About 28,000 attendees from over 130 countries gathered last week at the ESMO 2018 Congress held in Munich, Germany, to hear the latest and greatest in the world of oncology.

DRG experts were on the ground to follow the exciting data releases and take the pulse of the oncology community in the ever-expanding and dynamic cancer landscape.

In this piece, we focus on two practice-changing Phase III trials in breast cancer, for which data were first unveiled at the ESMO 2018 Congress: IMpassion 130 for Roche’s immune checkpoint inhibitor Tecentriq, and SOLAR-1 for Novartis’s PI3Kα inhibitor alpelisib.

IMpassion 130 is the first Phase III trial to demonstrate a benefit with immunotherapy in first-line metastatic triple-negative breast cancer

The prognosis of triple-negative patients is poor relative to that of other breast cancer subtypes, with median OS estimates at 18 months or less,1-2 and the current treatment paradigm for metastatic patients remain centered on chemotherapy regimens.

The PD-L1 inhibitor Tecentriq is approved for certain patients with bladder cancer and NSCLC and has shown promising activity in several other cancer types, including breast cancer. A Phase Ib trial of single-agent Tecentriq conducted in metastatic triple-negative patients reported activity in both PD-L1-positive and PD-L1-negative tumors, and a separate Phase Ib trial of Tecentriq plus Abraxane provided a proof-of-concept for PD-1/PD-L1 inhibition in combination with chemotherapy in this indication.3-4

These results led to the design of the Phase III IMpassion 130 trial to evaluate Tecentriq plus Abraxane as a first-line treatment for locally advanced or metastatic triple-negative breast cancer. The first key results from this landmark trial, presented at the Presidential Symposium and simultaneously published in the New England Journal of Medicine, are summarized below.5-6


Key Results from the Phase III IMpassion 130 Trial of Tecentriq Plus Abraxane in Metastatic Triple-Negative Breast Cancer


Key highlights from IMpassion 130 include the following:

  • The final PFS analyses demonstrated significant improvements for Tecentriq plus Abraxane over Abraxane alone, with a greater magnitude of improvement in median PFS among PD-L1-positive patients (2.5 months) than in the overall population (1.7 months). Subgroup analyses showed that the PFS benefit was consistent across all subgroups tested, with the notable exception of PD-L1 expression—there was no PFS benefit in PD-L1-negative patients (HR 0.95).
  • At this first interim analysis, a 3.7-month improvement in OS was reported in the ITT population (albeit not statistically significant). Importantly, a clinically meaningful 9.5-month improvement in OS was observed among PD-L1-positive patients, with a HR of 0.62—formal statistical testing was not performed in this population (the study design requires that OS be tested in PD-L1-positive patients only if found significant in the ITT population).

Although OS data are still immature (59% of death events has occurred at the time of this interim OS analysis), these results are impressive and finally bring breast cancer—one of the largest oncology indications by incidence—into the immunotherapy era.

Using PD-L1 expression can help enrich the population of metastatic triple-negative breast cancer patients who may benefit from combined immunochemotherapy as a first-line treatment.

These data are also a key win for Roche, which already dominates the HER2-positive breast cancer space, and will likely help expand their reach into the underserved triple-negative setting.


SOLAR-1 is the first Phase III trial to demonstrate a clinically significant benefit with a PI3K inhibitor in metastatic HR-positive, HER2-negative breast cancer

The phosphatidylinositol-3-kinase (PI3K) pathway is commonly altered in cancer and its activation has been shown to confer resistance to endocrine and HER2-targeted therapies.7 Four isoforms of the catalytic subunit of PI3K (p110) have been characterized (α, β, γ, and δ); the α isoform is encoded by PIK3CA.8 In hormone receptor (HR)-positive, HER2-negative breast cancer, the median prevalence of activating PIK3CA mutations is 36%, thus making PI3K an attractive target in this indication.9

Alpelisib is an oral inhibitor of the α isoform of PI3K. The Phase III SOLAR-1 trial sought to evaluate the addition of alpelisib to Faslodex in advanced or metastatic HR-positive, HER2-negative breast cancer patients with disease recurrence or progression after prior aromatase inhibitor therapy. Novartis reported in August 2018 that the trial met its primary end point of PFS in PIK3CA-mutant patients.10 Key results unveiled at the ESMO 2018 Congress are summarized below.11


Key Results from the Phase III SOLAR-1 Trial of Alpelisib Plus Faslodex in Advanced or Metastatic HR-Positive, HER2-Negative Breast Cancer


Key highlights from SOLAR-1 include the following:

  • Results are impressive and show that the addition of alpelisib to Faslodex nearly doubled median PFS (5.3-month improvement) among patients with activating PIK3CA PFS improvements were consistent across different PIK3CA mutation exons and subtypes (data not shown).
  • Importantly, subgroup analyses also suggest that the PFS benefit in PIK3CA-mutant patients was observed irrespective of prior CDK4/6 inhibitor therapy—although we note that 94% of PIK3CA-mutant patients enrolled in the SOLAR-1 trial were naive to CDK4/6 inhibitors.
  • There was no signal of PFS benefit in patients without PIK3CA mutations, suggesting that PIK3CA mutations may be a predictive biomarker for alpelisib-based therapy.

Alpelisib is the first PI3Kα inhibitor to demonstrate clinically meaningful PFS improvements in metastatic HR-positive, HER2-negative breast cancer with activating PIK3CA mutations. These results suggest that isoform-specific PI3K inhibitors display greater clinical efficacy and a more-favorable safety profile.

Previously, in the Phase III SANDPIPER trial, Roche’s PI3K inhibitor taselisib showed a modest 2.0-month improvement in PFS when added to Faslodex compared with Faslodex alone in PIK3CA-mutated patients, but at the cost of greater serious side effects, notably gastrointestinal toxicities—these results led Roche to decide against pursuing regulatory approvals.12

Another pan-PI3K inhibitor, buparlisib, in combination with Faslodex met PFS in two Phase III trials (BELLE-2 and BELLE-3) in previously treated metastatic HR-positive, HER2-negative breast cancer but the poor safety profile of the combination led to frequent treatment discontinuations.13-14

If approved, alpelisib will create the need to test patients for PIK3CA mutations in routine practice—a major change in the current diagnostic workup for breast cancer. However, the biggest question is on where alpelisib will end up fitting in the treatment algorithm for metastatic HR-positive, HER2-negative patients.

Indeed, CDK4/6 inhibitors are now firmly established as the standards of care in this setting, and very few patients in the SOLAR-1 trial has been pretreated with CDK4/6 inhibitors, making alpelisib’s optimal positioning somewhat uncertain at this point.


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  1. Gobbini E, et al. Time trends of overall survival among metastatic breast cancer patients in the real-life ESME cohort. Eur J Cancer. 2018;96:17-24.
  2. Yardley DA, et al. Nab-Paclitaxel plus carboplatin or gemcitabine versus gemcitabine plus carboplatin as first-line treatment of patients with triple-negative metastatic breast cancer: results from the tnAcity trial. Ann Oncol. 2018;29:1763-1770.
  3. Emens LA, et al. Long-term outcomes and biomarker analyses of atezolizumab therapy for patients with metastatic triple-negative breast cancer: a Phase I study. JAMA Oncol. 2018 Sep 13. [Epub ahead of print]
  4. Adams S, et al. Atezolizumab plus nab-paclitaxel in the treatment of metastatic triple-negative breast cancer with 2-year survival follow-up: a Phase Ib clinical trial. JAMA Oncol. 2018 Oct 19. [Epub ahead of print]
  5. Schmid P, et al. IMpassion130: results from a global, randomised, double-blind, phase 3 study of atezolizumab (atezo) + nab-paclitaxel (nab-P) vs placebo + nab-P in treatment-naive, locally advanced or metastatic triple-negative breast cancer (mTNBC). Proceedings of the ESMO 2018 Congress. Abstract LBA1_PR.
  6. Schmid P, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018 Oct 20. [Epub ahead of print]
  7. Keegan NM, et al. PI3K inhibition to overcome endocrine resistance in breast cancer. Expert Opin Investig Drugs. 2018;27:1-15.
  8. Lux MP, et al. The PI3K pathway: background and treatment approaches. Breast Care (Basel). 2016;11:398-404.
  9. Mollon L, et al. A systematic literature review of the prevalence of PIK3CA mutations and mutation hotspots in HR+/HER2- metastatic breast cancer. Proceedings of the AACR 2018 meeting. Abstract 1207.
  10. Novartis, press release, August 23, 2018.
  11. André F, et al. Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): results of the Phase 3 SOLAR-1 trial. Proceedings of the ESMO 2018 Congress. Abstract LBA3_PR.
  12. Baselga J, et al. Phase III study of taselisib (GDC-0032) + fulvestrant (FULV) v FULV in patients (pts) with estrogen receptor (ER)-positive, PIK3CA-mutant (MUT), locally advanced or metastatic breast cancer (MBC): primary analysis from SANDPIPER. Proceedings of the ASCO 2018 meeting. Abstract LBA1006.
  13. Baselga J, et al. Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, Phase 3 trial. Lancet Oncol. 2017;18:904-916.
  14. Di Leo A, et al. Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, Phase 3 trial. Lancet Oncol. 2018;19:87-100.


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