, albeit there were other toxicities which were an issue from the data. But there are definitely people who are getting durable benefit in small cell, so I think that these data are promising.”11

Regarding the supreme efficacy aforementioned, nivolumab with or without ipilimumab was recently added to the National Comprehensive Cancer Network(NCCN) Guidelines for the treatment of recurrent SCLC.12 Moreover, the accrual of the expansion of this study with 250 additional patients with second- and third-line SCLC randomized to receive nivolumab ± ipilimumab has recently been completed.

Presented in the recent ASCO meeting, the initial results of the extension study showed ORRs similar with those presented in the WCLC meeting, favoring the combination therapy (21% vs. 12%) regardless of treatment history, platinum sensitivity, or resistance.13 These results demonstrated the sustained efficacy of the combination treatment.

“Survival with nivolumab, with or without ipilimumab, represents a promising step forward for patients with small cell lung cancer, with an estimated 2-year overall survival of 30% in patients treated with combination immunotherapy. This result is simply not possible with other types of anticancer therapy in late-stage disease. But still, work is desperately needed to identify predictors of response, especially as PD-L1 does not appear to associate with benefit in this disease,” Dr. Hellmann remarked.9

  1. Cancer. World Health Organization. (Accessed August 8 2017, at http://www.who.int/mediacentre/factsheets/fs297/en/).
  2. New treatments changing future of lung cancer. International Association for the Study of Lung Cancer. (Accessed August 8 2017, at https://www.iaslc.org/news/new-treatments-changing-future-lung-cancer).
  3. Immunotherapy combinations gain traction in lung cancer. The ASCO POST. (Accessed August 8 2017, at http://www.ascopost.com/issues/march-10-2017/immunotherapy-combinations-gain-traction-in-lung-cancer/)
  4. Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol. 2007;2(8):706-14.
  5. Massarelli E, Papadimitrakoupoulou V, Welsh J, et al. Immunotherapy in lung cancer. Transl Lung Cancer Res. 2014;3(1):53.
  6. Papadimitrakopoulou V, Gadgeel SM, Borghaei H, et al. First-line carboplatin and pemetrexed (CP) with or without pembrolizumab (pembro) for advanced nonsquamous NSCLC: Updated results of KEYNOTE-021 cohort G. J Clin Oncol. 2017;35 (suppl; abstr 9094).
  7. Pembrolizumab full prescribing information. US FDA. (Accessed August 8 2017, athttps://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s016lbl.pdf).
  8. Besse B, Garrido P, Puente J, et al. Efficacy and safety of necitumumab and pembrolizumab combination therapy in stage IV nonsquamous non-small cell lung cancer. 2016 World Conference on Lung Cancer. Abstract MA09.11. Presented December 6, 2016.
  9. Hellmann MD, Ott PA, Zugazagoitia J, et al. Nivolumab (nivo) ± ipilimumab (ipi) in advanced small-cell lung cancer (SCLC): First report of a randomized expansion cohort from CheckMate 032. 2017 ASCO Annual Meeting. Presented June 5, 2017.
  10. Hellmann MD, Antonia SJ, Ponce S, et al. Nivolumab alone or with ipilimumab in recurrent small cell lung cancer: 2-year survival and updated analyses from the CheckMate 032 trial. 2016 World Conference on Lung Cancer. Abstract MA09.05. Presented December 6, 2016.
  11. Rizvi recounts recent immunotherapy advances in lung cancer. OncLive. (Accessed August 8 2017, at http://www.onclive.com/web-exclusives/rizvi-recounts-recent-immunotherapy-advances-in-lung-cancer)
  12. NCCN Clinical Practice Guidelines in Oncology. Small Cell Lung Cancer. V2. 2017. National Comprehensive Cancer Network® (NCCN®). (Accessed August 8 2017, at https://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf).
  13. Hellmann MD, Ott PA, Zugazagoitia J, et al. Nivolumab (nivo) ± ipilimumab (ipi) in advanced small-cell lung cancer (SCLC): First report of a randomized expansion cohort from CheckMate 032 Abstract 8503. ASCO 2017. Abstract 8503.

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