Roche’s Tecentriq shows promise in resectable NSCLC: key takeaways for the market

Tecentriq, Roche’s flagship anti-PD-L1 therapy, gets one step closer to becoming the first immunotherapy to gain approval as adjuvant therapy in resectable non-small cell lung cancer (NSCLC). As part of our Drugs to Watch™ series, Clarivate oncology experts Arman Esfandiari, Amardeep Singh and Khurram Nawaz review new data shared at ASCO 2021, and implications for patients and life sciences companies.

Multiple immune checkpoint inhibitors are in Phase III development as adjuvant therapies for resectable NSCLC Results from the pivotal Phase III IMpower010 trial, presented at the 2021 ASCO Annual Meeting, showed that adjuvant Tecentriq versus best supportive care (BSC) confers meaningful clinical benefit to completely resected stage II-IIIA NSCLC patients after adjuvant cisplatin-based chemotherapy1. This makes Tecentriq the first immune checkpoint inhibitor to show promise in resectable NSCLC. Although resectable NSCLC incident cases account for a small proportion of all NSCLC cases, there is great unmet need for more efficacious targeted therapies in this setting. Here, we briefly discuss the clinical and commercial implications of these results for Tecentriq across the major markets (i.e., United States, Europe, and Japan) and Mainland China.

In March 2021, Roche announced that the Phase III IMpower010 trial met its primary endpoint of disease-free survival (DFS) and that the results will form the basis of regulatory submissions in the United States and Europe. Results from the preplanned interim analysis of IMpower010 were revealed at ASCO 2021 (Table 1).

Table 1: Key data from the Phase III IMpower010 trial presented at ASCO 2021

Patient populations and enrollment Trial design Select efficacy data Select safety data
  • Stage IB-IIIA NSCLC after complete resection and adjuvant cisplatin-based doublet chemotherapy.
  • N = 1,005
  • Treatment: Tecentriq (16 cycles, q21d) vs. BSC (randomized 1:1).
  • Primary endpoint: DFS (tested hierarchically in three primary analysis populations).
  • Secondary endpoints: OS, percentage disease free at 3 years and 5 years, safety, and PK/PD.

Hierarchical statistical analysis:

  • Step 1: DFS in PD-L1-positive (TC ≥ 1%) stage II-IIIA NSCLC.
  • Step 2 (if previous step positive): DFS in all-randomized stage II-IIIA NSCLC patients.
  • Step 3 (if previous step positive): DFS in ITT population (stage IB-IIIA).
  • Step 4 (if previous step positive): OS in ITT population.
Among PD-L1-positive (TC 1%) stage II-IIIA patients (n = 476):

Tecentriq vs. BSC (median follow-up: 32.8 months):

  • Median DFS: NR vs. 35.3 months (HR 0.66; P = 0.004).

Among all randomized stage II-IIIA patients (n = 882):

Tecentriq vs. BSC (median follow-up: 32.2 months):

  • Median DFS: 42.3 vs. 35.3 months (HR 0.79; P = 0.02).

Among ITT (stage IB-IIIA) patients:

Tecentriq vs. BSC (median follow-up: 32.2 months):

  • Median DFS: NE vs. 37.2 months (HR 0.81; P = 0.04 [statistical significance boundary not crossed]).

 

Exploratory analysis in key NSCLC subpopulations among all randomized stage II-IIIA patients:

Tecentriq vs. BSC (median follow-up: 32.2 months):

  • DFS in PD-L1-high (TC > 50%): HR 0.43.
  • DFS in PD-L1 negative (TC < 1%): HR 0.97.
Among all patients:

Tecentriq vs. BSC:

  • Any cause adverse events: 92.7% vs. 70.7%.
  • Treatment-related adverse events: 67.7% vs. NA.
  • Grade 3/4 adverse events: 21.8% vs. 11.5%.
  • Treatment-related grade 3/4 adverse events: 10.7% vs. NA.
  • Serious adverse events: 17.6% vs. 8.5%.
  • Treatment-related serious adverse events: 7.5% vs. NA.
  • Grade 5 adverse events: 1.6% vs. 0.6%.
  • Treatment-related grade 5 adverse events: 0.8% vs. NA.
  • Adverse events leading to dose interruption of Tecentriq: 28.7%.
  • Adverse events leading to discontinuation of Tecentriq: 18.2%.
  • Immune-mediated adverse events: 51.7% vs. 9.5%.
  • Grade 3/4 immune-mediated adverse events: 7.9 vs. 0.6%.
  • Immune-mediated adverse events requiring the use of corticosteroids: 12.1% vs. 0.8%.
Abbreviations – DFS: disease-free survival; HR: hazard ratio; ITT: intention-to-treat; NA: not applicable; NE: not evaluable; NR: not reached; OS: overall survival; PD-L1: programmed death-ligand 1; PK/PD: pharmacokinetics/pharmacodynamics; TC: tumor cell.

 

N.B. Prespecified subgroups included age (<65 years vs. > 65 years), sex (male vs. female), race (White vs. Asian), ECOG performance status (0 vs. 1), tobacco use history (never vs. previous vs. current), histology (squamous vs. nonsquamous), stage (IIA vs. IIB vs. IIIA), regional lymph node stage (N0 vs. N1 vs. N2), SP263 PD-L1 status (TC > 50% vs. TC > 1% vs. TC < 1%), EGFR mutation status (yes vs. no vs. unknown), and ALK rearrangement status (yes vs. no vs. unknown).

Source: Wakelee HA, 20211.

 

Why are the data from IMpower010 clinically meaningful?

Although improved DFS does not always translate to increased overall survival (OS)2, it is widely considered an appropriate primary endpoint for adjuvant therapies in NSCLC partly because it allows the assessment of efficacy without confounding from subsequent therapies.

In IMpower010, adjuvant Tecentriq reduced the risk of disease recurrence or death by 34% in resected PD-L1-positive (TC > 1%) stage II-IIIA NSCLC and by 21% in all randomized resected stage II-IIIA NSCLC patients.

  • In PD-L1-positive patients, the results were consistent across the majority of the prespecified subgroups except for ALK-positive patients and for current smokers.
  • Subgroup analysis of all-randomized stage II-IIIA patients also revealed that tumor PD-L1 expression was a biomarker of clinical benefit. Of note, adjuvant Tecentriq conferred no clear DFS benefit to PD-L1-negative (TC < 1%) patients.
  • Despite encouraging trends at the time of this interim analysis, DFS did not cross the significance boundary in the intent-to-treat population (stage IB-IIIA) and OS data were immature. Analysis of these subpopulations continues.
  • As expected, immune-related adverse events were a lot more common for adjuvant Tecentriq vs. BSC. However, these events were consistent with those previously reported for Tecentriq monotherapy across indications and settings and were manageable overall.

 

What are the commercial implications of these data for Tecentriq?

Recently, adjuvant Tagrisso became the first targeted therapy to gain approval for completely resected early-stage NSCLC in the United States and Europe, based on the Phase III ADAURA trial. However, its use is limited to NSCLC harboring EGFR-sensitizing mutations. Therefore, the current standard of care for most resectable NSCLC patients remains surgery followed by one to four cycles of adjuvant platinum-based chemotherapy. This means that there is great unmet need for more targeted therapies in this setting.

Based on the data presented at ASCO 2021, Tecentriq will likely become the first immune checkpoint inhibitor to gain a label expansion into the adjuvant resectable NSCLC setting, across the major markets. If so, adjuvant Tecentriq may become the standard of care in this setting and experience strong uptake, particularly in PD-L1-positive patients. Despite a smaller number of drug-treatable cases in the adjuvant NSCLC setting compared with metastatic NSCLC, adjuvant Tecentriq’s sales could be significant for Roche. However, multiple rivals are not far behind—including Imfinzi (AstraZeneca), Keytruda (Merck & Co.) and Opdivo (Bristol Myers Squibb, Ono Pharmaceuticals)—and competition in this space is set to intensify.

What are the implications of these data for Tecentriq in Mainland China?

Adjuvant platinum-based chemotherapy remains the standard of care for resectable NSCLC patients in Mainland China, owing to only one targeted therapy option of adjuvant Tagrisso for EGFR-positive stage IB-IIIA patients. However, multiple domestic- and -manufactured immune checkpoint inhibitors are being investigated as adjuvant therapies in late-phase studies for resectable NSCLC. As in major markets, Roche’s Tecentriq is the frontrunner in the clinical development race in Mainland China. In IMpower010, the treatment became the first immunotherapy to show meaningful clinical benefit in resectable NSCLC, making it likely to earn a label expansion for this setting within Mainland China.

With a first-to-market status and anticipated inclusion in the National Reimbursement Drug List (NRDL) that will lead to significant price reductions, we expect Tecentriq will likely see rapid uptake in Mainland China. However, with the anticipated launch of four additional immune checkpoint inhibitors in Mainland China starting in 2024, particularly that of the less expensive, domestically-developed Baizean (tislelizumab; BeiGene), Tecentriq will face increasing competition in this treatment setting.

 

To learn more about our take on other oncology treatment landscape game changers, follow our ASCO 2021 analysis here.

Clarivate will update its Disease Landscape and Forecast™ content for non-small cell lung cancer with a new forecast horizon (2020-2030) where we will capture the many updates from ASCO 2021. Learn more about this research here.

 

References:

  1. Wakelee HA, et al. IMpower010: Primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC). Journal of Clinical Oncology 39, 2021 (abstract 8500). doi: 10.1200/JCO.2021.39.15_suppl.8500
  2. Prasad V, et al. The Strength of Association Between Surrogate End Points and Survival in Oncology: A Systematic Review of Trial-Level Meta-analyses. JAMA Internal Medicine. 2015;175(8):1389–1398. doi:10.1001/jamainternmed.2015.2829

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