I-SPY Graduates: Where Are They Now?

Five neoadjuvant breast cancer regimens have been tested successfully in I-SPY Phase II program, but three have not moved on to sponsor-driven pivotal testing and the I-SPY 3 master protocol has yet to be used.

The afterlife of the first group of drug candidates to successfully “graduate” from the I-SPY 2 adaptive platform trial suggests that real-world hurdles may hamper the ability of novel trial designs to accelerate drug development.

Since its inception in 2010, the Phase II study has identified five product candidates as having a high probability of success in Phase III in specific, biomarker-defined groups of early breast cancer patients.

So far, however, only one of five regimens successfully tested in the Phase II program has moved on to Phase III in that cohort. Another was already approved by the time I-SPY results were released.

I-SPY, which stands for Investigation of Serial Studies to Predict Your Therapeutic Response through Imaging and Molecular Analysis, is sponsored by the non-profit QuantumLeap Healthcare Collaborative and was launched in partnership with the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium. The idea behind I-SPY 2 is to quickly test multiple candidates at the same time against a common control. Experimental drugs, or more commonly combination regimens, are combined with standard neoadjuvant (pre-surgery) chemotherapy to treat early-stage breast cancers with a high risk of recurrence. Patients are extensively tested for biomarkers, and adaptive randomization is used within subtypes to focus testing of regimens with better performance than standard chemotherapy.

Ideally, drugs that show an 85% or greater probability of success in Phase III "graduate” from the Phase II study and are quickly moved to pivotal trials organized with a master I-SPY protocol. Performance in the mid-stage testing is determined by pathological complete response (pCR), an emerging endpoint for early-stage breast cancer, which hopefully will be predictive of disease-free survival in Phase III studies.

The I-SPY adaptive trial design relies on Bayesian statistics, which do not yet have much history in clinical programs leading to approval, although enthusiasm over the potential of adaptive trials to accelerate drug development is widespread. Publication of results for AbbVie Inc.'s veliparib and Puma Biotechnology Inc.'s neratinib showing performance for particular biosignatures, or subsets of patients, in the New England Journal of Medicine and a positive editorial about I-SPY on July 7 could give the model a big boost. (Also see "I-SPY 2 Helping To Normalize Adaptive Trial Designs" - Pink Sheet, 10 Jul, 2016.).

I-SPY has tested a range of targeted therapies with different mechanisms in Phase II for neoadjuvant breast cancer, including Roche's HER2-directed therapies Perjeta (pertuzumab) and Kadcyla (ado-trastuzumab emtansine, or T-DM1), as well as Merck & Co. Inc.'s AKT inhibitor MK-2206 (see box).

Proprietary Drugs Tested In I-SPY

• Roche’s Perjeta, Kadcyla and Herceptin
• Puma’s neratinib
• AbbVie’s veliparib
• Amgen’s trebananib (AMG 386)
• NantWorks’ AMG 479
• Merck’s Keytruda and MK-2206
• Synta’s ganetespib
• Daiichi Sankyo’s pexidartinib (PLX3397)

Off To A Fast Start

The master protocol used in I-SPY 2 helped speed the start of Phase II evaluation for candidate drugs. Typically, it takes only five or six months from the time a pharma partner presents with Phase I data to the opening of a Phase II study arm, said Melissa Paolini, director of advanced clinical trials at QuantumLeap Healthcare Collaborative.

"The I-SPY 2 study start-up period takes approximately 45-60 days, with more than 50% of the sites opening and enrolling patients, as opposed to the traditional study start-up timing of 10 to 13 months, with less than 25% of the sites opening and enrolling," QuantumLeam reported in a July 7 statement.

A master protocol for a Phase III program, I-SPY 3, has been reviewed by the FDA and EMA and provides a path forward for graduates of I-SPY 2. The idea is that QuantumLeap would run the study, but funding would come from pharmaceutical partners. The whole point is, after all, to get new drugs and regimens to the market so companies must be on board.

Graduates Slow To Move On

The model is exciting from a clinical and statistical point of view, but experience to date suggests challenges with implementation of the Phase II to Phase III transition.

Neratinib and veliparib were the first of the five products identified to date to show promise as Phase III candidates. Both candidates officially graduated from I-SPY 2 in March 2014, neratinib for patients with the HER2-positive, hormone receptor-negative signature and veliparib plus carboplatin for triple-negative breast cancer (see chart below).

Based on the findings, AbbVie promptly started a Phase III study of veliparib in triple-negative breast cancer on its own, as the I-SPY 3 master protocol was not formalized at that time.

Advantages of using the I-SPY 3 protocol include use of a master protocol with shared control arms, working with a team that has collaborated with FDA on development of drugs for high-risk early stage breast cancer and harmonized regulatory processes globally, Paolini said in an interview.

"We are obviously eager, just like I am sure the rest of the community is … to see what their Phase III results will be," Paolini said.

QuantumLeap would also like to see neratinib move forward based on I-SPY 2 results.

The Phase II study, however, tested Puma’s neratinib with chemo against Herceptin/chemo. Since I-SPY 2 began, the standard of care has arguably changed, thanks to FDA’s September 2013 accelerated approval of the combination of Perjeta and Herceptin (trastuzumab) with docetaxel in the neoadjuvant HER2+ breast cancer setting. (Also see "Life After I-SPY Graduation: Neratinib Likely To Be Tested With Roche’s Perjeta" - Pink Sheet, 22 Apr, 2014.)

QuantumLeap is currently doing additional Phase I testing with Puma.

While Puma has not moved neratinib into a Phase III study in HER-2 positive, hormone receptor negative neoadjuvant breast cancer, either on its own or through I-SPY, the company does have two Phase III studies in other breast cancer indications.

The next experimental drug to officially graduate from I-SPY 2 was Merck's AKT inhibitor MK-2206 in June 2015.

QuantumLeap said that it would like to see the MK-2206 regimen tested in I-SPY 2 move into Phase III for the three biomarker signatures where it has a high probability of success: hormone receptor-negative, HER2-positive, and HER-negative/HER2-positive breast cancer.

However, a spokesman for Merck told the Pink Sheet that "we have not disclosed any development efforts for MK-2206 at this time. The compound remains on our pipeline chart under Phase II development."

I-SPY Adaptive Trial Graduates: Neoadjuvant , High-Risk Breast Cancer
To graduate from I-SPY 2, experimental drugs must show much a better pathological complete response (pCR) rate against a control arm, with performance reported for 10 biomarker signatures*. Out of five I-SPY 2 graduates so far, one – AbbVie's veliparib – has progressed to a company-sponsored Phase III study for the indication highlighted in Phase II. Another – Roche's Perjeta/Herceptin – was already approved at the time of I-SPY 2 graduation. QuantumLeap has a master protocol for pivotal testing called I-SPY 3, but it has not been used yet.
Neoadjuvant Regimen Tested	Mechanism of Action	Official Graduation Date, Phase II I-SPY Results	Where Are They Now? Sponsors’ Phase III trials
Puma Biotechnology’s neratinib with paclitaxel followed by doxorubicin/cyclophosphamide	Irreversible tyrosine kinase inhibitor with chemo	March 2014: Neratinib regimen has superior pCR vs. standard chemo in one biomarker type: hormone receptor-negative and HER2-positive primary breast cancer (56% vs. 33%). Probability of Phase III in trial of 300 patients is 79%. Some evidence of superior activity over control in several other biomarker signatures. Diarrhea is problematic side effect, but may be managed. Results reported by JW Park et al. in NEJM July 7, 2016.	ExteNET: Neratinib after adjuvant Herceptin in early stage HER-2/Neu overexpressed/amplified breast cancer. (Start: July 2009, End: November 2016). NCT01808573 tests neratinib plus capecitabine vs lapatinib plus capecitabine in HER2+ metastatic breast cancer after two or more prior HER2 (Start: March 2013, End: May 2018).
AbbVie’s veliparib (ABT-188) with carboplatin	PARP inhibitor with chemo	March 2014: Veliparib combo graduates in triple-negative breast cancer. In this type, pCR was better for veliparib-carboplatin (33%) vs. paclitaxel (22%). Results predict 88% probability of success in Phase III trial. Data reported by Hope Rugo et al. in NEJM July 7, 2016.	Phase III BRIGHTNESS study tests veliparib and carboplatin vs. carboplatin with standard chemo vs. standard chemo in early triple-negative breast cancer (Start: April 2014, End: March 2016). NCT02163694 tests carboplatin and paclitaxel with or without veliparib in HER2-negative metastatic BRCA-associated breast cancer (Start: July 2014, End: Jan 2017).
Merck's MK-2206 + paclitaxel and Herceptin if HER2-positive, followed by doxorubicin and cyclophosphamide	AKT inhibitor + chemo and HER2 therapy	June 2015: MK-2206-containing regimen has high probability of success for three biomarker signatures: all hormone receptor-negative, all HER2-positive and HER-negative/HER2-positive.	No Phase III trials ongoing.
Roche’s Kadcyla (T-DM1) and Perjeta (pertuzumab), followed by doxorubicin and cyclophosphamide	Dual HER2 therapy followed by chemo	April 2016: T-DM1/Perjeta/chemo regimen outperformed Herceptin/paclitaxel/chemo, with less toxicity. 90%-94% chance of success in 300-patient Phase III trial of HER2-positive breast cancer with any of these three biomarkers: HER2-positive, HER2-positive and hormone receptor positive and HER2-positive and HR-negative.	Roche announced in its 1Q earnings call plans to file Kadcyla/Perjeta combo for approval in neoadjuvant breast cancer in 2016, but the regimen failed against Perjeta/Herceptin/docetaxel in the KRISTINE study, released at ASCO in June. Studies in other settings ongoing.
Roche’s Perjeta plus Herceptin (trastuzumab) and paclitaxel	Dual HER2 therapy	April 2016: Perjeta/Herceptin paclitaxel superior to Herceptin/paclitaxel.	Granted accelerated approval by FDA for neoadjuvant breast cancer in September 2013. Arguably changed standard of care in US.
*I-SPY assesses performance for 10 clinically relevant biomarker signatures in the protocol: any biomarker; hormone-receptor–positive; hormone-receptor–negative; HER2-positive; HER2-negative; high-risk category 2 on the 70-gene MammaPrint assay; HER2-positive and hormone-receptor–positive; HER2-positive and hormone-receptor–negative; HER2-negative and hormone-receptor–positive; and triple-negative (HER2-negative, estrogen-receptor–negative, and progesterone-receptor–negative).
Source: QuantumLeap Healthcare, ClinicalTrials.gov, Biomedtracker

In April 2016, coinciding with the American Association for Cancer Research annual meeting, QuantumLeap announced two graduations for combinations of Roche products: Perjeta with Herceptin and docetaxel (Taxotere and generics) and Perjeta with Kadcyla, followed by chemo.

However, by then Perjeta had already been approved for use with Herceptin and chemotherapy in neoadjuvant breast cancer in September 2013. The I-SPY arm was already open at that time. QuantumLeap said that it is "gratified to see that our results are concordant" with the data supporting accelerated approval.

As for the Perjeta/Kadcyla combo, as with the neratinib arm, the comparator in I-SPY 2 was behind the standard of care established with the Perjeta approval (including dual HER2 therapy with Perjeta/Herceptin) at the time of the graduation.

Roche progressed a different regimen with a different comparator into the Phase III KRISTINE neoadjuvant study in HER2+ early breast cancer, testing Perjeta plus Kadcyla against an FDA-approved neoadjuvant regimen of Perjeta, Herceptin, docetaxel and carboplatin.

However, at the American Society of Clinical Oncology annual meeting in June, the company announced that the Kadcyla/Perjeta arm missed the pCR primary endpoint in the trial – 44.4% vs. 55.7%, a statistically significant result.

Genentech notes that it is not appropriate to make cross-trial comparisons between I-SPY 2 and KRISTINE because there were several differences, including patient eligibility criteria, trial design and control arms.

"Although we are disappointed in the results of the KRISTINE trial, we remain committed to investigating Kadcyla in other settings and tumor types where unmet need remains high," a Genentech spokesperson said in an email.

For example, the KATHERINE study tests Kadcyla vs. Herceptin in adjuvant HER2+ early breast cancer and KAITLIN compares Kadcyla and Perjeta to Herceptin/Perjeta and taxane therapy in the adjuvant setting for people with HER2+ early breast cancer.

Genentech declined to speculate about whether it would progress the regimen tested in I-SPY 2 to Phase III.

QuantumLeap's Paolini emphasized the high value to patients of lower toxicity associated with Perjeta/Kadcyla, which was reported in both I-SPY 2 and KRISTINE. KRISTINE investigators reported a severe adverse event rate of 13% for Kadcyla/Perjeta vs. 64.4% for the comparator arm.

Edith Perez, VP and head of BioOncology, U.S. Medical Affairs, at Genentech, noted that safety alone is still not an endpoint accepted for regulatory purposes.

Paolini said that I-SPY investigators are hopeful that it may be possible to determine which patients do well with Kadcyla (T-DM1) and which patients also need chemotherapy. That would be a "big save for patients who might benefit solely from the T-DM1/Perjeta regimen," Paolini said.

QuantumLeap is very eager to develop the T-DM1/pertuzumab combination and is open to changes to the design in follow-up trials, as opposed to using the same design from Phase II in Phase III, the non-profit group indicated.

"We are in discussions with Genentech in regards to a path forward for this regimen," QuantumLeap said.

Waiting For APHINITY

As the neratinib and Perjeta/Kadcyla experience in I-SPY shows, changes in the standard of care and medical knowledge are a general challenge for drug developers.

The oncology community is now awaiting confirmation of the Perjeta/Herceptin approval for neoadjuvant breast cancer, which was cleared under accelerated approval based on pCR as a surrogate endpoint. The confirmatory APHINITY trial, which tests Perjeta with Herceptin and chemotherapy in adjuvant HER2+ early breast cancer, is due to produce results this year. (Also see "Roche’s Master Plan: Perjeta Gains Early Breast Cancer Approval, Late-Stage Kadcyla Data" - Pink Sheet, 7 Oct, 2013.)

Planning for expensive, resource-intensive pivotal trials is difficult without knowing how the confirmatory trial will turn out. "As the community has waited for that, there has been somewhat of a cessation of development in Phase III, because there's been a challenging question of what is the right comparator," Paolini said.

In addition to providing clarification about the appropriate comparator, APHINITY will provide more information about the value of pCR as a surrogate endpoint.

The 2014 failure of the ALTTO study, despite evidence of pCR effect, created controversy over the endpoint. (Also see "Failed ALTTO Breast Cancer Trial Casts Doubt On pCR Marker" - Pink Sheet, 2 Jun, 2014.) At the time, I-SPY lead investigator Laura Esserman defended pCR as a surrogate marker and noted differences between I-SPY and ALTTO. (Also see "After ALTTO: I-SPY Will Hold More Clues About pCR Surrogate Endpoint" - Pink Sheet, 9 Jun, 2014.)

During the American Society of Clinical Oncology 2014 meeting, Genentech's Perez, then at the Mayo Clinic, suggested re-evaluation of reliance on pCR as a marker and of the I-SPY design was in order.

Today, Perez sees pCR as a novel endpoint that may eventually help speed up drug development. Patients with a good pCR tend to do better, as a general rule. And the rate of pCR does offer clues about potential efficacy, Perez said

"Most people have realized that this [pCR] is really like response rate in metastatic disease. It's not the ultimate endpoint, but it can be a helpful endpoint to [help] predict what may happen with patients," she said.

It's also still unclear how big of a differential needs to be seen in pCR in a neoadjuvant trial to translate into a disease-free survival improvement.

APHNITY may help to address this question, she said.