Immune checkpoint inhibitors continue to yield encouraging results among early-stage NSCLC patients at ASCO 2019
Impressive five-year survival data for Keytruda monotherapy in previously untreated patients was presented at ASCO 2019 (Abstract: LBA9015). Until recently, Keytruda’s label in NSCLC has only included patients with metastatic disease. In April 2019, the U.S. FDA granted a label expansion for patients with tumour PD-L1 expression exceeding 1% (Merck & Co., press release, April 11, 2019), down from its previous 50% threshold. As part of this expansion, the label now also includes NSCLC patients with stage III disease that are not candidates for surgery, or definitive chemoradiation therapy (CRT).
PACIFIC’s Three-Year Follow-Up
Although a first for Keytruda, the PD-1 inhibitor isn’t the first, and is unlikely to be the last, targeted therapy to enter the earlier stages of NSCLC. AstraZeneca’s Imfinzi was the first immune checkpoint inhibitor to receive approval in stage III NSCLC in February 2018, when the FDA granted the PD-L1 inhibitor approval for patients who had not progressed following concurrent CRT, based on data from the Phase III PACIFIC trial (AstraZeneca, press release, February 19, 2018). Patients with unresectable stage III disease typically receive sequential or concurrent CRT, therefore the stage III population eligible for Imfinzi is much larger than that now included on Keytruda’s label, and acted as a significant catalyst for boosting Imfinzi’s 2018 global sales to $633 million. Updated OS data for Imfinzi were presented from PACIFIC (Abstract: 8526), which show 57% of patients remained alive at three years after receiving Imfinzi following concurrent CRT (versus 43.5% for placebo). The British-based company is not looking to stop there with their pipeline and new oncology R&D head, José Baselga, looking to build on this success in the early-stage setting. However, as is often the case in the lucrative NSCLC market, ASCO 2019 has shown us that AstraZeneca isn’t going to be alone.
Combining with Chemoradiation Therapy
Following Imfinzi’s success as a consolidation treatment in PACIFIC, several pivotal Phase III trials are now including immune checkpoint inhibitors in combination with chemoradiation therapy (CRT). Details for two of such trials were presented as Trial in Progress posters in the local-regional NSCLC poster session (Abstracts TPS8573 and TPS8574). The first, PACIFIC2 (NCT03519971), is a trial for Imfinzi plus standard of care CRT versus placebo plus standard of care CRT with both PFS and ORR included as co-primary endpoints. The second, RATIONALE001 (NCT03745222), is evaluating the PFS for BeiGene’s tislelizumab as a consolidation following CRT, and when given in combination with CRT. Interestingly, although both trials include placebo plus CRT followed by placebo maintenance as the comparator, RATIONALE001 will enable direct comparison of efficacy for an immune checkpoint given with CRT and as consolidation versus consolidation alone, while this will require cross-trial comparisons between PACIFIC and PACIFIC2 for Imfinzi.
Roche and Merck & Co. also presented promising early-phase data for their PD-L1 and PD-1 inhibitors—Tecentriq and Keytruda—in this setting (Abstracts: 8512 and 8511 , respectively). Tecentriq given with concurrent CRT, followed by Tecentriq plus platinum-based chemotherapy consolidation therapy was associated with a median PFS of 13.2 months in the Phase II DETERRED trial, while Phase I data for 18 patients who had received 2 or more doses of Keytruda showed a median PFS of 20.3 months. Although data are from a small number of patients, these results are comparable to that already shown by Imfinzi in PACIFIC (17.2 months; Antonia SJ, 2018). However, whether including an immune checkpoint inhibitor with concurrent CRT offers a substantial benefit relative to their use as a consolidation therapy remains to be seen.
Immune Checkpoint Inhibitors in Resectable NSCLC
Alongside these clinical trials in combination with CRT, ASCO 2019 also offered some insight into the future treatment of patients with stage III resectable NSCLC. The Phase II NEOSTAR trial for Bristol-Myers Squibb’s PD-1 inhibitor, Opdivo both as a monotherapy and in combination with the CTLA-4 inhibitor, Yervoy as neoadjuvant treatments was associated with a major pathological response in 17% and 33% of patients (Abstract: 8504), while neoadjuvant Tecentriq monotherapy produced a major pathological response in 18% of patients in the Phase II LCMC3 trial (Abstract: 8503). Although no immune checkpoint inhibitor is currently approved as a neoadjuvant treatment in NSCLC, the data is encouraging for the ongoing pivotal trials in this setting.
Select Ongoing Phase III Trials for Currently Available Immune Checkpoint Inhibitors in Early-stage NSCLC