Like last year, the 2021 American Society of Clinical Oncology (ASCO) conference was held virtually, from June 4-8. Hearing the latest developments in oncology in this annual event is always hugely interesting, although, I am looking forward to once again walking the halls of the conference centre in Chicago, filled with 1’000’s of people, meeting clients and colleagues, soaking up the awe-inspiring atmosphere, giving ASCO my full undivided attention…here’s hoping for 2022!
Every year, members of HRW’s OR:BIT (Oncology Research: Business Insights Team), attend the ASCO’s annual conference, and share what we feel are the key topics emerging (please see HRW’s published infographic for an overview).
The theme for this year’s ASCO was “Equity: Every Patient. Every Day. Everywhere”, looking to identify ways to ensure that all patients can access and benefit from the latest cancer advances and high-quality cancer care.
In this blog, I discuss in more detail a prominent area of focus emerging from the conference: Increasing adjuvant treatment options for early-stage disease. The use of more targeted therapies in the adjuvant setting is especially pertinent to ASCO’s overarching theme of ‘Equity’, given that the adjuvant cancer patient population invariably represents the largest number of patients across all lines of treatment. It will be a significant undertaking to ensure that every patient, every day, everywhere will have access to likely costly adjuvant therapies. In this blog, I will outline adjuvant data presented from 3 key abstracts.
OlympiA: Adjuvant Lynparza extends disease-free survival in germline BRCA1/2-mutated early-stage HER2-negative breast cancer
AstraZeneca is evaluating Lynparza, a PARP inhibitor, as an adjuvant treatment for patients with high-risk, early-stage, HER2-negative breast cancer with BRCA1/2 germline mutations – the only PARP inhibitor being evaluated in this setting. The double-blind phase III OlympiA trial enrolled 1,836 patients, who were randomly assigned to receive either 1 year of adjuvant Lynparza or placebo following surgery (with or without radiation and chemotherapy).
In February 2021, AstraZeneca announced that OlympiA met its primary endpoint of superior invasive disease-free survival (iDFS) over placebo. Data presented at ASCO 2021 indicated that at 3 years of follow-up, the rate of iDFS was 85.9% for Lynparza vs. 77.1% for placebo, with a distant DFS rate of 87.5% for Lynparza vs. 80.4% for placebo. Furthermore, there was an early separation of OS curves, with interim data showing a 3-year OS rate of 92.0% for Lynparza vs. 88.3% for placebo.
The data presented support a label extension for Lynparza into the adjuvant setting – currently in breast cancer Lynparza is only indicated in the metastatic setting (and locally advanced setting in the EU) in patients with germline BRCA1/2-mutations, who have HER2 negative disease. Adjuvant approval of Lynparza, would support early genetic testing to inform treatment choice. Given Lynparza’s current indication, adjuvant approval would also likely bring into question of where the optimal setting is to use Lynparza; in early setting or metastatic/recurrent setting?
KEYNOTE-564:First positive phase III study of an adjuvant immunotherapy in renal cell carcinoma
KEYNOTE-564 is evaluating Keytruda as an adjuvant treatment for RCC patients who have intermediate-high risk, high risk, or stage M1 no evidence of disease (M1 NED) following nephrectomy and/or metastasectomy. Prior to ASCO 2021, in April this year, Merck announced that KEYNOTE-564 had met the primary endpoint of improving DFS over placebo. The prespecified interim analysis presented at ASCO 2021 showed that at a median follow-up of around 24 months, adjuvant Keytruda significantly reduced the risk for recurrence or death by 32% vs placebo, with the median DFS unreached in both study arms. The estimated 1-year DFS rates were 85.7% for Keytruda vs. 76.2% for placebo, respectively, with estimated 2-year DFS rates of 77.3% and 68.1%. The OS data for this study are not yet mature.
Currently, in RCC Keytruda is approved in combination with Inlyta in the advanced first-line setting. A label extension for Keytruda into the adjuvant setting, supported by KEYNOTE-564, would represent significant opportunity for the PD-1 inhibitor, particularly given that Sutent, for which there are conflicting clinical data, is the only currently approved adjuvant therapy (in the US only). A label extension would also force HCPs into considering the optimal positioning of Keytruda in the RCC treatment pathway.
IMpower010: Tecentriq extends disease-free survival in stage II-IIIA NSCLC with PD-L1 ≥1%
IMpower010 is a global, randomized trial evaluating Tecentriq (for 16 cycles) vs. BSC in the adjuvant setting for NSCLC, which has enrolled 1’005 patients with stage II-IIIA disease who had completed surgical resection and chemotherapy. In March 2021, Roche announced that the trial had met the primary endpoint of DFS, making Tecentriq the first immune checkpoint inhibitor to demonstrate a significant benefit in the adjuvant setting for NSCLC. At ASCO 2021, the DFS data were presented.
The protocol mandated hierarchical statistical testing, first analysing DFS in NSCLC with tumour cell PD-L1 expression of at least 1% (using the SP142 assay). In the patient population with tumour PD-L1 ≥1%, a significant 34% reduction in the risk for disease recurrence or death with Tecentriq vs BSC was observed (HR 0.66, P = 0.0039). The DFS rates at 24 months, in this PD-L1 ≥1% group, were 74.6% for Tecentriq vs 61.0% for BSC, and at 36 months 60.0% vs 48.2%, respectively.
In the ITT study population, the DFS results favoured the PD-L1 inhibitor (stratified HR=0.81), but the prespecified boundary for statistical significance was not crossed, indicating that PD-L1 is a useful marker of response. OS data are not yet mature.
In terms of safety, any-grade adverse events occurred in 92.7% of patients treated with Tecentriq vs 70.7% of patients receiving BSC. The rate of grade 3/4 adverse events for Tecentriq was almost double that for BSC, at 21.8% and 11.5%, respectively.
PD-1/L1 inhibitors have become established in the advanced/unresectable setting for NSCLC, where Tecentriq competes with Opdivo, Keytruda, Bavencio, and Imfinzi. The significance of PD-L1 as biomarker for PD-1 inhibitors in the metastatic setting appears to vary depending on whether the PD-1 inhibitor is used as monotherapy or in combination with chemotherapy. Early PD-L1 testing, likely representing a shift in testing behaviours for some HCPs, would be required to maximise the opportunity for Tecentriq in the adjuvant setting.
The premise of treating cancer early for better outcomes is a message that is widely broadcasted. The prognosis for early-stage cancer detection is undoubtedly better than for a late-stage diagnosis. But upon early-stage cancer diagnosis, is the best approach always to treat aggressively, using all available treatment options upfront, in the knowledge that for some patients this represents ‘over-treatment’?
Indeed, for some patients, surgery +/- chemo/radiotherapy alone would have been sufficient to prevent their cancer from returning. For the three therapies discussed above, Lynparza, Keytruda, and Tecentriq, the current standard of care in the adjuvant setting in their respective indications is BSC/no further treatment, meaning that the decision to treat with either one of these therapies results in exposing patients to toxicities that they need not have experienced, with a negative impact on their QoL. Of course, for other patients, whose disease would have recurred without such treatment, the toxicities are likely a welcome trade-off.
Additionally, if therapies are used in the adjuvant setting, does this mean that this therapy or other therapies within the same drug class will not be effective in the advanced setting should the disease recur? How will HCPs determine, on a case-by-case basis, whether the adjuvant setting is the best place to use a therapy that is also approved in the advanced setting?
Better identifying patients who would benefit from adjuvant treatment is still an area that could be improved. Indeed, for Impower010, the HR for DFS in PD-L1>50% was 0.43, strikingly in favour of Tecentriq. Longer-term data, with subgroup analysis will hopefully help in better selecting the patients most likely to benefit.
For all of the adjuvant trials discussed, DFS was the primary endpoint, resulting in the trial outcomes being determined more quickly than if OS was used, ultimately bringing therapies to the market, and to patients, sooner. However, in the absence of OS data, the question remains of whether patients are being cured – if OS is the same, is the best approach to treat all patients in the adjuvant setting, in the hope of delaying relapse for some?
And although cost is not typically at the forefront of HCPs’ treatment decision-making considerations, there is the societal impact of increased healthcare costs associated with using costly treatments in the adjuvant setting. Circling back to the theme of this year’s ASCO, will every patient, every day, everywhere have access to these adjuvant therapies?
- OlympiA: A phase 3, multicenter, randomized, placebo-controlled trial of adjuvant olaparib after (neo)adjuvant chemotherapy in patients with germline BRCA1/2 mutations and high risk HER2-negative early breast cancer. ASCO 2021; Abstract LBA1.
- Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for patients with renal cell carcinoma: Randomized, double-blind, phase III KEYNOTE-564 study. ASCO 2021; Abstract LBA5.
- 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). ASCO 2021; Abstract 8500.
By Gemma McConnell