Lifastuzumab vedotin, also known as DNIB0600A (RO5541081) and RG-7599, is an antibody-drug conjugate or ADC.

In clinical trials the investigational drug is compared to pegylated liposomal doxorubicin for the treatment of patients with platinum-resistant ovarian cancer.

Lifastuzumab vedotin is a humanized anti-NaPi2b monoclonal antibody conjugated to a potent anti-mitotic agent, monomethyl auristatin E or MMAE, which inhibits cell division by blocking the polymerization of tubulin. The monoclonal antibody is linked to the cytotoxic agent via a cleavable maleimidocaproyl-valyl-citrullinyl-p-aminobenzyloxycarbonyl (mc-val-cit-PABC) type linker on an average of 3-4 cysteinyl (vedotin refers to MMAE + its linking structure to the antibody).

NaPi2b is expressed in ovarian cancer and other malignancies including NSCLC (Non–Small-Cell Lung Cancer) and papillary thyroid cancer.

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According to the American Cancer Society, ovarian cancer ranks fifth in cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system. On average, a woman’s risk of getting ovarian cancer during her lifetime is about 1 in 79, while the lifetime chance of dying from ovarian cancer is about 1 in 108.

ovarian cancer cells
Photo 1.0: Ovarian cancer. Courtesy: © 2010 – 2018 Fotolia. Used with Permission.

A study by researchers from Royal Marsden NHS Foundation Trust and Institute of Cancer Research (London, United Kingdom), the Princess Margaret Hospital (Toronto, Canada), the Massachusetts General Hospital/Harvard Medical School (Boston, Massachusetts, USA) as well as Genentech/Roche and others, is the first to compare an antibody-drug-conjugate to standard-of-care in ovarian cancer patients. [1]

The results were published in the February 1, 2018 edition of Annals of Oncology.[2]

Trial design
The phase II trial included 95 patients. Forty-seven platinum-resistant patients with ovarian cancer were randomized to receive LIFA (2.4 mg/kg, intravenously, every 3 weeks [Q3W]). The remaining forty-eight patients received pegylated liposomal doxorubicin (PLD) (40 mg/m2, intravenously, Q4W). NaPi2b expression and serum CA-125 and HE4 levels were assessed.

Participating patients were followed for a median of 6.6 months.

The primary endpoint was progression-free survival (PFS) in intent to treat (ITT) and NaPi2b-high patients. The secondary outcome measures included the percentage of participating patients with an objective response according to RECIST v1.1, the duration of objective response, Overall Survival (OS), the percentage of patients with Adverse Events, and others.

Study Schematic: A Randomized Study of DNIB0600A in Comparison With Pegylated Liposomal Doxorubicin in Patients With Platinum-Resistant Ovarian Cancer (NCT01991210)

Trial results
The stratified Progression Free  Survival (PFS) hazard ratio was 0.78 (95% CI, 0.46-1.31; p=0.34) with a median PFS of 5.3 vs. 3.1 months (lifastuzumab vedotin vs. pegylated liposomal doxorubicin arm, respectively) in the intend to treat population.

In the NaPi2b-high patients this was 0.71 (95% CI, 0.40-1.26; p=0.24) with a median Progression Free  Survival of 5.3 vs. 3.4 months (lifastuzumab vedotin vs. pegylated liposomal doxorubicin arm, respectively).

The researchers reported that in the full cohort, the objective response rate or ORR to the therapy was 34% (95% CI, 22-49%, lifastuzumab vedotin) vs. 15% (95% CI, 7-28%, pegylated liposomal doxorubicin) in the intent to treat (ITT) population (p=0.03), and 36% (95% CI, 22-52%, lifastuzumab vedotin) vs.14% (95% CI, 6-27%, pegylated liposomal doxorubicin) in NaPi2b-high patients (p=0.02).

Adverse events
Toxicities included grade ≥3 adverse events. (46% lifastuzumab vedotin; 51% pegylated liposomal doxorubicin), serious AEs (30% both arms), and AEs leading to discontinuation of drug (9% lifastuzumab vedotin; 8% pegylated liposomal doxorubicin). Five (11%) lifastuzumab vedotin vs. 2 (4%) pegylated liposomal doxorubicin patients had grade ≥ 2 neuropathy.

Overall, the researchers concluded that lifastuzumab vedotin Q3W was well-tolerated and improved objective response rate with a modest, non-statistically significant improvement of Progression Free  Survival compared to pegylated liposomal doxorubicin in platinum-resistant ovarian cancer.

While the response rate for the MMAE-containing ADC was promising, the researchers noted that the response durations were relatively short.

According to the researchers, the study also highlights the importance of evaluating both response rates and duration of response since an objective response rate alone may not translate to durable responses when evaluating antibody-drug conjugates in the treatment of ovarian cancer.

Although based on earlier trial results clinical investigators expected that positive results from a previous trial could lead to a phase III trial with a high likelihood of success, Genentech/Roche has discontinued the development of lifastuzumab-vedotin.[3]

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