The non-small cell lung cancer (NSCLC) market experienced several major developments within the past year, notably the first approval of an immune checkpoint inhibitor (Merck & Co.’s Keytruda ) for first-line metastatic disease. Although results released for NSCLC at this year’s ASCO meeting may not have captured the biggest headlines, the conference still provided many exciting pieces of data that will influence the management of this disease. The key abstracts for NSCLC mainly covered the two most dynamic drug classes in this indication, which are the focus of extensive drug development efforts: ALK inhibitors and immune checkpoint inhibitors.
ALEX: Alecensa’s time to shine
Results from the ALEX trial were widely anticipated following Roche's announcement back in April that Alecensa met its primary endpoint of PFS, and the positive results already reported from the Japanese J-ALEX trial. ALEX evaluated Alecensa against the standard of care Pfizer’s Xalkori in first-line, ALK+ metastatic NSCLC. Alecensa demonstrated an impressive 26 months mPFS versus only 10 months for Xalkori and a 53% reduction in risk disease progression or death (per IRC assessment; HR 0.47, p<0.0001). Furthermore, the agent was highly active on CNS lesions with an 84% reduction in risk of progression in the CNS (p<0.0001). Treatment of CNS lesions is an area of high unmet need in ALK+ NSCLC since it's a common site of metastasis for these patients and are ineffectively targeted by Xalkori due to its poor penetration of the blood-brain barrier. The mPFS demonstrated by Alecensa far exceeds data for other ALK inhibitors in the first-line setting, including Novartis’ Zykadia, which was recently approved for first-line use based on improved efficacy benefits over chemotherapy. Unlike Zykadia, Alecensa was compared to the current standard of care for first-line ALK+ NSCLC (Xalkori), which places the agent in a very strong position for securing regulatory approval and favorable reimbursement. Based on data from the ALEX and J-ALEX trials, Alecensa is likely to displace Xalkori as the standard of care in the first-line setting, generating significant sales for Roche in the upcoming years.
Lorlatinib: Another ALK inhibitor on the horizon
Another ALK inhibitor of interest at ASCO 2017 was Pfizer’s next-generation ALK/ROS1 inhibitor lorlatinib. Pfizer is pursuing a rapid development program for lorlatinib and recently initiated a Phase III trial in first-line, ALK+ advanced NSCLC against Xalkori. Data released from an ongoing Phase I/II study at ASCO showed that lorlatinib achieved ORR of 57% in patients previously treated with Xalkori only, while ORRs were 44%, 25% and 31% for patients previously treated with 1, 2, or 3 ALK inhibitors ± chemotherapy, respectively. The agent was also active on CNS lesions with ORRs ranging from 43% to 60%. Although for a small number of patients, these response rates for lorlatinib appear promising and comparable to other available ALK inhibitors. Lorlatinib holds Breakthrough Therapy Designation from the FDA for ALK+ metastatic NSCLC previously treated with an ALK inhibitor, and similar to other ALK inhibitors this mid-Phase data could support its regulatory filing in this patient population. However, lorlatinib aims to enter an increasingly competitive space with a number of available therapies. As such, additional data, particularly from previously untreated patients, will be important to gauge the potential of lorlatinib in NSCLC.
Immune Checkpoint Inhibitors
Keytruda plus Epacadostat: Mixed signals in NSCLC
Combination regimens involving immune checkpoint inhibitors is one of the most active areas of oncology drug development. The combination of Keytruda and Incyte’s IDO inhibitor epacadostat has shown promise in early phase trials in malignant melanoma. Results from the ECHO-202/KEYNOTE-037 trial in solid tumors were highly anticipated as an indicator of the combination's potential in other tumor types. Data released for previously-treated NSCLC, while indicative of activity, fell short of a home-run. Trial results showed that Keytruda plus epacadostat achieved an ORR in high (≥50%) PD-L1-expressing NSCLC, consistent with that observed in KEYNOTE-010 and KEYNOTE-024 (which supported Keytruda’s approval in previously-treated and first-line patients, respectively), and therefore do not suggest a benefit for the addition of epacadostat over Keytuda monotherapy. However, the ORR was 35% in the overall trial population which is higher than observed for Keytruda, Opdivo, and Tecentriq as single-agents in this patient population. Given the low use of PD-L1 testing in second-line NSCLC, improved response rates in patients with low or no tumor PD-L1 expression could support the uptake of Keytruda plus epacadostat. Nonetheless, these results need to be interpreted with caution given the small number of patients in the trial. More robust efficacy data and a better understanding of toxicities will be crucial for the combination to be able to compete with available immune checkpoint inhibitors.
Keytruda plus chemotherapy: Benefits continue to hold up
In May, the FDA granted Keytruda a label expansion in combination with Eli Lilly’s Alimta and carboplatin for first-line non-squamous NSCLC under priority review. This approval made Keytruda the first immune checkpoint inhibitor to gain approval with chemotherapy, and significantly expanded the agent’s potential first-line market by extending its use to PD-L1-negative patients. At ASCO, updated results with 14.5 months follow-up from KEYNOTE-021, which supported the label expansion, indicated that Keytruda plus chemotherapy continues to provide significantly higher ORR (57% vs. 30%, p<0.0016) and PFS (NR vs. 8.9 months; HR=0.49, p<0.0035) benefits versus chemotherapy alone. These results are likely to drive the uptake of Keytruda plus Alimta and carboplatin in the first-line setting, particularly in patients with low or no tumor PD-L1 expression. A confirmatory trial Phase III trial (KEYNOTE-189) of the combination is ongoing.
CheckMate-012: Re-kindled hopes for Opdivo
After the failure of Opdivo to meet its endpoint in the CheckMate-026 trial, trials evaluating combinations with Yervoy and chemotherapy are crucial for Bristol-Myers Squibb to capture any market share in first-line NSCLC. Following the company's announcement back in January that they will not seek accelerated approval for Opdivo plus Yervoy in the first-line setting, the release of long-term OS data from the Phase I CheckMate 012 study in previously untreated patients were eagerly anticipated. The results were certainly promising with Opdivo plus Yervoy (Q12W) showing an ORR of 47%, and an 83% 1-year OS rate. ORR was 57% in patients with ≥1% tumor PD-L1 expression (n=46), and exceeded 90% in those with ≥50% tumor PD-L1 expression, albeit the number of patients in this cohort was small (n=13). The results will come as a breath of fresh air for Bristol-Myers Squibb who have previously failed to produce convincing results in treatment-naïve patients, despite their dominance in the second-line patient segment. Of note, above data for the combination in patients with ≥1% tumor PD-L1 expression exceed those observed for Keytruda in the first-line KEYNOTE-024 study. These promising results mean that updates from the Phase III Checkmate 227, which is evaluating Opdivo plus Yervoy in the first-line setting, will be much awaited.
Imfinzi makes the cut but fails to impress
AstraZeneca are aiming to be the next to launch an immune checkpoint inhibitor into the NSCLC market, with their PD-L1 inhibitor Imfinzi. The agent has recently entered the spotlight following AstraZeneca's announcement that it reduced the risk of disease progression or death in Stage III patients after concurrent chemoradiotherapy. Updated results from an ongoing Phase I/II study in previously treated patients show that Imfinzi demonstrated 25% ORR in patients with high (≥25%) PD-L1 expression (n=109) and 6% in those with low (<25%) PD-L1 expression (n=108); MOS was 15.4 and 7.6 months, respectively. In addition to previously evaluated methods of determining PD-L1 status, AstraZeneca used yet another test with a different cutoff for high/low PD-L1 expression, which complicates analysis. At first glance, the efficacy profile can be interpreted as promising and comparable to Tecentriq, the only approved PD-L1 inhibitor for NSCLC. However, the data falls short of indicating improvements over all of the available therapies. Although this will not preclude Imfinzi from potentially securing an approval, the NSCLC space is now highly crowded with well-established immune checkpoint inhibitors, and a novel therapy is likely to struggle for patient share without an improved efficacy or safety profile.
The approvals of multiple ALK and immune checkpoint inhibitors for advanced NSCLC in the past couple of years have had a transformative impact on the management of this disease. Results from ASCO 2017 signal increased treatment options and a larger influence of these drug classes on the treatment algorithm. The NSCLC therapy market as a whole remains highly dynamic with an extensive late-phase pipeline consisting of agents from multiple drug classes. The indication is at the forefront of personalized medicine with a growing number of biomarker-defined patient populations and targeted therapies. Decision Resources Group expect the approvals of novel branded therapies and label expansions into earlier disease settings to generate significant growth in the NSCLC market in the upcoming years.
Decision Resources Group has a finger on the pulse of the dynamic NSCLC and immune checkpoint inhibitor markets. Our NSCLC Disease Landscape and Forecast, Access and Reimbursement, and Unmet Need content give expert insight into market dynamics and the reimbursement landscape.
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