Overall Survival Analysis from IMpassion130 in Triple-negative Breast Cancer

Triple-negative breast cancer (TNBC) is a breast cancer subtype that typically affects younger women, metastasizes early and carries a poor prognosis.¹ However, it has a number of characteristics associated with enhanced response to immune checkpoint inhibitors, including increased tumour-infiltrating lymphocytes and programmed death-ligand 1 (PD-L1) expression.² In 2018, the IMpassion130 clinical trial (ClinicalTrials.gov Identifier: NCT02425891) found that atezolizumab in combination with nab-paclitaxel improved survival in locally advanced or metastatic TNBC.³ Disappointingly, recently presented initial findings from the IMpassion131 clinical trial (ClinicalTrials.gov Identifier: NCT03125902), in which atezolizumab was combined with paclitaxel rather than nab-paclitaxel, showed no significant survival benefits.⁴

In an expert interview during the Virtual 2020 European Society of Medical Oncology (ESMO) Congress, 19–21 September 2020, Prof. Leisha A Emens discusses the final overall survival (OS) analysis of IMpassion 130, as well as the failure of IMpassion131 to meet its primary endpoints, and future directions for atezolizumab research. The late-breaking abstract ‘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’ (LBA16) was presented at the Virtual 2020 ESMO Congress, 19–21 September 2020.⁵

Q. Could you give us a brief overview of the IMpassion130 study and its efficacy and safety findings?

IMpassion130 was the first global randomised placebo-controlled clinical trial to demonstrate a clinical benefit for the addition of programmed cell death protein 1 (PD-1) or PD-L1 blockade to standard therapy for advanced TNBC.³ It investigated the addition of the PD-L1 inhibitor, atezolizumab, or placebo to the chemotherapy drug nab-paclitaxel. The patient population had histologically documented, locally advanced, incurable or metastatic TNBC, they had not received prior therapy for their advanced disease, and were required to provide a tissue sample for analysis of PD-L1 expression. Nine hundred and two patients were randomised 1:1 to receive atezolizumab or placebo plus nab-paclitaxel, and continued their treatment until disease progression or the development of unacceptable toxicities. The study had three stratification factors: the presence or absence of liver metastases, a history of prior taxane therapy, and PD-L1 immune cell status. The study also required an interval since the last chemotherapy given in the curative setting of at least 12 months. The study had four pre-specified co-primary endpoints: progression-free survival (PFS) in both the intent to treat and PD-L1 immune-cell–positive populations, and OS in both of these populations.

At the first analysis, there was a statistically significant improvement in PFS in both the intent to treat and PD-L1 immune-cell–positive populations. Notably, a 2.5-month improvement was reported in the PD-L1 immune-cell–positive group. At the time of the first analysis, there was a numerical prolongation of OS in the intent-to-treat patient population that did not reach statistical significance. However, there was a 9.5-month improvement in the PD-L1 immune-cell–positive group, which had a hazard ratio of 0.62, identical to the improvement in PFS in the same patient population. This was not statistically tested due to the hierarchical statistical analysis plan.

Overall, the treatment was quite well tolerated. Numerical increases were seen in adverse events, including serious adverse events and immune-related adverse events, but these tended to be of low grade and were easy to manage. They typically did not result in treatment discontinuation. The most common immune-related adverse events were rash, and hyperthyroidism, both of which were typically low grade. The most common reason for treatment discontinuation was development of neuropathy, which was related to the nab-paclitaxel.

At ESMO, we presented an update for the OS analysis, which was the final OS data for the study, so the data are quite mature, with around 75% of the events coming in. At this final analysis we saw a 7.5-month improvement in OS, specifically in the PD-L1 immune-cell–positive patient population. The difference in the intent-to-treat patient population still did not reach statistical significance. The important finding is that this therapy is very well tolerated and maintains or improves a patient’s quality of life. There is also a consistent improvement in OS in the PD-L1 immune-cell–positive patient population across all three IMpassion130 analyses, with a hazard ratio of 0.62, 0.71 and 0.67 respectively.^5–7 The combination of atezolizumab and nab-paclitaxel represents the preferred option for the first-line therapy of patients with PD-L1 immune-cell–positive advanced incurable TNBC.

Q. What have we learned from the final overall survival analysis of this study?

We have learned that the benefit is clearly limited to the PD-L1 cell positive population. The hazard ratio for OS in the final analysis was 0.67, corresponding to a 7.5 month prolongation of OS. By contrast, in the PD-L1 cell negative population, there was no treatment effect at all. Therefore patient selection is key for this treatment. Even with this biomarker-based patient selection, not all patients with PD-L1 immune-cell–positive disease respond, so we still have some work to do with regard to better selection of patients most likely to benefit from this drug combination. In addition, there remains a major unmet need for the PD-L1 negative patient population.

Q. What are your thoughts on the failure of IMpassion131 to meet its primary endpoints?

These findings surprised everyone. IMpassion131 enrolled a very similar patient population to IMpassion130 in terms of eligibility criteria.⁴ It was a first-line study, patients were required to provide a tissue sample for PD-L1 status evaluation and they had to have a 12-month interval from prior chemotherapy. The design was slightly different in terms of the statistical analysis plan as well as the randomisation. Patients were randomised in a 2:1 ratio to receive atezolizumab or placebo in combination with paclitaxel rather than nab-paclitaxel. There was no difference in PFS, which was the primary endpoint.

Potential reasons for these findings are that the drugs are very different; they enter the tumour microenvironment and act differently there. The delivery method of the drug is different: nab-paclitaxel is albumin bound and paclitaxel is solvent formulated. There may be some unappreciated heterogeneity in the patient population. IMpassion130 was designed with nab-paclitaxel because premedication with steroids is not needed with nab-paclitaxel, whereas steroids are needed for paclitaxel. In IMpassion130, steroid medication was encouraged for the first few cycles, after which physicians could elect to wean off. In IMpassion131, steroids were taken throughout the duration of the chemotherapy. This could have played a role, but the reason for the difference in outcomes remains unclear. Given the similarity of the patient populations, it gives us an opportunity to do some good translational science and research on the samples that were collected during the study so that we can dissect the biology that underlies these differences.

Q. What are the implications of the findings of IMpassion130 and 131 for future clinical practice?

One of the reasons that IMpassion131 was conducted was that nab-paclitaxel is not available in some areas of the world. It therefore aimed to broaden the availability of immunotherapy for people with this aggressive disease. The two trials have told us that the only effective chemotherapy partner for atezolizumab is nab-paclitaxel. This remains the treatment of choice for the first-line therapy of patients with advanced PD-L1 immune-cell–positive TNBC.

I would be inclined to use nab-paclitaxel based on information available today, should pembrolizumab become available. KEYNOTE-355 is an ongoing trial evaluating the addition of pembrolizumab to chemotherapy; the chemotherapy options could be paclitaxel, nab-paclitaxel, or gemcitabine/carboplatin.⁸ It is not clear how much of a difference there was between those particular regimens, but given what we know today, my inclination would be to pair pembrolizumab with nab-paclitaxel.

Q. How can the efficacy of atezolizumab be improved in this hard-to-treat patient population, and what future studies are planned?

There is great interest in moving immunotherapy into the early disease setting. Two phase III studies, one with pembrolizumab⁹ and one with atezolizumab,¹⁰ are showing an improvement in pathological complete response rate when these agents are added to standard neoadjuvant chemotherapy. Most of us think that the earlier you use these immunotherapy drugs in treatment, the more likely it is that patients will derive a lasting benefit. Both trials are at an early stage in terms of results, so we still need long-term follow-up data on event-free survival and other long-term clinical outcomes. I think it is very positive for patients that we have signals of clinical benefit in both the metastatic disease setting as well as in the locally advanced early disease setting.

There is interest in looking at the addition of immunotherapy to human epidermal growth factor receptor 2 (HER2)-positive disease. We studied the addition of atezolizumab to trastuzumab emtansine, the antibody–drug conjugate, in HER2-positive metastatic disease, and found a signal of clinical benefit in the PD-L1 immune-cell–positive population in an exploratory analysis.¹¹ This will be further investigated with hopes of realising a benefit for immunotherapy in that particular patient population.

A large unmet need continues to be oestrogen receptor-positive breast cancer. It tends to be the least immune activated of all the breast cancer subtypes and very driven by myeloid biology, so we have a lot of work to do in that space with regard to immunotherapy.

References

1. Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med. 2010;363:1938–48.
2. Keenan TE, Tolaney SM. Role of immunotherapy in triple-negative breast cancer. J Natl Compr Canc Netw. 2020;18:479–89.
3. Schmid P, Adams S, Rugo HS, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379:2108–21.
4. Miles DW, Gligorov J, André F, et al. LBA15 – 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). Ann Oncol. 2020;31(Suppl 4):S1142–S215.
5. Emens LA, Adams S, Barrios CH, et al. LBA16 – 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. Ann Oncol. 2020;31(Suppl 4):S1142–S215.
6. Schmid P, Adams S, Rugo HS, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379:2108–21.
7. Schmid P, Rugo HS, Adams S, et al. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2020;21:44–59.
8. Cortes J, Cescon DW, Rugo HS, 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. J Clin Oncol. 2020;38(15 suppl):1000s.
9. Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382:810–21.
10. Mittendorf EA, Zhang H, Barrios CH, et al. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet. 2020;396:1090–100.
11. Emens LA, Esteva FJ, Beresford M, et al. Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): a phase 2, multicentre, randomised, double-blind trial. Lancet Oncol. 2020;21:1283–95.

Author profile: Prof. Leisha Emens is Professor of Medicine at the University of Pittsburg Medical Center Cancer Center at the Univeristy of Pittburg, Pennsylvania, US. Prof. Emens has specialised in breast cancer immunotherapy for 25 years.

Disclosures: Prof Leisha A Emens would like to declare the following: consulting/advisory board/honoraria – honoraria to self; AbbVie – honoraria; Amgen – honoraria; AstraZeneca – honoraria, travel/accommodation/expenses; Bayer – honoraria, travel/accommodation/expenses; Bristol Meyers Squibb – travel/accommodation/expenses; Celgene – honoraria; Chugai – honoraria; CytomX – no compensation; eTHeRNA – no compensation; Genentech – travel/accommodation/expenses; Gritstone – honoraria; Medimmune – honoraria; Molecuvax (potential for stock in future); Macrogenics – honoraria, travel/accommodation/expenses; Novartis – travel/accommodation/expenses; Peregrine – honoraria; Replimune – honoraria, travel/accommodation/expenses; Roche – travel/accommodation/expenses; Shionogi – advisory board, honoraria; Silverback – no compensation; Syndax – honoraria; Vaccinex – honoraria, travel/accommodation/expenses.

Support: Commissioned, edited and supported by Touch Medical Media. Writing assistance was provided by Katrina Mountfort of Touch Medical Media. The IMpassion trial was sponsored by F. Hoffmann-La Roche, Ltd.

Published: 12 November 2020

This interview can be viewed in video format on touchONCOLOGY here.