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By Members of the Oncology Insights Team: Angela Diana, Arman Esfandiari, Liseth Parra, Paul Wilcock

A look at the high-impact news from the ESMO Virtual Congress 2020

As a result of the current COVID-19 pandemic, the annual ESMO Congress was held virtually between 19th and 21st September 2020. Over 2,100 oral presentations and posters were presented, showcasing exciting novel data across oncology, with the ultimate aim of improving cancer patient care. Here DRG/Clarivate highlights the most impactful presentations on drug treatment landscapes.

  • Evolving landscape of immune checkpoint inhibitors in triple-negative breast cancer

Mixed results for Tecentriq puts Keytruda in pole position in metastatic triple-negative breast cancer; early-stage disease still up for grabs.

Roche’s Tecentriq was the first immune checkpoint inhibitor approved for metastatic PD-L1-positive triple-negative breast cancer (TNBC), in combination with Abraxane based on positive PFS data in IMpassion130. Analysis from this trial presented at ESMO 2020 demonstrated a statistically significant median OS benefit for Tecentriq + Abraxane (25.4 months) compared to placebo + Abraxane (17.9 months) in the PD-L1-positive population1. However, in data presented for IMpassion131, no difference was found between metastatic TNBC patients that received Tecentriq plus paclitaxel and placebo plus paclitaxel in terms of PFS and OS, irrespective of PD-L1 status2. In previously reported data, the addition of Merck & Co.’s Keytruda to several chemotherapy backbones (including Abraxane and paclitaxel) led to a statistically significant improvement in median PFS (9.7 months vs. 5.6 months) in inoperable/metastatic PD-L1-positive TNBC (KEYNOTE-355)3. The reasons behind these conflicting data are currently unknown and under investigation but nonetheless, will likely influence physicians’ choice of immune checkpoint inhibitor.

In high-risk early-stage TNBC, the addition of neoadjuvant Tecentriq to chemotherapy has shown a significant improvement in pCR rates regardless of PD-L1 status (57.6% vs. 41.1%)4, according to data presented at ESMO 2020 from IMpassion031. Previously, data from KEYNOTE-522 at SABCS 2019 demonstrated that adding neoadjuvant Keytruda to chemotherapy in patients with lymph-node-positive early-stage TNBC significantly improved pCR in the ITT population (64.8% vs. 51.2%)5. While these results provide complimentary evidence for adding an immune checkpoint inhibitor to neoadjuvant chemotherapy for early-stage TNBC, differentiating between the two drugs is currently challenging; EFS data could prove pivotal to the future roles of these drugs in the early-stage setting.

  • Ibrance stumbles while Verzenio exceeds in early-stage HR-positive / HER2-negative breast cancer

While Ibrance falters in the pivotal PALLAS study, Verzenio succeeds in monarchE, paving the way for approval in the most lucrative subpopulation of breast cancer.

Since entering the market in 2015, the CDK4/6 inhibitors―Pfizer’s Ibrance, Eli Lilly’s Verzenio/Verzenios and Novartis’ Kisqali―have become the standard-of-care for first-line advanced / metastatic HR-positive / HER2-negative breast cancer. These three agents are being evaluated in early-stage HR-positive / HER2-negative breast cancer, with Ibrance and Verzenio leading the way; however, the latest data from ESMO 2020 has contrasting outcomes for these key competitors.

The PALLAS trial recruited stage II-III HR-positive / HER2-negative breast cancer patients, which were randomized to receive adjuvant endocrine therapy +/- Ibrance; at an interim analysis, data presented at ESMO 2020 demonstrated that 3-year iDFS was similar between the two arms (88.2% vs. 88.5%)6. In a different approach, Verzenio was combined with endocrine therapy for high-risk early-stage HR-positive / HER2-negative breast cancer in the monarchE study. Data presented at the Congress showed 2-year iDFS was superior in the Verzenio + endocrine therapy arm compared to endocrine therapy alone (92.2% vs. 88.7%), resulting in an impressive 25.3% reduction in the risk of an iDFS event7. Although still under investigation, it is likely that the difference in outcome between these two studies is a result of the target patient populations, with Verzenio being assessed in patients with high risk of relapse, a population more likely to derive a benefit from additional pharmacological intervention. A lifeline for Pfizer’s Ibrance is the ongoing PENELOPE-B trial, which is focussed on high-risk patients.

  • The COMBI-i impasse: spartalizumab in combination with targeted therapy fails to add a significant benefit as treatment for BRAF mutation-positive metastatic melanoma8

A positive trend for the triplet regimen favors metastatic melanoma patients with high disease burden.

While the introduction of targeted therapies and immune checkpoint blockade has changed the treatment landscape of melanoma for the better, disease progression is still common for a number of patients. The COMBI-i study was set to evaluate Novartis’ Tafinlar plus Mekinist doublet, in combination with the investigational PD-1 inhibitor, spartalizumab, in metastatic BRAF mutation-positive melanoma. However, the investigator-assessed PFS primary endpoint set in the trial design failed to meet the threshold for statistical significance, resulting in median PFS rates of 16.2 vs. 12.0 months for the triplet regimen, compared to the placebo-controlled doublet, respectively (P = 0.042; HR = 0.82). Notably, ongoing subset analysis has demonstrated a benefit trend favoring the triplet regimen for patients with considerable bulk of disease (e.g., high TMB), who represent the highest unmet need group. In comparison, the IMspire150 study evaluating Roche’s Tecentriq, in combination with Zelboraf plus Cotellic, using a similar strategy as COMBI-i, but a different statistical design, has recently obtained approval in the United States for the treatment of metastatic disease.9,10 Nevertheless, long-term benefits from combining targeted therapies and immune checkpoint inhibition are yet to be demonstrated, as these findings cannot definitively prove whether concomitant therapy is superior to the sequential treatment options currently available.

  • Libtayo’s success in the EMPOWER-Lung 1 trial will not threaten Keytruda’s dominance in first-line metastatic NSCLC11

While Libtayo prolongs survival in first-line patients with PD-L1 expression ≥ 50%, it will face Keytruda head on.

The Phase III EMPOWER-Lung 1 trial is investigating the therapeutic potential of Libtayo monotherapy for the front-line treatment of PD-L1 > 50% TPS metastatic NSCLC compared with platinum doublet chemotherapy. In April 2020, Regeneron Pharmaceuticals and Sanofi announced that this trial would be stopped early for overwhelming efficacy. Interim data released in a late-breaking abstract at ESMO 2020 showed that median OS was not reached vs 14.2 months for Libtayo vs platinum doublet chemotherapy (HR 0.57, P < 0.001), in first-line metastatic NSCLC patients with confirmed PD-L1 expression ≥ 50%. The safety profile of Libtayo was consistent with earlier trials of this agent, and those of other PD-1/PD-L1 targeted immunotherapies. Regulatory filings for Libtayo are expected in the United States and Europe in 202012. However, given that Keytruda monotherapy was the first drug to be approved for the treatment of high PD-L1 expressing NSCLC in this setting, Libtayo will face an uphill struggle for patient share in this NSCLC patient population.

  • Positive results from the Phase III CROWN trial signal the imminent approval of Lorbrena / Lorviqua for the first-line treatment of metastatic ALK-translocation-positive NSCLC13

Pfizer’s ALK inhibitor, Lorbrena (marketed as Lorviqua in Europe), will not challenge Alecensa’s supremacy in the front-line treatment of ALK-translocation-positive metastatic NSCLC.

Planned interim analysis data from the CROWN trial, presented at ESMO virtual congress 2020, showed better efficacy outcomes for Lorbrena over Xalkori in first-line ALK-translocation-positive metastatic NSCLC. Blinded independent review committee’s (BIRC) assessment of PFS showed a 72% reduction in the risk of PFS events in the Lorbrena arm (HR 0.28, P < 0.001). Interestingly, the BIRC assessed secondary endpoint of intracranial-OR and CR also favored Lorbrena in patients with measurable and non-measurable brain metastases at baseline. Overall survival data, another secondary endpoint in this trial, was immature at the time of the analysis. There are currently four ALK inhibitors approved for the first-line treatment of ALK-positive metastatic NSCLC in the United States and Europe, namely Alecensa, Alunbrig, Xalkori and Zykadia. Alecensa has completely displaced other ALK inhibitors, including Xalkori, as the preferred first-line therapy. The comparison of Lorbrena vs Xalkori is no longer relevant given the current firs-line landscape, and therefore Lorbrena will struggle to unseat Alecensa in real practice.

  • Opdivo/Keytruda show promise in first-line gastroesophageal cancer Phase III trials

After the success of immune checkpoint inhibitors in several cancer types, Opdivo and Keytruda are now aiming to become the new standard-of-care for first-line gastroesophageal cancer patients

Results from three studies presented at ESMO 2020 highlighted the beneficial impact of immune checkpoint inhibitors for first-line patients with gastric and esophageal cancer. The ATTRACTION-4 and the CheckMate-649 trials evaluated Opdivo plus chemotherapy versus chemotherapy alone in patients with non-HER2-positive adenocarcinoma; the CheckMate-649 trial met its endpoint by improving both OS and PFS14. However, the ATTRACTION-4 trial, which only recruited Asian patients, showed an improvement in the coprimary endpoint PFS, but not OS15. The KEYNOTE-590 trial demonstrated superior OS, PFS, and ORR in locally advanced/unresectable or metastatic esophagogastric junction adenocarcinoma patients treated with Keytruda + chemotherapy in comparison with chemotherapy alone16. These outcomes suggest that immune checkpoint inhibitors + chemotherapy have the potential to become the new standard-of-care for first-line patients with gastric and esophageal cancer.

References 

  1. Emens LA, et al. IMpassion130: Final OS analysis from the pivotal phase III study of atezolizumab + nab-paclitaxel vs placebo + nab-paclitaxel in previously untreated locally advanced or metastatic triple-negative breast cancer. ESMO 2020; Abstract LBA16.
  2. Miles DW, et al. Primary results from IMpassion131, a double-blind placebo-controlled randomised phase III trial of first-line paclitaxel (PAC) ± atezolizumab (atezo) for unresectable locally advanced/metastatic triple-negative breast cancer (mTNBC). ESMO 2020; Abstract LBA15.
  3. Cortes J, et al. KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. JCO; 2020. 38(15); 1000.
  4. Harbeck N, et al. IMpassion031: Results from a phase III study of neoadjuvant (neoadj) atezolizumab + chemotherapy in early triple-negative breast cancer (TNBC). ESMO 2020; Abstract LBA11.
  5. Schmid P, et al. Keynote-522 study of pembrolizumab + chemotherapy vs placebo + chemotherapy as neoadjuvant treatment, followed by pembrolizumab vs placebo as adjuvant treatment for early triple-negative breast cancer: Pathologic complete response in key subgroups. SABCS 2019; GS3-03.
  6. Mayer EL, et al. PALLAS: A randomized phase III trial of adjuvant palbociclib with endocrine therapy versus endocrine therapy alone for HR+/HER2- early breast cancer. ESMO 2020; Abstract LBA12.
  7. Johnston SRD, et al. Abemaciclib in high risk early breast cancer. ESMO 2020; Abstract LBA5.
  8. Nathan P, et al. Spartalizumab plus dabrafenib and trametinib (Sparta-DabTram) in patients (pts) with previously untreated BRAF V600–mutant unresectable or metastatic melanoma: Results from the randomized part 3 of the phase III COMBI-i trial. ESMO 2020; Abstract LBA43.
  9. Chmielowski B, et al. Mastering the art of the management of patients with metastatic melanoma. ESMO 2020; Abstract 4816.
  10. Gutzmer R, et al. Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAF V600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020; 395:1835-1844.
  11. Sezer A, et al., EMPOWER-Lung 1: Phase 3 first-line (1L) cemiplimab monotherapy vs platinum-doublet chemotherapy (chemo) in advanced non-small cell lung cancer (NSCLC) with programmed cell death-ligand 1 (PD-L1) _50%. ESMO 2020; Abstract LBA52.
  12. Sanofi and Regeneron Pharmaceuticals, press release, April 27, 2020.
  13. Solomon B, et al., Lorlatinib vs crizotinib in the first-line treatment of patients (pts) with advanced ALK-positive non-small cell lung cancer (NSCLC): Results of the phase III CROWN study. ESMO 2020; Abstract LBA2.
  14. Moehler M, et al, Nivolumab (NIVO) Plus Chemotherapy (Chemo) Versus Chemo as First-Line (1L) Treatment for Advanced Gastric Cancer/Gastroesophageal Junction Cancer (GC/GEJC)/Esophageal Adenocarcinoma (EAC): First Results of the CheckMate 649 Study. ESMO 2020; Abstract LBA6.
  15. Buku N, et al. Nivolumab plus chemotherapy versus chemotherapy alone in patients with previously untreated advanced or recurrent gastric/gastroesophageal junction (G/GEJ) cancer: ATTRACTION-4 (ONO-4538-37) study. ESMO 2020; Abstract LBA7.
  16. Kato K, et al, Pembrolizumab Plus Chemotherapy Versus Chemotherapy as First-Line Therapy in Patients With Advanced Esophageal Cancer: The Phase 3 KEYNOTE-590 Study. ESMO 2020; Abstract LBA8.