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DURVALUMAB DIVES DEEP INTO THE PACIFIC

by Stephanie Hawthorne | Sep 10, 2017

Co-authored by Connie Tat, Ph.D.

Approximately one third of non-small cell lung cancer (NSCLC) patients have Stage III, locally-advanced disease at diagnosis (1). The current standard of care (SOC) for these patients with good performance status and unresectable disease is platinum-based doublet chemotherapy, concurrent with radiotherapy.  There have been no major advances in the treatment of locally-advanced NSCLC for over a decade, and therefore there is a significant unmet medical need for novel therapeutic approaches to boost the survival beyond concurrent chemoradiation therapy (ccRT).  Response rates for ccRT range from 65-84% (2-3).  The median progression free survival (PFS) with ccRT is approximately 8-10 months (from the start of ccRT) and the overall survival (OS) is around 5 years, though only 15% of patients are alive after 5 years (4-7). Historically, the median OS with radiotherapy alone has been 10 months, 14 months with chemotherapy added, and 18 months with concurrent chemotherapy, respectively. Over the past two decades, attempts to improve outcomes with either changes in radiation dosage [RTOG 0617; HR 1.38 (8)], changes in types of chemotherapy [PROCLAIM; HR 0.98 (9)] or targeted therapy (RTOG 0617; HR 1.07) have failed.  PACIFIC is the first randomized Phase III trial to evaluate immune checkpoint blockade in patients with stage III, locally advanced, unresectable NSCLC in the consolidation setting.  

Data from the Late Breaking Abstract 1 (LBA1) for the PACIFIC trial was presented at ESMO 2017 (10), demonstrating statistically significant and clinically meaningful improvement in progression free survival (PFS) of  Imfinzi® (durvalumab, AstraZeneca), a PD-L1 inhibitor, compared to placebo by more than 11 months in patients with locally advanced (Stage III), unresectable NSCLC (mPFS: 16.8 months arm versus 5.6 months, HR 0.52, p<0.0001) across all study groups.  The PACIFIC trial enrolled 713 Stage III patients with locally advanced, unresectable NSCLC who had not progressed following definitive platinum based cCRT (1-42 days post cCRT). These patients were randomized 2:1 and stratified by age, sex, and smoking history to receive either Imfinzi (10 mg/kg q2w for 12 months) or placebo (10 mg/kg q2w for 12 months). Co-primary endpoints were PFS by Blinded Independent Committee Review (BICR) and OS, and key secondary endpoints were ORR, DOR, and safety and tolerability.  Interim analysis from this study was conducted at 371 events, at a median follow up of 14.5 months.  Subgroup analysis of patients indicated a PFS benefit for all patients.  However, subgroup analysis evaluating PD-L1 expression found that those patients with ≥25% PD-L1 expression performed slightly better with Imfinzi than those with expression of PD-L1 <25% (≥25% PD-L1, HR 0.41; <25% PD-L1 or unknown, HR 0.59).  The objective response was significantly improved with Imfinzi (28.4% versus 16.0%, relative risk 1.78, p<0.001) and the duration of response was improved (median not reached versus 13.8 months, HR 0.43).  Additionally, patients that received Imfinzi had a lower incidence of new lesions (20.4% versus 32.1%), including new brain metastases compared to placebo (5.5% versus 11.0%) as well as an improved time to distant metastasis or death (23.2 months versus 14.6 months, HR 0.52, p<0.0001).

Among patients receiving Imfinzi, 29.9% of patients experienced a grade 3 or 4 adverse event (AE) compared to 26.1% for patients receiving placebo, and slightly more patients discontinued treatment due to AEs (15.4% versus 9.8%).  The most frequent treatment-related adverse events (TRAEs) of any grade were cough (35.4% versus 25.2%), pneumonitis/radiation pneumonitis (33.9% versus 24.8%), fatigue (23.8% versus 20.5%), dyspnea (22.3% versus 23.9%) and diarrhea (18.3% versus 18.8%).  Safety was consistent with what was previously reported; there were no new safety signals. The PACIFIC trial continues to evaluate overall survival, and the trial remained blinded to that endpoint.  AstraZeneca projected at their ESMO investor’s presentation that this data will be available in 2019.  The company also noted that they plan to file for FDA approval later this year; this could be favorably received as the FDA has already granted the agent Breakthrough Therapy Status based on the results of this trial (AstraZeneca press release, July 31, 2017).  Detailed results of the available data for PACIFIC have also been published (11).

In evaluating the study setting, design and data from PACIFIC trial, the discussant of the session, Dr. Johan Vansteenkiste, noted that the overall design was appropriate: this was a global, international trial, placebo controlled study with co-primary endpoints of PFS and OS, 2:1 randomization and well balanced patient groups with Stage III NSCLC. With regard to the therapy itself, he suggested that radiotherapy and checkpoint inhibitors are excellent partners, as radiotherapy primes the immune system, inflaming the tumor microenvironment, increasing neoantigens.

It has been highly discussed whether or not PFS is a good primary endpoint for immunotherapy trials.  With the exception of KEYNOTE-024, PFS has not shown to be a good primary endpoint, and it has been an especially poor readout for Stage III NSCLC, as progression has traditionally not correlated well with overall survival. Moreover, as one KOL (Dr. Jack West) commented online, “with a cost in the range of $200,000 for that year of treatment, and patients required to receive treatment for more than a year instead of less than 2 months, I would contend that we need to see durvalumab improve overall survival to make it a truly compelling new standard of care” (12).  Physicians will therefore wait anxiously for presentation of the overall survival data.  Nonetheless, this is the first strong interim-PFS positive Phase III trial with systemic therapy in Stage III NSCLC in decades. The large degree of benefit in the PFS endpoint bodes well for the final outcome. 

This is certainly welcome news for this agent, which recently experienced somewhat negative news in another phase III trial, MYSTIC (NCT02453282).  AstraZeneca had noted in a press release that the combination of Imfinzi plus tremelimumab failed to improve PFS in previously-untreated patients with metastatic NSCLC (press release, July 27, 2017).  Although it was only one of two co-primary endpoints, the other was overall survival, data for which was not provided, MYSTIC raised questions about Imfinzi.  These concerns can now be set aside, at least partly, with the data presentation of PACIFIC.

The only ongoing developments in the chemoradiation setting for locally advanced NSCLC are PACIFIC and a recently initiated Phase III study with Opdivo® (nivolumab, Bristol-Myers Squibb / Ono Pharmaceuticals).  With the recent failure of Opdivo in the first-line metastatic setting, and its trial the locally-advanced setting is still enrolling, it looks as though the success of PACIFIC in the post-chemoradiation consolidation setting for unresectable Stage III NSCLC could position Imfinzi as a new, paradigm shifting therapeutic option.  As noted previously, AstraZeneca is in discussions with global health authorities regarding regulatory submissions for Imfinzi based on the PACIFIC data.  This allows AstraZeneca to avoid competing with other PD-1 targeted inhibitors, Opdivo, Keytruda® (pembrolizumab, Merck), and PD-L1 inhibitor, Tecentriq® (atezolizumab, Genentech / Roche / Chugai) in the metastatic and adjuvant settings, a crowded market.   With its newly granted Breakthrough Therapy Designation in the post-chemoradiotherapy consolidation setting, it is the only therapeutic riding and crushing waves in a niche setting in the PACIFIC.

 

References

  1. Aupérin A, Le Péchoux C, Rolland E, et al.; “Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer;” J Clin Oncol, 28 (13): 2181-2190, 2010
  2. Furuse K, Fukuoka M, Kawahara M, et al.; “Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer;” J Clin Oncol, 17 (9): 2692-2699, 1999.
  3. Curran WJ Jr, Paulus R, Langer CJ, et al.; “Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410;” J Natl Cancer Inst, 103 (19): 1452-1460, 2011.
  4. Yoon SM, Shaikh T, Hallman M. “Therapeutic management options for stage III non-small cell lung cancer;” World J Clin Oncol, 8 (1):1-20, 2017.
  5. Ahn JS, Ahn YC, Kim JH, et al.;  “Multinational randomized phase III trial with or without consolidation chemotherapy using docetaxel and cisplatin after concurrent chemoradiation in inoperable stage III non-small-cell lung cancer: KCSG-LU05-04;” J Clin Oncol, 33 (24):2660-2666, 2015.
  6. Furuse K, Fukuoka M, Kawahara M et al.; “Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer;” J Clin Oncol, 17 (9): 2692-2699, 1999.  
  7. CancerMPact® Treatment Architecture. Kantar Health. Available from www.cancermpact.com. Accessed 9 Sep 2017.
  8. Bradley JD, Paulus R, Komaki R, et al.; “Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 trial; Lancet Oncol, Lancet Oncol, 16 (2): 187-199, 2015.
  9. Senan S, Brade A, Wang L-H, et al.; “PROCLAIM: Randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non–small-cell lung cancer;” J Clin Oncol, 34 (9): 953-962, 2016.
  10. Paz-Ares L, Villegas A, Daniel D, et al.; “PACIFIC: A double-blind, placebo-controlled phase III study of durvalumab after chemoradiation therapy in patients with stage III, locally advanced, unresectable NSCLC;” Ann Oncol, 28 (supp 5): LBA1, 2017.
  11. Antonia SJ, Villegas A, Daniel D et al., “Durvalumab after chemoradiotherapy in Stage III non-small-cell lung cancer;” N Engl J Med, 2017; online first, DOI: 10.1056/NEJMoa1709937.
  12. West J. “Top five lung cancer abstracts at ESMO 2017;” http://www.medscape.com/viewarticle/885150; accessed 10 Sept 2017.

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